FM June Edition P

₹ 250.00 VOL 8 | ISSUE 2 PAGES 100 June 2021 FUTUREMEDICINEINDIA.COM INDIA SETTING ITSELF UP FOR A DEVASTATING THIRD WAVE OF SARS-CoV-2 MUCORMYCOSIS I MIS-C IS COVID-19 OPENING A PANDORA'S BOX OF DISEASES? IN THE NEWS RESEARCH ACCESSORIES COVID-19 UPDATES RESERVE BEDS FOR TACKLING RISKS POSED PLANT-DERIVED HCPs: MEDICS MULTI-WAVE BY UNSAFE VACCINE ENTERS DYNAMICS OF PPE KITS PHASE II COVID-19



June 2021 / Vol. 8 / Issue 2 editor’s note Founder & Managing Editor DeeadriDtoocrt’osr, note CH Unnikrishnan editor’s noteI know you have been not only worried about the virus and the vaccine, but editor’s notealso about various other things related to the profession in these testing times. ExeSceupttievme Ebdeirto2r020 / Vol. 7 / Issue 5 YDoeuarhaDvoecttoor,worry about ventilator and oxygen shortage, about medicine and S HFaoruanchdaenr d& Managing Editor mDeaasrkDsohcotrotra, ge and now, even about your own safety at the workplace. Yes, 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TctPswheohhioenesicktcTpttwsoaphhpeohasihuviiunenpwstcTresspibiwptrirhtcbekeasonthaheeehilaapiphhcedlinrepsvticicnrwssituurckupsitiuntiiaciepiabbhhiacirlrepnpbetscahwtisieuoulllevtunuidliiirhpcoiibvcct.alsrbebnspisalheciislnsaaatlidhaldilgurrnciiiicsrttospscrle.eapiicaiiyariccoohvartasrrnAddiersrtphouiisrnlnetutoeintrdivgcuioivtmsrecovsfieharuoiasntbtcrenmuodinedisdemrrdplhexsomreatiaetvrgeeoucaoatdsderpfirsubmdrgabcnnerttnovgenutaheetleayoficratrptiebficnnoafcrnenotenoPtcleopaocrbgattieitynscrncoenrateheetr.Oe,begaenpissttrsgaafnnoTshhhetetscmoa.etlee.inihaaof,naeerorsTonrcoTi,eeutctwrysntthKafeerhhhithtssro,elleoeersitteeaayoaeecnfhohahwsvdruclowryaaogoaeleteteitnwstaihhuclwenwrybrinuyeecnicntetoosvnynlesicraygaoeetadenscnoveescahagnnnrreagetthroynosouranyhitmnsarciannhedonssnapooohannfantcfienaefdnotsipocedoutmpoaimtydernettncorssufmoaihm.momdftenaefosnfctosaetTfpfydraefhatfcwaocrtoh6attho.ydrpmyeettcrtrhidenarehi.Tatmrupe8oelhadenoneebdThiepbtorpnaomtaeotoo6eheexetlpipubutmtitofmleosaibciiurb0oitonanlafblmhabrieobaoilpntabikpitreceemhn1orlspciaybkiisptknrasleh2tncioyissaiasnsarilhptieosniofyspp.oy,iptiibuepoirnosntnyesppRapsbseraKarrtnesrfsrra.oaenereacismofidn.orcdipaRdeacakeoenrrppeRakirdknnetrrepseifrridrvnneernnaeodaespdirioaiaodaeaodwirroetrriordwvftresrowtnedwlistvleorhnonieeeadhlreuoliaersirerefstdueoswrcsfofstrdo.hdwsgcofocheteargrspigphaeerssoirtdoresueohardduecento,rdctertdphred,o.bhtphmpso..aueasvrNnolateuepoNnoiNedtboiiictmdobsusnsotmoaavrorlraavresleibreeeeiiiipdceiiitepsnscipdladsnsdaooiiaaesedaaeosasededfnrtdritdrthidiirndoitedsinonoietsefotneo,n’raontrriontoirnsnoassinofassf,rf’,’’ C H Unnikrishnan partriceuttrlhaieirsvcapilurscbyuliscmtaestmitoanonrcoetrrsa.nTsyhmpeiatorttwedonfeintrhsaehnicpyofonoftremtnratwsdiethmeoaruertkotsfhmiesapayecrbkmeniorswespiloernoddgouefcdte.hdNe, opstupobarleritsdhoienfrsa [email protected] triK©rPSGpnheehrorovtiiioetwsnnri2tiepdttP©rSGipKare0pneewehiyhrorov1Studdviie8ai.©GKpSPriraoetwnnhbnnPSpp©Ki2eetrmhreopdlrotteNaralgeuh0rretvaiieiewosthnniirypcn.ibrd21eStettnnddyiepd2e86tatia.raeh0dlpAhxtntesewi0hir8lmyevDSset1SetthaeNnatgdeda1e8iaiG.6ahdPedthr8Conepn.detrmrle0eee6mueNarngehdaAexNasadd1ne8xpnbD.SdeePtte2nynte6eodG6hdPolAtxrCSrsaSt,dix8rmrDSe0eeSt,eesruntttSKceG6Pedt1nrhCxrpsGabKPPtipte2reDe0eeemuseereereneluoSrtS,trd1niCxaeebmnPdn,ensi2yabttKceotneoPlchStrrtstS,lKiBl,ipmeSnaia,atpsesrbseveetKcsKoo,trchrs,ymeatKnytdihpieaoietKMoMseiaoretIPsrcoetetrlnkaei,nottLdmnRaauieabtvetndtostKndhPctttt,ylaldtaoy,c,tnteaadi,sobMieveaIsbvKaiyifaeD,ymnd,tmaytrLKmReiaiyyoMatIetdshMtaaenadaimIiCthePLmRDd,ebtiennRtnvermdyhiattdevada,aeyrKa,daeKdi,addieaitevyiae,Kavlaedu,mcIiai.rPKgDaianbzanKipneresoLavremhIieyyPCa,PdDbedunntrDaPtntnoraeKvrleuavdey.rfa,dgbnavetdnikatpatoeesleL,aKelurtlet.aCg,aknilu.trr,ateRpolnessaLbrreeamdyLCLbndCuntrNhaDtitoemelDo,arteaosdltafbeneniCdIh,ewRolfeelswn,abeultad,otNiadr,NhDeRvlese,hrbDiRBmrbluteediNhDCaIrhfeeDfDNhoemdleEeoNtCaIhroCvfPoewoohIBxdderolNaueDpvabafukNfatiBoaorlBmuteemrtCaresftlouhmooffNaeoxmlet,rDpomtbookofetcloBxomeh,DpDmKrbCeuskfntktbfo(xNGaemrC,esWrsEtatsteeoNaocBNeC,rGyR,DtKpeernukcBoteoxheADKeEsDeEnsttssKdboxtoKexrCsnEtrNGRt,etoEeuketi)CmCGASRpezE,GDdGukRssaAKSehErhernNesMs,i/eEK,KeericsnfeCrN2a,enzDdGeNuioamsipipSPz0kDdhGzea/mri,SGKSrhhcfhoC1ko2ai/n,ocs/2fCic2aeitaPeo0bnkzo2cesdihr/PKi0krkemvo1kahe0rine4Keue2oo1koiktnaeoia1nz42cidth-c/ueofn2ezcnmvMhhpk/c5e44emvr/hme4taSteaeko4u204ieahudha4ntMpuk5ef904urdnMrer,pkE5uMtpkru2m5reiettihku2sdriea0iheeho9p2redueEut9rduap1edmEu9sEtuoipmt3drPia,mroiedrdhabruopai,uaKvseIuaaulstu,nPmorEtiteoPhdmrPmesihb.dvfGidtuvvh,PouEltt,ii,oLoEatftaan.es.fGd.a.ftGodmOGPyhrPdLoafiLLoaadoaaf.s.rea.t,,,oOmattomOnomdridddi.drdd.sr,,,,,, [email protected] [email protected] www.futuremedicineindia.com futuremedicineindia FutureMedIndia AUGUST 2018/ FUTURE MEDICINE / 3

Vol 8 Issue 2 June 2021 ₹ 250.00 16 VOL 8 | ISSUE 2 PAGES 100 IN THE NEWS JUnE 2021 FUTUREMEDICInEINDIA.COM MEDICS DEMAND FUNDS FOR HCPs INDIA SETTING ITSELF UP FOR HIT BY COVID-19 A DEVASTATING THIRD WAVE OF COVID-19 No reserved beds or compensation is MUCORMYCOSIS I MIS-C being provided to doctors who get infected in the line of duty, IS COVID-19 OPENS A PANDORA'S BOX OF DISEASES? even though an ex gratia payment is promised for HCPs who die IN THE NEWS RESEARCH ACCESSORIES COVID-19 UPDATES 38 RESERVE BEDS FOR TACKLING RISKS POSED PLANT-DERIVED HCPS: MEDICS MULTI-WAVE BY UNSAFE VACCINE ENTERS STRAIGHT TALK DYNAMICS OF PPE KITS PHASE II COVID-19 MUCORMYCOSIS CAN SPREAD REGULAR FEATURES 18 RAPIDLY IN COVID-19 06 Letters RESEARCH PATIENTS WITH 08 News updates UNCONTROLLED 32 Drug approvals HMOUWLTTI-OWTAAVCEKLE DIABETES 40 Research snippets DYNAMICS OF 63 Hospital news COVID-19 Dr V Mohan 64 Cardio genetics Director & Chief of Diabetes Research at 66 Accessories Inter-wave strolling is the most Madras Diabetes Research Foundation 69 Devices&gadgets important aspect of controlling the 72 In focus number of new infections 78 Gynecology & paediatrics 80 Public health 81 Events 84 Guidelines 96 Calendar 98 Holy grail Columns 21 TRIALOMICS Dr Arun Bhatt 44 THE CELLVIEW Dr Rajani Kanth Vangala 62 FROM THE INDUSTRY Rajinish Menon

54 FM COVID-19 UPDATES WORLD’S FIRST COVID-19 VACCINE BOOSTER STUDY LAUNCHED IN UK 46 When sugars are 22 very high, the SPECIAL FEATURE innate immunity COVER STORY is further hit BLACK FUNGUS and allows for WAITING FOR THE NEW CRISIS opportunistic THE THIRD WAVE fungi like mucor The fast-rising incidents of to harbour and Epidemiologists and medical mucormycosis casts a shadow over grow. experts give scores of reasons critical treatments in severe COVID-19 why India can’t avoid a truly lethal patients with underlying medical Dr Dilip Gude third wave after the current spike conditions, mostly diabetics. While in cases dies down. These include treatment options are limited for Chief Consultant new, mutated virus variants, a critical and immunocompromised Physician, suboptimal vaccination strategy, COVID patients, the misuse of steroids Diabetologist, vaccine breakthroughs via immune and unsterile hospital practices Department of evasion and the natural expiry of are blamed for the new healthcare Internal Medicine, vaccine protection and finally, the calamity Virinchi Hospitals, natural tendency of the virus to Hyderabad find new and unprotected hosts

letters to the editor ₹ 250.00 were attributed to the double Brazil and India have both shortage of amphotericin B, VOL 8 | ISSUE 1 mutant coronavirus variant been detected in the US. the drug used to treat the PAGES 100 both more contagious and India’s COVID crisis is still condition. Lower immunity MAy 2021 more resistant to vaccines. a tough war that we need and climatic conditions have FUTUREMEDICINEINDIA.COM However, more importantly, to fight. Wearing masks led many patients to develop the rising cases also resulted substantially reduces the risk the black fungus disease, ININOAFCEUFCTLTEAIRTOIONN from relaxed public behaviour of infection and transmission. across India. Several cases COVID-19 VACCINE BREAKTHROUGH and large social gatherings. Even though CDC has eased were linked to the use of CNAOSTEHSINGGATLOOWREOIRNRIyNDyEIAT::REEXPPOERRTTSS. This is more evident as the face-mask guidelines for fully steroids while the aetiology cases have started to decline vaccinated people outdoors, of many others is unknown. IN THE NEWS RESEARCH MARKETING FM COVID-19 UPDATES grossly each day following I strongly recommend people Experts suggest that poor lockdowns at various places. to still wear masks outdoors sanitary conditions and DOCS RUE RE-INFECTION SHOULD ASYMPTOMATIC But many people still and remain vigilant. contamination in the pipes VIP CULTURE AND VACCINE A DOCTOR COVID-19: COVAXIN hesistate to test for COVID-19 Jain K used for oxygen cylinders DEVELOPMENT PAY FOR MRs? 70% EFFECTIVE and deliberately go out Chennai and humidifiers could neglecting theirs as well as also increase the risk of Be vigilant of the others' health. Black fungus: More developing infections. While variants In the US, even though studies warranted some note that hospitals vaccines appear to be were dirty even before, Hi starting to curb new Dear Editor and the infection is seen In early May, we had been COVID-19 infections, we Misuse or overuse of drugs widely just recently. More seeing a scary outbreak in still need to remain vigilant. has been one of the factors epidemiological studies are India, with the staggering Coronavirus variants are still that has contributed to the required to assess why these number of over 400,000 causing outbreaks in the US crisis of the black fungus cases are rising now. covid cases per day, the and throughout the world. in India, suggest studies. Juby Mathew world’s biggest single-day Aggressive variants from The infection has led to a Patna spike. The skyrocketing cases SUBSCRIBE % &GET 20NOW OFF Please send me my subscription of FUTURE MEDICINE for (Select your plan) One year Rs. 2,400/- Two years Rs. 4,800/- Three years Rs. 7,200/- NAME ADDRESS CITY POSTAL CODE E-MAIL PHONE Fill complete details and send it along with the cheque/DD in favour of ‘NEXTGEN SCIENCE MEDIA (P.) LTD.’ to Future Medicine, B-503, Carrara, Hiranandani Estate, Off. Ghodbunder Road, Thane, Mumbai, MH - 400607 For NEFT/RTGS : Account No. 50200032001372, IFSC:- HDFC0000684 Name: NextGen Science Media Pvt Ltd, HDFC Bank Ltd, Kakkanad Branch, Cochin l For more details call - 9061 969996 or mail - [email protected]



news updates INDIA MAKES MUCORMYCOSIS DCGI approves A NOTIFIABLE DISEASE 2-DG for emergency use India’s health ministry has urged the states facilities to report all suspected and in COVID-19 and union territories to make cases of confirmed cases to the health department patients mucormycosis a notifiable disease under the through the district-level chief medical Epidemic Diseases Act, 1897. officers and subsequently, to the The Drugs Controller Integrated Disease Surveillance General of India (DCGI) has A systemic fungal infection, mucormycosis Programme (IDSP),” stated a letter issued by approved 2-deoxy-D-glucose has been reported among COVID-19 the ministry. (2-DG) as an anti-COVID-19 patients in many states, especially those drug for emergency use. on steroid therapy and deranged sugar Indian Council of Medical Research control. The infection is leading to prolonged (ICMR) has begun tracking COVID Associated The drug has been morbidity and mortality among COVID-19 Mucormycosis (CAM) through its national developed by Institute of patients. registry since May 15; the exact case burden Nuclear Medicine and Allied is, however, not known yet. With the new Sciences (INMAS), a lab The health ministry made it mandatory directive, every suspected and confirmed of Defence Research and for states to report both suspected and case of CAM has to be reported through Development Organisation confirmed cases to the Integrated Disease the district-level chief medical officer to (DRDO), in collaboration with Surveillance Programme (IDSP). the IDSP in order to effectively track the Dr Reddy’s Laboratories (DRL), burden and address issues related to the Hyderabad. “You are requested to make infection. mucormycosis a notifiable disease under The drug comes in the Epidemic Diseases Act, 1897, wherein Mucormycosis is an opportunistic the powder form inside a all government and private health facilities, infection normally seen in patients in an sachet, which is taken orally medical colleges will follow the guidelines immunocompromised state such as those by dissolving it in water. It for screening, diagnosis, management of with HIV, those on long-term steroid accumulates in the virus- mucormycosis issued by the Ministry of treatment, and diabetes patients with poor infected cells and prevents Health and Family Welfare and the Indian glycaemic control. It is not a contagious virus growth by stopping Council of Medical Research (ICMR). disease. viral synthesis and energy production. Its selective “And, make it mandatory for all these accumulation in virally infected cells makes this drug unique. Clinical trial results have shown that this molecule helps in faster recovery of COVID-19 hospitalised patients and reduces supplemental oxygen dependence. A higher proportion of patients treated with 2-DG showed RT-PCR negative conversion. 8 / FUTURE MEDICINE / June 2021

In April 2020, during the and efficacy of the drug in (SoC) on various endpoints. A Tamil Nadu. The detailed data first wave of the pandemic, COVID-19 patients. In phase-II significantly favourable trend of phase III clinical trials was INMAS-DRDO scientists trials (including dose-ranging) (2.5 days difference) was seen presented to DCGI. conducted laboratory conducted from May to in terms of the median time experiments with the help October 2020, the drug was to achieving normalisation of In the 2-DG arm, a of Centre for Cellular and found to be safe in COVID-19 specific vital signs parameters significantly higher proportion Molecular Biology (CCMB), patients and showed when compared to SoC. of patients improved Hyderabad, and found that significant improvement in symptomatically and became this molecule works effectively their recovery. Phase IIa was Based on the successful free from supplemental against the SARS-CoV-2 virus conducted in six hospitals and results, DCGI permitted oxygen dependence (42% vs and inhibits viral growth. phase IIb (dose-ranging) was phase III clinical trials in 31%) by day-3 in comparison Based on these results, DCGI conducted at 11 hospitals all November 2020. The phase to SoC, indicating an early permitted a phase II clinical over the country. The phase III clinical trial was conducted relief from oxygen therapy/ trial of 2-DG in COVID-19 II trial was conducted on 110 on 220 patients between dependence. patients in May 2020. patients. December 2020 to March 2021 at 27 COVID hospitals A similar trend was The DRDO, along with In efficacy trends, the in Delhi, Uttar Pradesh, West observed in patients aged its industry partner DRL, patients treated with 2-DG Bengal, Gujarat, Rajasthan, more than 65 years. Hyderabad, started clinical showed faster symptomatic Maharashtra, Andhra Pradesh, trials to test the safety cure than the standard of care Telangana, Karnataka and DRDO’s 2 DG drug is a repurposed medicine, earlier used for cancer treatment. Health ministry issues guidance for import of COVID-19 vaccines The health ministry of India has issued If the vaccine to be imported is free to supply remaining 50% doses guidelines for the import of vaccines already approved and an import licence to state governments and in the other by the private sector or any person has been obtained from CDSCO, then channels. as per the Liberalized Pricing and any entity, including a private sector Accelerated National COVID-19 entity, can procure the vaccine from the Manufacturers would, in a transparent Vaccination Strategy. importer/ licensee for its use as per the manner, make an advance declaration of national guidelines. the price for the 50% supply that would Based on the guidelines, ready-to- be available to state governments and use imported COVID-19 vaccines would The main elements of the Liberalised in the non-governmental channel before be allowed to be utilized entirely in non- Pricing and Accelerated National May 1, 2021. governmental channels. COVID-19 Vaccination Strategy that came into effect from May 1, 2021, are:- Vaccine Based on this price, states, private The health ministry stated that any manufacturers would supply 50% of their hospitals and industrial establishments private entity or government sector entity monthly Central Drugs Laboratory (CDL) may procure vaccine doses from which wants to import COVID-19 vaccine released doses to the manufacturers. Private hospitals for vaccination is required to follow the the government of India and would be would have to procure their supplies of COVID-19 vaccine exclusively from procedures as stipulated. the 50% supply earmarked for the As per the procedures laid down, if non-government-of-India channel. The the vaccine is not yet approved/licensed price charged for vaccination by private in India, the importer/authorized agent hospitals would be monitored. of the manufacturer of the vaccine shall obtain permission/license from Central Consequently, the earlier Drugs Standard Control Organisation dispensation, where private COVID-19 (CDSCO). vaccination centres receive doses from Besides, it has been stipulated to the government and can charge up to Rs take new drug permission under the New 250 per dose, will cease to exist. Drugs and Clinical Trials (NDCT) Rules, 2019, import registration under the Drugs The division of the vaccine supplies Rules, 1945, import licence under the into 50% for the government of India Drugs Rules, 1945. and 50% for everyone else would be After obtaining the import licence, the applicable uniformly for all vaccines importer or authorized agent can import manufactured in the country. However, the vaccine and any private sector entity the fully ready-to-use imported can procure the vaccine from them as per vaccine would be allowed to be utilized the national guidelines. entirely in the non-government-of-India channel. June 2021 / FUTURE MEDICINE / 9

Acitretin to be (a birth defect). Classes of had approved acitretin for released regulations for Foreign Schedule H drug teratogens include radiation, severe psoriasis in adults Medical Graduates (FMGs). in India maternal infections, chemicals (excluding females of and drugs. childbearing potentials) According to the draft The psoriasis treatment on September 09, 2005, regulations, the foreign acitretin will be included A retinoid has a structure with the condition that medical graduates will have in the Schedule H of Drugs similar to vitamin A and is the label of the immediate to qualify a National Exit Test Rules, 1945 to prevent involved in the normal growth container of the drug as (NExT) within two years of adverse events during of skin cells. Acitretin works well as the packing in completing the MBBS from pregnancy, the health ministry by inhibiting excessive cell which the container is abroad. informed. growth and keratinisation enclosed should contain (a process by which skin the following warning; The draft, released by the The ministry’s decision cells become thickened due “Acitretin should be secretary, NMC, Dr RK Vats, comes following the to the deposition of a prescribed by dermatologists on April 23, 2021, is called recommendation of Drugs protein within them) seen in knowledgeable in systemic Foreign Medical Graduate Technical Advisory Board psoriasis. It, therefore, use of retinoids.” Regulations, 2021, and lays (DTAB), which advises the reduces the thickening of the down the eligibility criteria for drug regulator on technical skin, plaque formation and NMC comes up the enrolment of those who issues. scaling. with new draft studied MBBS abroad as a regulations for medical practitioner in India. Drugs listed in Schedule A representation was foreign medical NMC has sought comments H cannot be purchased over made to DTAB on February graduates from stakeholders to finalise the counter without the 06, 2021, requesting the the policy. prescription of a qualified inclusion of the drug in The National Medical doctor. the Schedule H of Drugs Commission (NMC) has As per the new draft and Cosmetics (D&C) Rules regulations for FMGs, a person Acitretin is one of the 1945. intending to practice in systemic retinoids used India after obtaining primary in medicine particularly in In the representation medical qualifications in the dermatological diseases and made to DTAB, it has modern system of medicine has a serious side effect been stated that the drug from abroad needs to qualify profile specifically in pregnant acitretin is not included in women (teratogenic drug). A any Schedule of the D&C teratogen is an agent Rules 1945, which requires that can disturb the a prescription from the RMP. development of the embryo Acitretin possesses the status or foetus. Teratogens halt of non-prescription and over- the pregnancy or produce the-counter drugs (OTC) in a congenital malformation India. Central Drugs Standard Control Organisation (CDSCO) 10 / FUTURE MEDICINE / June 2021

for the Foreign Medical Verve publishes proof-of- Graduate Examination concept on one-time gene (FMGE) until the National Exit editing to treat LDL Test (NExT) becomes operational. US biotechnology The paper reports lipid nanoparticles, with company Verve that the demonstration of concomitant reductions in NExT examination will be Therapeutics has published durable editing in target blood levels of PCSK9 and merged with FMGE. As per its preclinical, proof-of- organs of nonhuman low-density lipoprotein the NMC draft regulations, concept paper on the primates is a key step cholesterol of approximately NExT will consist of NExT successful use of base before in vivo administration 90% and about 60%, Step 1 and NExT Step 2. editing to turn off a gene in of gene editors to respectively; all of these For FMGs, the first step will the liver and thereby lower patients in clinical trials. changes remained stable include an additional paper blood levels of either LDL The company said it has for at least 8 months after a to assess the knowledge cholesterol or triglyceride- demonstrated that CRISPR single-dose treatment,” the of pre and para-clinical rich lipoproteins, two base editors that are authors wrote in the paper. subjects. According to the factors leading to coronary delivered in vivo using lipid draft rules, the eligibility atherosclerosis. The paper nanoparticles can efficiently In addition to supporting criteria for licensing to was published in the 20th and precisely modify a ‘once-and-done’ practice in India have been May edition of Nature — disease-related genes in approach to the reduction divided into two parts. The https://www.nature.com/— living cynomolgus monkeys of low-density lipoprotein first part is for students who The paper establishes that (Macaca fascicularis). cholesterol and the have completed their senior gene-editing technologies, treatment of atherosclerotic secondary education in which include the CRISPR– “We observed a near- cardiovascular disease (the India and are pursuing Cas nucleases and CRISPR complete knockdown leading cause of death MBBS abroad and the base editors, have the of PCSK9 in the liver worldwide), the results second part is for those potential to permanently after a single infusion of provide a proof-of-concept who have completed modify disease-causing for how CRISPR base their senior secondary genes in patients. editors can be productively education and MBBS applied to make precise abroad. Future Medicine India single-nucleotide changes had in its August-’20 in therapeutic target genes The ones pursuing edition reported Verve’s first in the liver, and potentially MBBS abroad after doing presentation of its data on in other organs, added the their Class 12 from India this research. authors. must have passed the Class 12 board exam from any recognised board in India with the minimum eligible marks. They must have had physics, chemistry, biology or biotechnology as their core subject. These candidates must have also qualified National Eligibility Entrance Test (NEET) UG exam to seek admission abroad. Those who completed their Class 12 and MBBS abroad must have done a minimum of 12 years of schooling with physics, chemistry, biology or biotechnology and English as their core subjects. They must have also completed at least the first year of graduation in science with subjects like physics, chemistry, biology or biotechnology (in case such an exam was held). The candidates must have also completed at least 54 June 2021 / FUTURE MEDICINE / 11

Dr Sandhya Bhullar takes charge as new secretary of NMC Dr Sandhya Dr Sandhya Bhullar has Medical Commission at the of Gujarat cadre. In 2019, Bhullar been appointed as the time of its formation when she was appointed as the new secretary of the National this new body replaced the director of the Department Medical Council (NMC), India’s MCI. of Health and Family Welfare, top medical regulator. Government of India, under As per confirmation from the Central Staffing Scheme. The move comes after a new notice issued by the In 2020, she was transferred former NMC secretary Dr Department of Personnel to the post of director in the RK Vats quit the post after and Training, Government of Department of Economic submitting his resignation to India, his resignation has been Affairs. Then in 2021, she the government. Dr Vats was accepted and he will now be was made joint secretary in in charge of the replaced as Secretary NMC by the Department of Economic Medical Council of India Dr Sandhya Bhullar. Affairs under the ministry of (MCI) in 2019. He remained finance. the secretary of the National Dr Sandhya Bhullar is a 2003 batch IAS officer months of undergraduate PM&R, otorhinolaryngology, To make sure that department has been medical training along with ophthalmology, casualty these medicines are used receiving numerous 12 months of internship in services, lab services, judiciously, the state health applications and requests the same country where the elective posting in either of department has also formed a from the hospitals for the medical qualification was dermatology-venereology- task force which will regulate supply of tocilizumab, an awarded. The MBBS degree leprosy, tuberculosis & the supply and administration immunosuppressant medicine, must have been done in respiratory medicine, of complicated medicines and which is recommended to be English radiodiagnosis, forensic injections to the patients. The given to COVID-19 patients medium. medicine and toxicology, task force panel will evaluate only during certain conditions blood bank and transfusion the cases and accordingly like cytokine storm. Also eligible are the services. allocate and supply the candidates who have medicines to the concerned According to the director completed a minimum It says that a person hospitals. of health and medical four years (48 months) of will be eligible to be education, Ramesh Reddy, theoretical and practical registered to practice in the Of late, the health it has been observed that training for acquiring an country where MBBS or its and medical education the majority of private MBBS degree in English equivalent medical degree hospitals are indiscriminately after graduation and with has been awarded by a using immune-suppressant practical/clinical training foreign institute. The license medicines and antiviral conducted additional 12 to practise medicine in that medicines, irrespective of months of internship in the country shall be valid for at patients’ condition and the same country where the least 10 years. status of the disease. This is medical qualification was causing various other side awarded. Telangana effects and giving scope for restricts use other dangerous diseases The draft guidelines of tocilizumab, among the COVID patients, specify that primary remdesivir resulting in an increased qualifications to be obtained number of fatalities. in a foreign medical institute The state government of shall include theoretical Telangana has issued However, the Telangana classes, practical clinical restrictions on the supply drug control administration training and 12 months of COVID-19 treatments like authorities have instructed of compulsory rotating tocilizumab and remdesivir the pharma companies that internship commensurate and other medicines used for they can directly supply with a rotating internship treating black fungus infection the important drugs to in India which shall include in the COVID patients as treat fungal infections, and hands-on training in the a measure to ensure their COVID-19 treatment drugs, clinical subjects of community judicious use and reduce to the private hospitals, but medicine, general medicine, potential side effects in before that the concerned psychiatry, paediatrics, patients. hospitals and pharma general surgery, anaesthesia, companies need to get the obstetrics and gynaecology, approval of the task force orthopaedics including team. 12 / FUTURE MEDICINE / June 2021

in the news PIMSUALTISCNYSOTDEMVOINIFRLDAMA-MA1’TS9ORYBOSYNOPDRXEOM?ENING A FM reported between the ages of 5 and 15. Medical experts and clinicians In the second wave After Mucormycosis, can of COVID-19, Multisystem Inflammatory from several hospitals from across Syndrome (MIS-C) play havoc the country, including National Capital more than 2,000 cases in India in the wake of the COVID-19 Region and Gujarat, confirmed that the of MIS-C have been pandemic? cases of MIS-C are increasing among reported in children who have recovered from the country The condition has already been coronavirus infection. reported in more than 2,000 children who have recovered from COVID-19 or As of Jun 1, Delhi alone recorded were born to COVID affected women 109 cases of MIS-C syndrome in in India, and is likely to see an increase children recovered from COVID-19, while going forward. another 68 other cases were reported in Gurugram and Faridabad. At least 10 MIS refers to a condition where cases of MIS-C have been reported from the patient develops fever, along with Ahmedabad Civil Hospital in the past inflammation in multiple organs such few days, while two children have lost as the heart, lungs and the brain. Fever, their lives to the disease. More than 100 difficulty in breathing, stomach pain cases of MIS-C have been reported from and a bluish discolouration of skin and Rajkot. nails are telltale signs of this disease, according to medical experts. The age The Rising Graph of the children contracting this disease ranges from 6 months to 15 years. The According to data by Indian Academy maximum cases, however, are being of Paediatrics Intensive Care Chapter, during the second wave of COVID-19, more than 2,000 cases of MIS-C have been reported in the country. June 2021 / FUTURE MEDICINE / 13

“Acute infection of COVID-19 in to be linked to COVID-19. are studying this disease at the Civil children leads to two kinds of changes In children who develop multisystem Hospital. Children who have been — a child may get pneumonia or infected by MIS-C are under observation. there could be an antibody-mediated inflammatory syndrome, the organs and So far, it has been found that such inflammation called MIS-C. Only prompt tissues such as the heart, lungs, blood children have fever for three days and recognition can help catch the problem vessels, kidneys, digestive system, brain, also have diarrhoea, which leads to in time,” says skin or eyes become severely inflamed. weakness,” Dr Joshi told journalists. Dr Dhiren Gupta, chairperson- “This syndrome can affect different Very common in newborns elect of Indian Academy of Paediatrics body parts, including lungs, the Intensive Care Chapter and paediatrician nervous system and the heart. But, it is Medical experts, including senior at Sir Ganga Ram Hospital, New Delhi. curable and can have very less impact pediatricians, confirm that MIS-C has if diagnosed early,” says Dr Gunjan become common among children, In one instance, a newborn whose Kela, HoD (Dept. of Paediatrics) at Sri including newborns, during the current mother had recovered from the virus Aurobindo Institute of Medical Sciences wave of the pandemic. before delivery was detected with (SAIMS). the disease within 12 hours of birth, “The current double-mutant strain of according to sources at a private According to clinicians attending MIS COVID-19 has thrown up several cases hospital in Memnagar, Ahmedabad. The cases at various hospitals, most of the where newborns were found to be baby’s mother had been infected by children start showing symptoms of the affected by MIS-C. Of them, several also COVID-19 about a month and a half ago. test positive for COVID-19 antibodies,” Doctors at the hospital are checking the DOCTORS FIND A HIGH says Dr Sheila Aiyer, Head, Department women’s medical history to analyse the CONCENTRATION OF of Paediatrics, SSG Hospital, Vadodara COVID-19 linkage. ANTIBODIES IN THE CHILD, in Gujarat. THOUGH AN RT-PCR AND One of these cases, reported in ANTIBODY TESTS ON THE the last week of April from Akanksha BABY IS NEGATIVE FOR THE Hospital and Research Institute (AHRI) SARS COV-2 INFECTION in Anand, Gujarat, involved a newborn baby, born at 38 weeks gestation. The disease two to six weeks after recovering baby was admitted to the neonatal from COVID-19. Children who recover unit of the hospital within an hour of from COVID-19 typically have a sudden his birth with an extremely diseased increase of antibodies that affects the condition indicated by a weak cry, kidney, lungs and liver and this plays a shock, and low heart pumping rate, role in them getting infected by MIS-C. which pointed towards multisystem inflammatory syndrome in children “MIS-C is considered a post-COVID (MIS-C). complication among children. It could affect children from one to 18 years of Doctors from AHRI confirmed that age. While it usually does not affect the condition appeared to be linked children with high immunity, those with COVID-19 after they found a high suffering from obesity are more prone concentration of antibodies in the child, to MIS-C,” says Dr Rakesh Joshi, a child though an RT-PCR and antibody tests specialist and Additional Superintendent on the baby was negative for the SARS of Ahmedabad Civil Hospital. CoV-2 infection. An RT-PCR test on the mother also found her negative for the Children infected by MIS-C mostly virus. show symptoms like fever, red rashes, weakness, vomiting, stomach ache What is MIS? and breathing problems. If any of the problems are seen, the child would Multisystem inflammatory syndrome immediately require treatment. (MIS) in children (MIS-C) and adults (MIS-A) are febrile syndromes with “At present, doctors and researchers elevated inflammatory markers that usually start to show two to six weeks after a severe acute respiratory manifestation due to COVID-19 infection and is a serious condition that appears 14 / FUTURE MEDICINE / June 2021

Dr Aiyer, who treated at least 14 SYMPTOMS airborne. [In cases] where the RT-PCR newborns with COVID-19 antibodies for test is negative, but antibodies are the syndrome at SSG Hospital, says: “We Fever for 24 hours or more, present, the mother may have been do not check antibodies in all newborns inflammation in children’s bodies infected during the pregnancy and unless they are showing MIS-C. However and problems with several organs, produced antibodies, which was passed we are seeing it very frequently now, such as the intestines, heart, brain, onto the foetus through the placenta,” though it was rare in the first wave.” lungs, skin, and kidneys. Symptoms said Dr Biraj Thakkar, a neonatologist at may lead to thrombosis (blood AHRI. Child specialists are now discussing clots), poor heart function, or the possibility of a higher prevalence, kidney injury. According to Dr Thakkar, while especially since the numbers they are COVID-19 antibodies protect adults from seeing after the second wave are not at Other symptoms include: the virus, they can impair the immune all insignificant. l fever (100.4 degrees Fahrenheit system in newborns and the baby may have to be put on ventilator support and For instance, 13 out of 14 newborns or higher) lasting 24 hours or administered steroids. admitted at the SSG Hospital in more Vadodara with MIS-C symptoms had l abdominal pain, diarrhea or Asymptomatic parent and affected high levels of COVID-19 antibodies in vomiting newborns them. l neck pain l rash or changes in skin color In the AHRI case, the family was “A couple of the newborns admitted l bloodshot eyes unaware that the mother had with the MIS symptom did not survive. l tired appearance contracted COVID-19 during her It could be due to overlaps with other l shortness of breath pregnancy and recovered. neonatal comorbid conditions, like l pain or pressure in the chest that diabetics, anaemia, developmental doesn’t go away The medical team at AHRI could l confusion later confirm that the mother could l unable to wake up or stay awake probably have recovered without l bluish lips or face showing symptoms and the family was not aware of the same. But the Emergency warning signs of MIS-C presence of high-level antibodies in the l Severe stomach pain baby meant that it was passed by the l Difficulty breathing mother through the placenta. This is l Pale, gray or blue-colored skin, now known to be harmful to babies in the case of COVID-19. lips or nail beds — depending on skin tone “Even the baby’s lungs were affected and we had put him on a high- challenges, and seizures. But now, we frequency ventilator and administered are trying to put the first four cases of steroids. A D-dimer test on the newborn newborns with antibodies at SSG as revealed a level of 21,000 when case studies,” says Dr Aiyer. normally infected babies test up to the value of 3,000,” said Dr Thakkar According to her, if the concentration to reporters who spoke to him after of antibodies in a newborn is higher confirming the first case of MIS-C at the than that in the mother, it indicates hospital. that the baby has self-produced the antibodies. “If the antibodies are passed After 22 days of hospitalisation — on by the mother, the concentration of nine days on ventilator support and the baby’s antibodies will be lower than around 12 days on oxygen support, that of the mother. But we have had a the baby was discharged from NICU couple of cases where we have seen on May 13, Dr Thakkar informed. He the newborn with higher concentration, said the effects of COVID-19 antibodies which means that the babies have on newborns are “more visible” in the produced their own antibodies,” Dr Aiyer current wave because more expectant said. mothers seem to have been infected in the second half of 2020 as compared to “Newborns can get infected by the initial days of the pandemic. COVID-19 in three ways — by contact with an infected caretaker after birth, a —with inputs from Agencies vertical transmission within the womb by the infected mother. It can also be June 2021 / FUTURE MEDICINE / 15

in the news No reserved beds or compensation is being provided to doctors who get infected in the line of duty, even though an ex gratia payment is promised for HCPs who die DEFMOARNHDCMFPEUsDNHIDCITSS Demands have been growing for BY COVID-19 providing financial assistance to healthcare workers who get infected while treating COVID-19 patients. Currently, these workers, including doctors, are forced to pay hefty hospital bills which run into lakhs of rupees from their own pockets as there is no mechanism to compensate them for the same. Recently, Federation of Resident Doctors Association (FORDA) wrote to the union health minister requesting the government to reimburse the hospital expenses of healthcare workers. The association took up the matter after taking note of the case of Dr Amit Gupta, Senior Resident, Paediatrics at Satyavadi Raja Harish Chandra Hospital, Delhi. Gupta has been admitted in a private hospital as no bed was available in the hospital where he works. He was also not given any financial assistance by the government, according to FORDA. After the association took up the matter, the Delhi government stated that it will take care of all the hospital expenses of Dr Amit Gupta. Intervening in the matter, National Human Rights Commission had issued notices to both the centre and the Delhi government. The commission has also asked the union health ministry and the Delhi government to consider providing adequate medical care and financial protection to all the contractual medical and paramedical staff deployed by the centre and state governments 16 / FUTURE MEDICINE / June 2021

THE SELFLESS 420 Delhi 100 747 Tamil Nadu 91 SERVICE Bihar 96 Maharashtra 81 doctors in India have Uttar Pradesh 41 doctors had died West Bengal 71 More number of lost their lives due to the Gujarat 31 of COVID-19 during Andhra Pradesh 70 doctors in India COVID-19 second wave that Andhra Pradesh 26 the first wave of the Karnataka 68 are losing their life started around March-April, Telangana 20 Uttar Pradesh 65 battling COVID-19 Rest 106 pandemic 301 in the frontlines 2021, according to IMA Rest to serve the patients. The commission If a doctor gets infected while It is a war-like situation also observed that it is a serious issue on duty, his family members and the healthcare workers if the contractual doctors or resident have to run here and there should be protected at a doctors and paramedical staff of the to get him admitted as no maximum possible level, Delhi Government and other central hospital beds are reserved for otherwise we may lose many government hospitals are not getting healthcare workers. people. life care medical facilities when they fall ill during their service to save the lives Dr Partha Bora Dr J A Jayalal of the people during such a pandemic situation. Former President, FORDA President, IMA FORDA, in a letter sent to the health get him admitted as no hospital beds 326 doctors in the second wave of minister, stated that they are losing are reserved for healthcare workers. COVID-19. It is the responsibility of members of the fraternity and doctors Even though ex gratia compensation is everyone to protect the warriors who are not able to get medical care at their provided to the doctors who die due are working on the COVID frontline. own institutions. “In case the patient is to COVID, no compensation is being Protection and safety is the paramount shifted to a private setup since there provided to those who get infected. The responsibility of all the stakeholders are no dedicated facilities for doctors, problem is prevalent across the country in the area. So we have appealed to no financial assistance is offered unless and the governments should be ready private hospitals also to take care and one’s condition deteriorates and is to provide financial assistance to those give them substantial consideration.” on death bed and there is outrage,” who get infected.” He also demanded stated the association. In the case of that at least some beds should be He added that the governments Dr Amit Gupta, the association stated reserved for the healthcare workers. should make beds available for doctors his healthcare needs could not be on priority basis so doctors can get addressed at the hospital where he was Protect the Frontline: IMA treatment. It will augment the mental working. It warned that such a callous Supporting the demands of FORDA, strength of the doctors to face their attitude will not only dishearten COVID Dr J A Jayalal, President of Indian frontline duties. Dr Jayalal further warriors but also demotivate them. Medical Association, said, “It is a war-like said that it is the responsibility of the situation and the healthcare workers directors of the institutes to take care Extend cover to all doctors: should be protected at a maximum of the doctors who get infected while FORDA possible level, otherwise we may lose on duty. Unfortunately, resident doctors many people. We have already lost have had to raise their voice on the The association urged the government issue, he pointed out. to include all COVID positive doctors in the health insurance scheme. It also demanded that the government include the provision of a cashless treatment facility for all COVID positive doctors in the health insurance schemes in both government and non-government setups. Speaking on the issue, Dr Partha Bora, Former President, FORDA, said: “In the current scenario, if a doctor gets infected while on duty, his family members have to run here and there to June 2021 / FUTURE MEDICINE / 17

research HDYONWATMOICTSAOCFKLCEOVMIUDL-T19I-WAVE The inter-wave strolling is the most important aspect of controlling the number of new infections DR RAJANI KANTH VANGALA and early 1919. The present pandemic studied the effect of mobility on the too features a wave pattern, and may reduction of infections in the first wave Pandemics similar to the 1918 contain more waves. The SARS-CoV-2 and suggested that reduced mobility Spanish Flu and COVID-19 spread pandemic started in 2020 and is for a time-frame of 2-3 weeks can have through different regions in already going through the second wave an impact on the rate at which the the world in distinct waves. However, in India and potentially preparing for virus spreads. there are some factors that influence a third wave. At the same time, it was these patterns, particularly the human very difficult to predict the second wave Most of the European countries responses to these pandemics. Time- even with all the data generated in have already been hit by the second dependent statistical and complex 2020. wave of COVID-19 and the general network models have described the trend has been that the infection rates exponential spread of such diseases, Apart from a few countries like are lower than was seen in the first but are not accommodative of the China, Vietnam and New Zealand, the wave. On the other hand, the expected wave pattern of COVID-19. Giacomo C majority of the countries of the world cumulative number of infected cases et al (Scientific Reports 11, 6638 (2021) are suffering from multiple waves. were much more than during the first proposed an epidemic Renormalisation wave, considering the higher tests Group (eRG) framework based on the The eRG framework successfully being done during the second wave. global symmetries of the system. predicted the start of the second wave in Europe in September-October 2020. The emergence of the second The Spanish flu hit the world in This framework was based on the wave was explained by increased three consecutive waves between 1918 inclusion of several local conditions, interactions between countries, along non-pharmaceutical interventions and with an initial gap or the strolling socio-demographic characteristics. It effect. The spread of the infection 18 / FUTURE MEDICINE / June 2021

into interior regions or geographical and evaluate the causal reasons for taken during the strolling or gap period diffusion was also a reason behind the the spread of infections. These insights between two waves is to vaccinate the second wave infecting a larger portion can help in developing strategies for population, which can truly bring down of the population. In the US, which has containing such pandemics. Hence, the impact of COVID-19 infections. already seen distinct waves in April and identifying the strolling effect gives us While the vaccination of a large July-August of 2020 and is undergoing an opportunity to tackle the spread of population in a country like India is a the third wave, it was clear that the infection. It is therefore very important herculean task, technological and non- first two were geographically distinct. to inculcate among the population pharmaceutical interventions might The first wave was mainly in New York more important and sustainable habits play a major role in extending the and New England, with the second such as social distancing, wearing strolling period. Until now, most of the spreading to the remaining states. But masks and other non-pharmaceutical measures were taken only when the it was also observed that there were number of newly infected cases had sharp drops between the two waves. IT HAS BEEN OBSERVED already grown substantially. At such Finally, strolling, in terms of interactions THAT BRINGING DOWN a time, when the caseload is already between different states, resulted in THE INFECTION RATE TO high, only containment measures can the third wave. In many other countries APPROXIMATELY 10 CASES be taken which can have a serious such as South Africa and Saudi Arabia, PER MILLION INHABITANTS impact on lives and the economy. On a strolling effect was found during the PER DAY CAN HELP IN the other hand, faster vaccination can gap between two waves, suggesting an CONTAINING THE SPREAD OF effectively increase the strolling period, imminent third wave. COVID-19 thus reducing the disease burden and new cases. Moreover, the introduction In India which is undergoing practices. Policy makers too must of new measures at the end of a second wave, the same strolling strategize and develop measures to each wave as appropriate to local effect between first and second was enable such practices. On the other conditions can prove to be a better very clear. This inter-wave strolling hand, technologies which can enable value proposition. In most countries, it is the most important aspect of sustained and long-term continuation has been observed that bringing down controlling the number of new of behavioural changes are also the infection rate to approximately 10 infections. Controlling new infections needed. cases per million inhabitants per day during this gap or strolling period will can help in containing the spread of determine the dynamics of the new One very important step to be COVID-19. It is imperative that we in wave. COVID-19 is airborne, and non- India develop localised strategies to pharmaceutical interventions can help contain and keep new infections low delay or reduce the impact of future once the end of a wave has come and COVID-19 waves. One of the major continue vaccinating the majority of the aspects of studying the epidemics of population. infectious diseases is to understand June 2021 / FUTURE MEDICINE / 19



column trialomics COVID CONUNDRUM Antiviral pharmacokinetics vs dose and efficacy Because of the need for speed in a pandemic, drug development moves rapidly without due considerations DR ARUN BHATT Repurposing of known drugs with uptake of chloroquine is markedly reduced antiviral activity against SARS- in inflamed lungs characterized by acidic Writer is a consultant COV-2 has become a major focus pH. Remdesivir concentrations in the lung on clinical research & for developing effective treatments are not adequate to kill the virus. The lack of during the pandemic. The standard correlation between lab data and clinically development from development pathway for new drugs achievable plasma and lung concentrations Mumbai. includes an examination of in vitro activity, could be a reason why drugs predicted pharmacodynamic activity in SARS-COV-2 to achieve high lung concentrations - [email protected] infected animals, assessment of animal hydroxychloroquine, chloroquine, ivermectin, pharmacokinetics and toxicity, and Phase azithromycin and lopinavir-ritonavir, have not I, II & III trials in humans. Because of shown consistent efficacy in clinical trials. the need for speed in a pandemic, drug development moves rapidly from bench-in The gap between in-vitro antiviral vitro to bedside-in vivo clinical trials without concentration and effective in-vivo due consideration to the drug’s dose- concentrations may suggest the need for concentration-efficacy relationship. using higher-than-approved doses for clinical practice. For ivermectin, achieving therapeutic To be clinically effective in COVID-19, a plasma concentrations required for in vitro drug should reach therapeutic concentrations antiviral efficacy would require administration in the blood and the affected organ – lungs, of doses much higher than the approved in this case. For prophylaxis, the drug should therapeutic range. In a pandemic setting, be available in tissue concentrations sufficient clinical trials involving higher-than-approved to inhibit viral replication at multiple SARS- doses of antiviral agents may be justified if COV-2 infected sites - mucous membranes in pharmacodynamic and pharmacodynamic the nasal cavity and throat, eyes, tears, and data in SARS-COV-2 infected animal models the upper respiratory tract and the lungs. are available. However, for most drugs, such In selecting an antiviral for clinical trials, the data are not available. Hence, the use of ratio of peak plasma concentration (Cmax) high dose antivirals would be a safety risk at an approved dose to EC90 effective for seriously ill COVID-19 patients with multi- concentration 90% and lung tissue Cmax/ organ involvement. Changing the route of EC50 (half-maximal effective concentration) administration to enhance availability of drug is important to consider. Arshad et al in plasma by intravenous administration or derived these ratios by pharmacokinetic directly to lungs by nasal route would appear modeling based on physiochemical and attractive. But this approach is not feasible pharmacological parameters, and reported during a pandemic as the new route too that the majority of the drugs — 42 out of would require data on quality, stability, and 56 did not achieve plasma Cmax / EC90 > 1. human bioavailability, besides safety and dose These predicted ratios may not be achieved optimization data for the new formulation, in COVID-19 patients because of altered prior to conduct of clinical trials. This would pharmacokinetic processes - absorption, be time consuming. protein binding, distribution, metabolism & excretion - in patients suffering widespread In summary, selecting an antiviral drug for multi-organ infection and receiving multiple repurposing requires a consideration of the therapies - antibiotics, steroids, oxygen & complex interplay of in-vitro activity and in- ventilator therapy. For example, the cellular vivo therapeutic concentrations in seriously ill patients! June 2021 / FUTURE MEDICINE / 21

cover story 22 / FUTURE MEDICINE / June 2021

TWWATHITAHIINRVGEFODER Epidemiologists and FM medical experts give scores of reasons why On 17th May, Union Health Minister Dr Harsh India can’t avoid a truly Vardhan said in a press conference in New lethal third wave after Delhi that India’s new caseload numbers the current spike in cases for COVID-19 had dipped below the three lakh/ dies down. These include day mark for the first time, well below the peak of four lakh/day just two weeks earlier. Vardhan’s new, mutated virus statement also conveyed the sense that the variants, a suboptimal second wave was on an inexorable decline. vaccination strategy, However, the government’s failure to vaccine breakthroughs via acknowledge that the decline had come at the cost of an almost complete lockdown merely immune evasion and the served as a troubling reminder of its confidence natural expiry of vaccine just two months earlier, when it had declared victory over COVID-19 in India. protection and finally, the natural tendency of It was this confidence that underlay the the virus to find new and sense of complacency among the general public and the government machinery that ultimately unprotected hosts helped make India’s second COVID-19 wave more lethal than it needed to be. Contrary to the government’s optimism, India seems set to see new waves of COVID 19 every June 2021 / FUTURE MEDICINE / 23

time it relaxes the restrictive measures EPIDEMIOLOGISTS AND is common after infection. Moreover, the put in place to curb viral transmission. The MEDICAL EXPERTS CITE mutant can resist monoclonal antibodies reason for this is simple — the virus is still SEVERAL REASONS effectively,” the CDC cautioned. actively transmitting within the population, WHY INDIA CAN’T and generating more and more mutations AVOID A TRULY LETHAL According to medical experts, booster and variants as it does so. NEXT WAVE, MOST shots of the vaccines will be required to LIKELY THIS WINTER protect against emerging strains. However, As for the immediate future, such protocols are not yet in place in many epidemiologists and medical experts cite countries, including India. several reasons why India can’t avoid a truly lethal next wave, mostly likely this winter. Meanwhile, Institute for Health Metrics These reasons include newly mutated virus and Evaluation (IHME), an independent variants, a suboptimal vaccination strategy, global health research centre at University vaccine breakthroughs via immune evasion of Washington, predicts that daily deaths and the natural expiry of vaccine protection in India will peak at 5,600 soon. It has also and finally, the natural tendency of the virus projected 665,000 COVID deaths by August to find new and unprotected hosts. 1, 2021. Out of these, the biggest risks are the “Without drastic measures to decrease potential emergence of virus variants that social mixing and increase effective face- can override vaccines, and a large, vaccine- mask use, the situation currently looks naive host-base, i.e., those below 18 years quite grim in India,” the Institute warned. of age. It estimates that universal mask coverage could prevent 70,000 deaths and that if the US Centers for Disease Control and vaccination target for every Indian above 18 Prevention have warned recently that many is met on schedule, another 85,600 lives of these variants can override vaccines would be saved by August 1. and unleash severe disease. “They are fast movers. Some of the new variants, including Critical Winter the D614G mutant, can spread more rapidly than the original coronavirus by infecting Based on the history of the COVID- human respiratory epithelial cells. Death pandemic elsewhere, the third wave is most likely to take place during the winter 24 / FUTURE MEDICINE / June 2021

WHAT CAN BE DONE? There should be a surveillance system for immediate detection of deadly variants of SARS-Co-V2. All state and central government owned research institutions must be linked to a single online platform. Similar to what WHO is now beginning to set up in Berlin, a ‘Pandemic Surveillance Hub’ must be established, giving timely feedback to the government so that timely actions can be taken. The following basic facilities must be ensured to address the upcoming situation: Oxygen be used for the treatment of and updated. All healthcare personnel must COVID-19 patients. The supply be given training for their own Rather than attempting to of the required numbers of Healthcare Workforce personal protection and for the transport and distribute ventilators and beds should diagnosis and management of medical oxygen based on be ensured, with some Healthcare staff who have COVID-19 patients. There must demand, Oxygen Plants reserved to manage emergency recently retired should be be a window for registration of can be established in all situations. The availability of returned to practice. Those all the working health staff. government hospitals. beds, ventilators and other from academic or scientific There should be a real-time facilities must be documented facilities can also be shifted Hospital Hygiene monitoring mechanism for to frontline healthcare duties. the countrywide production, Ensure proper hygiene and storage and distribution sterile practices in every of medical oxygen. The clinical procedure in hospitals equipment developed by as well as the hospital DRDO for the army can be environment. Eliminate supplied to hospitals. possibilities of secondary infection to patients while in Drugs the hospital. Implement strong quality audits at hospitals All essential drugs used for and provision to punish the clinical management of hospital management/ COVID-19 and associated authorities if found fluting ailments like Mucormycosis quality standards. must be made ready to be supplied to all states. Global Scale Telemedicine Accessibility to these drugs must be ensured through Telemedicine consultation efficient procurement should be available to mechanisms. Indian companies COVID-19 patients also, can be given licences to make following the model generic versions of the drugs successfully followed by the like dexamethasone, remdesivir State Government of Kerala. and amphotericin-B. This can help patients to get immediate medical help and Vaccination guidance. This can be scaled up to a global level through The rate and speed of linking with other networks vaccination should be such as British Association of increased so that it covers Physicians of Indian Origin. people based on two factors instead of age alone: (1) Those Patient Mobility Services who are the most exposed to the disease, like courier agents, Transportation facilities must food vendors, etc. & (2) those be ensured for quick and safe who are most vulnerable due transportation of COVID-19 to their predisposed health infected patients to hospitals. conditions or whose immunity As the patients would require is impaired. Vaccines for oxygen during transit, the children must be brought in vehicles must be provided urgently. with such facilities. Apart from ambulances, other Ventilators and Beds types of rented vehicles also can be equipped for this The government should ensure purpose to address maximum hospital beds at emergency situations. its disposal and they must June 2021 / FUTURE MEDICINE / 25

AHOPWUBDLAITCAHCEAANLTHHERLEPSGPEONNESREATE DR MONIKA CHAUDHARY to significantly altered virus strains. More severe than the first one, the Manaus, a Brazilian city of more new wave took Manaus by surprise. The The third wave of COVID 19 is imminent discipline of masks and social distancing in India. In an article published in than two million populations, was one practise had been discarded in the belief Nature in September 2020, it was of the world’s leading COVID hotspots that the city had reached herd immunity. mentioned that a typical SARS-CoV-2 in the first wave. Brazil’s president Jair The month of January saw a surge of virus accumulates only two single-letter Bolsonaro had promoted the idea of caseloads and death rate. mutations per month in its genome letting the pathogen move throughout — a rate of change that is half that of the population until most people had The Manaus variant, or more formally influenza and one-quarter that of HIV. been infected to attain herd immunity. P.1, caused re-infections in people who Despite the virus’s sluggish mutation Manaus was the first city in the world to had earlier bouts with the virus, while at rate, researchers have catalogued more reach a point at which enough people the same time transmitting infection to than 12,000 mutations in SARS-CoV-2 were considered immune to a virus, as those who had been spared in the first genomes so far. they had already been infected by it. wave. William Hanage, an epidemiologist Preliminary preprint study of researchers at the Harvard T. H. Chan School of Public Scientists can spot mutations faster at the University of São Paulo estimated Heath, points out that herd immunity than they can make sense of them. Many that 66 percent of the population had through infection, instead of a vaccine, mutations will have no consequence been infected with SARS-CoV-2 (they later only comes at the cost of an enormous for the virus’s ability to spread or cause revised their figure to 76 percent as of amount of illness and death. disease, because they do not alter October). the shape of a protein. Scientists have The Manaus experience holds a claimed that a steady trickle of immune- Manaus -A Cautionary Message cautionary message for the rest of the evading mutations could help SARS- world about preparing basic public CoV-2 to develop a new power to infect In December 2020 a second wave hit health structures even as vaccination a human body. Our immune responses to the city of Manaus. By January, the city’s campaigns progress. Manaus got hit really coronavirus infections, including to SARS- health system had collapsed. ICUs were hard because it dropped all its mitigation CoV-2, aren’t strong or long-lived enough full to bursting, and oxygen supplies had measures, and didn’t have the level of to generate selection pressure that leads been exhausted. Some patients were herd immunity they expected. In fact, airlifted to other regions of Brazil, and the more the virus spreads, the more many died of asphyxiation on makeshift it is able to find vulnerable groups in beds in hospital corridors or their home. which mutations can arise. This fact also FATALITY 665,000 season in India, ie., towards the end of FOREWARNED COVID-19 deaths are November or early December 2021. This is projected by also going to be the festive season in the Daily death rates in India will rise August 1, 2021 country. According to a review published soon, predicts Health Metrics and in International Journal of Environmental Evaluation (IHME) at University of Research and Public Health, 5 August 2020, Washington it is very unlikely that the present pace of vaccination can cover the entire vulnerable 5,600 population of India within this short window of time before the festive season. people could die of COVID-19 in a day in Even though the inoculation with the current vaccines provides the much needed India, as per IHME protection at least from disease severity as predictions incidence of reinfection has now become pretty common in India, the challenging 26 / FUTURE MEDICINE / June 2021 part is how to cover the significantly large still unprotected population across the country within this short period.

underlines why only a global approach to immunizations will work. The P.1 mutation is believed to have emerged in Manaus in early November 2020, but by January, it made up three quarters of all variants detected in the city and had spread to Japan. It has since been detected in at least 34 other countries and regions, including the U.S. and the U.K. Like other variants first detected in the U.K. and South Africa, P.1’s 17 mutations occurred unusually quickly, and many of them are in the spike protein, which is used to penetrate the cells of an infected person. Fiocruz researchers discovered that the level of SARS-CoV-2, or the viral load, in patients infected with the variant was 10 times higher than with the earlier variant. CADDE study estimated that P.1 dodges 25 to 61 percent of protective immunity gained from infection with earlier variants. The immunity gained through vaccination appears to be more robust than the immunity achieved from infection. Johnson & Johnson’s jab proved 85 percent effective against severe disease in trials in Brazil—no less than it did in the US. Still, experts say that the situation is worrying because of the virus’s track-record of acquiring mutations in areas where it abounds. The above facts, derived from a number of studies done internationally, hold three lessons in the Indian context– The probability of a third wave increases if the virus cannot be controlled According to a recent media report EXPERTS ARE OF THE is the fact that children are likely to be citing the views of M Vidyasagar, senior OPINION THAT EVEN the most affected and vulnerable in the professor at IIT, Hyderabad, and a IF THE GOVERNMENT new wave. This is due to two reasons: mathematical modeling expert under COULD VACCINATE THE First, the vaccine naive children can easily the government of Karnataka, even if the ENTIRE POPULATION, become hosts to the virus, which is looking government could vaccinate the entire THE POSSIBILITY OF A for unprotected hosts, and secondly, the population, the possibility of a ‘Third THIRD WAVE CAN’T BE vaccination of children is still a question Wave’ of COVID-19 can’t be avoided. This RULED OUT mark, given that the clinical trials for child is because the vaccines currently form immunisation with existing vaccines have part of the National COVID-19 Vaccination just started and will take another six to Programme will lose their immunity within eight months to generate their primary 6 months. So, even those people who are data. Moreover, manufacturing the required vaccinated will begin to lose immunity doses too will take time. towards the festive period. Experts are also of the opinion that What can make things even even if the government could vaccinate the worse, according to Dr. Giridhar Babu, entire population, the possibility of a third Epidemiologist and Professor at Indian wave can’t be ruled out as those who get Institute of Public Health in Bengaluru, vaccinated now are likely to lose much of June 2021 / FUTURE MEDICINE / 27

quickly in the second wave as it will get climate has a crucial role to play because more opportunity to mutate. they have enough time to get established in the new environment. If there is a suitable Immunity gained through vaccination climatic slot for the virus to flourish, there is will provide a better security against a a chance for a ‘third or fourth wave’, when mutating virus but vaccinating a large the same season returns. population is difficult. Another study entitled—Severe Acute Public Health measures like masks, Respiratory Syndrome (SARS): A Year social distancing and lockdowns seem in Review, published in Annual Review to control the spread of the virus, and of Medicine, observed that SARS and indirectly control the processes of MERS are reported to be more related development of viral variants which are to climatological factors than secondary more infectious and fatal. circulation dynamics. This makes novel viruses much less predictable than In addition, an international established viruses with respect to their understanding on vaccination is required. persistence and re-emergence in the Accelerating the vaccination campaign following years or seasons. Sometimes they throughout the world will be helpful in can be more virulent in their later outbreaks. controlling the pandemic. If COVID is somewhere, it has the potential to be everywhere. Thus, vaccination of the entire population in the world is required. In addition to vaccination, immediate attention should be focused on another aspect – public health. The success of public health measures depend entirely on data. Restricting viral spreads to limited geographies would be much easier if data related to the disease is provided to researchers, epidemiologists and statisticians. Let us take an example. Data related to patients who have been hospitalised and those who have died — disaggregated on the basis of those who have or have not received a vaccine, the number of doses of vaccine received, comorbidities, age, gender, rural-urban and place of residence, collected on a real that immunity over the next six months. Rapid transmission In a series of papers published in the Journal of the American Medical Association entitled; Temperature, Humidity, and Latitude Analysis to Estimate Potential Spread and Seasonality of Coronavirus Disease-2019, authors Mohammad M Sajadi and others have observed certain links to the peak of infection and the climatic variations. They base their conclusions on insights gleaned from the experience with the COVID-19 pandemic so far. The impact of the weather on the progression of the pandemic was highlighted through a comparison of the experience of the southern and northern hemispheres of the earth. The authors point out that the COVID-19 situation in the southern hemisphere was different from that of the north. While the southern hemisphere was moving out of the winter at the peak of infections, the southern hemisphere was moving into winter. They point out that in the case of novel viruses, the prevailing 28 / FUTURE MEDICINE / June 2021

time basis and flashed on a dashboard heed the request for data on an urgent eliminate the wastage of vaccines, which — would be highly helpful in developing basis. Recording of real time data at the is almost criminal in the present scenario. targeted vaccination drives, testing for hospitals and vaccination centers and Only with vaccination will we be able affected populations, taking public health transferring it to a centralised database to control the pandemic and stop the measures and creating awareness. which is made publicly available would emergence of new viral variants. For a help researchers analyse it and derive densely populated country like India, a If it is found that hospitalisation of useful inference about the spread of the third, fourth or fifth wave may occur. In patients from nearby areas is increasing disease, the effectiveness of vaccination the second wave, the virus has moved to in one city, care could be taken closer and correlation of disease outcomes with small towns and villages and tracking is by establishing makeshift COVID centres comorbidities. Digitising patient data at urgent and essential. or care units. If vaccine hesitancy or the hospitals would not take much time casual attitudes towards social distancing with the help of technological tools like Numerous examples can be given measures are found, targeted awareness scanners and spreadsheets. where systemic data management and campaigns could be launched. In a analytics can help make hospital supply country which has robust IT infrastructure, IN THE WAKE OF A NEW chains robust and the prediction of it is not difficult to create dashboards WAVE, DATA FROM demand for resources like equipment, and easily accessible databases. If data THE EARLIER WAVES CAN medicines and beds possible. In the wake can save lives, doctors and data scientists BE EXTRAPOLATED FOR THE of a new wave, data from the earlier should work together. PURPOSE OF PREDICTION waves can be extrapolated for the purpose of prediction and that would help in While the Indian Council of Medical Declining hesitancy controlling the pandemic better, if only Research has granular data on all Vaccine hesitancy is on the decline in the government responds to the call of residents who’ve been tested so far, the cities where the COVID second wave providing the data. Of course, there is a it restricts access to this database. has happened. But it is still prevalent possibility that the virus weakens itself 300 scientists have asked PM Modi to in smaller towns and villages. In the during multiple mutations. In spite of the give access to the data for charting early stage of vaccination, even in major anguish, pain and agony that is prevalent COVID-19 spread. Their petition says cities, vaccines were wasted because all around, there is the hope of the virus - “The ICMR database is inaccessible people did not show up in adequate dying its own death. Nevertheless, data to anyone outside of the government numbers for vaccination. A data check collected during the current pandemic can and perhaps also to many within the on foot-falls at vaccination centers would go a long way in managing future ones. government... While new pandemics can have unpredictable features, our inability The author is Associate to adequately manage the spread of Professor, IIHMR University, infections has, to a large extent, resulted Jaipur from epidemiological data not being systematically collected and released in a timely manner to the scientific community.” State governments too should The CIDRAP Viewpoint Working Group EPIDEMIOLOGISTS A relatively small amount of water vapour on COVID-19 at the University of Minnesota THEORISE THAT THE is able to saturate cold air, whereas more have presented their conclusions in Part I CURRENT RESURGENCE water vapour is required to bring warm of their report: “The Future of the COVID-19 OF COVID-19 IN INDIA air to saturation. Moreover, the viability of Pandemic: Lessons Learned from Pandemic IS CAUSED TO A LARGE pathogens in exhaled aerosol droplets is Influenza”. This study observes that until a EXTENT BY A DOUBLE crucial as a potential driver of COVID-19 novel virus becomes endemic and recycles MUTANT SARS-COV-2 transmission, according to the paper from its existing form to other mutated VARIANT published by Tellier, R. in the Journal of forms, its seasonal prevalence would be Royal Society Interface, 2009: (Aerosol difficult to predict. At the same time, they transmission of influenza virus: A review confirm an extended period of persistence of new studies). So, winter season is for the current SARS-CoV-2 pandemic. considered as the most ideal time for the third resurge of COVID-19 in India. Among the various climatic factors, humidity seems to occupy a prominent Double and triple mutants role, as it is related to the amount of water vapour held by the air. It must be noted Epidemiologists theorise that the current that atmospheric pressure and temperature resurgence of COVID-19 in India is caused also can modulate the humidity of the air. to a large extent by the double mutant June 2021 / FUTURE MEDICINE / 29

variant, B.1.617, first discovered in the country. The B.1.617 NVWFAOAHRRMOIIASNBANGRRTISSNSY-GCSSOTVE-M2 variant was detected in Maharashtra in October 2020. It was found to carry two key mutations — E484Q and L452R — and The variant first found in hence referred to as the ‘Double Mutant’. But now, more Britain to be called Alpha and key mutations have entered the scene. A new virus variant the one first spotted in containing three key mutations — E154K, P681R and Q1071H India is the Delta variant — has also been found and is often referred to as the ‘triple mutant’. According to some sources, the vaccines currently in The World Health Organization (WHO) use in India can fight this variant and reduce the severity of announced a new naming system the disease, though they cannot block it from proliferating in that it devised for so-called variants of the body completely. So some experts believe that B.1.617 can interest and variants of concern, the forms remain dominant in India’s third wave of COVID-19. of the SARS-CoV-2 virus with important mutations. The three mutations found in the ‘triple mutant’ can make the virus more infectious in nature with a high rate of Each variant will be given a name mortality. from the Greek alphabet, in a bid to both simplify the public discussion and to strip These mutations, initially observed separately in other some of the stigma from the emergence ‘Variants of Concern’ from the UK, South Africa and Brazil, of new variants. A country may be more comprise: (i) Deletion and two changes in the spike protein willing to report it has found a new variant (ii) Deletion of H146 and Y145, and (iii) Mutation in E484K if it knows the new version of the virus and D614G in the spike protein. will be identified as Rho or Sigma rather than with the country’s name, Maria Van According to Dr. Vinod Scaria, chief scientist at the Kerkhove, the WHO’s coronavirus lead, said. Institute of Genomic and Integrative Biology (CSIR-IGIB), New Delhi, the variant B.1.618 makes 12% of all the SARS-Co-2 \"They will not replace existing scientific found in India whereas B.1.617, with three key mutations, names, but are aimed to help in public constitutes about 28%. discussion of variant of concern and variant of interest VOI/VOC,\" she further stated. Besides the above two Indian variants, other variants of concern circulating in India include the UK variant (B.1.1.7), the Under the new scheme, B.1.1.7, the South African variant (B.1.351) and the Brazilian variant (P.1). variant first identified in Britain, will be known as Alpha and B.1.351, the variant Regarding the potential of these variants to cause a ‘third first spotted in South Africa, will be Beta. wave’ of COVID-19, Dr. Vinod opines that nothing can be P.1, the variant first detected in Brazil, will said conclusively at this stage, as more research is needed to be Gamma and B.1.671.2, the so-called connect these variants with the surge of infections. However, Indian variant, is Delta. since some of the mutant variants are feared to be able to escape RT-PCR based detection tests, there is a chance that When the 24 letters of the Greek they can increase the chance of transmission of the disease alphabet have been exhausted, another even more. series like it will be announced, Van Kerkhove said. — with inputs from N S Arunkumar and Agencies The Greek alphabet suggestion drew 30 / FUTURE MEDICINE / June 2021 the approval of the experts the WHO convened to come up with the naming system, some of whom are members of the International Committee on the Taxonomy of Viruses. That group is charged with naming new species of viruses — it named SARS-CoV-2, the virus that causes COVID-19. But it does not name subspecies of viruses, which is why this fell to the WHO. The WHO will maintain a list of variants with their new names on its website.

SARS-COV-2 VARIANTS VARIANTS OF INTEREST UPDATED 31 MAY 2021 WHO Pango GISAID Nextstrain Earliest Date of label lineage clade/ clade VARIANTS OF CONCERN documented designation lineage WHO Pango GISAID Nextstrain Earliest Date of samples label lineage clade/ clade documented designation Epsilon B.1.427/ GH/452R.V1 20C/S.452R USA, 5-Mar-2021 lineage samples B.1.429 Mar-2020 Alpha B.1.1.7 GRY 20I/S:501Y.V1 United 18-Dec-2020 Zeta P.2 GR 20B/S.484K Brazil, 17-Mar-2021 (formerly Kingdom, Apr-2020 GR/501Y.V1) Sep-2020 Eta B.1.525 G/484K.V3 20A/S484K Multiple 17-Mar-2021 Beta B.1.351 GH/501Y. 20H/S:501Y.V2 South Africa, 18-Dec-2020 countries, V2 May-2020 Dec-2020 Gamma P.1 GR/501Y. 20J/S:501Y.V3 Brazil, 11-Jan-2021 Theta P.3 GR 20B/S:265C Philippines, 24-Mar-2021 Jan-2021 V3 Nov-2020 Iota B.1.526 GH 20C/S:484K USAA, 24-Mar-2021 Delta B.1.617.2 G/452R.V3 21A/S:478K India, VOI: 4-Apr-2021 Nov-2020 Oct-2020 VOC: 11-May-2021 Kappa B.1.617.1 G/452R. 21A/S:154K India, 4-Apr-2021 V3 Oct-2020 Updated on 31 May 2021 IINNOPCRUOLGARTEISOSN WAVE AFTER WAVE Figures (below) show the percentage of people who may have received more than one dose of the vaccine PFUELOLPYLEVACCINATED Figures show the percentage of people who may have received more than one dose of the vaccine Israel 57.7 2,81,75,044 Chile 42 40.6 people in India are infected with US 39.8 SARS-CoV-2, according UAE 36.2 to the official data 35.3 UK 28.2 3,20,000 3,31,895 Hungary 18.5 2,40,000 18.4 1,60,000 is the total number of Serbia 17.9 deaths that occurred Italy 17.6 80,000 in India due to COVID-19 17.5 0 Spain 16.6 Greece 16.5 Switzerland 16.4 Romania 16.1 Poland 15.8 Germany 15.5 Portugal 15.4 Bergium 14.9 Austria 13.9 Netherlands 12.9 France 12.6 Turkey 11.1 Moroco 11.1 Czechia 10.3 Sweden 3.1 El Salvador Cambodia Brazil India April 2020 June 2020 Oct 2020 Jan 2021 Apr 2021 Data as on 31st May 2021 June 2021 / FUTURE MEDICINE / 31

drug approvals Setmelanotide to treat obesity and control hunger Amivantamab The European Medicines significant and clinically by child age and sex, were to treat NSCLC Agency’s (EMA) meaningful weight loss achieved. with exon 20 Committee for Medicinal and reduction in hunger in mutation Products for Human Use patients with POMC, including These two studies, (CHMP) has recommended PCSK1, and LEPR deficiency which are the largest studies US FDA has granted the marketing authorization obesity. conducted in these disease accelerated approval for setmelanotide for the states to date, were identically of amivantamab-vmjw treatment of obesity and Across both studies, designed one-year, open-label (Rybrevant) for the treatment the control of hunger statistically significant studies, each with a double- of adult patients with locally associated with confirmed and clinically meaningful blind, placebo-controlled advanced or metastatic loss-of-function biallelic reductions in body mass withdrawal period. Additional non-small cell lung cancer proopiomelanocortin (POMC), index (BMI) for adults and supportive data were (NSCLC) with epidermal including PCSK1, deficiency BMI-Z scores, which represent gathered in an investigator- growth factor receptor (EGFR) or biallelic leptin receptor the number of standard led study and an ongoing exon 20 insertion mutations, (LEPR) deficiency in adults deviations from median BMI extension study. as detected by an FDA- and children 6 years of age approved test, whose disease and above, Rhythm Pharma has progressed on or after announced. platinum-based chemotherapy, Janssen Pharma said. POMC, PCSK1 or LEPR deficiency obesities are Amivantamab is the first ultra-rare diseases caused fully human, bispecific antibody by variants in POMC, PCSK1 approved for the treatment or LEPR genes that impair of patients with NSCLC that the MC4 receptor pathway, targets EGFR exon 20 insertion which is a pathway in the mutations, which are the third hypothalamus that regulates most prevalent activating EGFR hunger, energy expenditure mutation. and, consequently, body weight. People living with Amivantamab is directed obesity due to POMC, PCSK1 against EGFR and MET or LEPR deficiency struggle receptors. The drug binds with extreme, insatiable extracellularly inhibiting tumour hunger beginning at a young growth and leading to tumour age, resulting in early-onset, cell death. severe obesity. The accelerated FDA The CHMP based its approval is based on positive positive opinion on the results from the phase 1 results from two pivotal CHRYSALIS study, a multicentre, trials in which setmelanotide open-label, clinical study achieved statistically evaluating amivantamab as a monotherapy in patients enrolled in the prior platinum- containing chemotherapy cohort. Initial results from the CHRYSALIS EGFR exon 20 32 / FUTURE MEDICINE / June 2021

insertion mutation population, EMA panel recommends vehicle-controlled, randomized, which supported the BTD, were vericiguat for chronic HF parallel-group, multi-centre presented at the American phase III clinical trials, which Society of Clinical Oncology The Committee for event,” said Dr Burkert included 702 patients from 2020 Virtual Scientific Program, Medicinal Products for Pieske, professor of internal 62 clinical sites across the US, and updated results were Human Use (CHMP) of the medicine and cardiology showed that application of presented at the IASLC WCLC European Medicines Agency at Charité and principal tirbanibulin ointment 1% (10 2020. (EMA) has recommended investigator of the phase III mg/g) in adults with AK on the vericiguat, a soluble VICTORIA trial. face or scalp is effective and The FDA simultaneously guanylate cyclase (sGC) well-tolerated. approved Guardant Health’s stimulator, for marketing The positive CHMP Guardant360 CDx liquid biopsy authorization in the opinion is based on the Both phase III studies blood test as a companion European Union. results of the pivotal achieved their primary diagnostic for use with phase III VICTORIA trial. endpoint, which was defined amivantamab. Once approved, the The data showed that as 100% clearance of the AK use of vericiguat (2.5 vericiguat significantly lesions at Day 57 within the Tirbanibulin for mg, 5 mg, and 10 mg) reduced the combined risk face or scalp treatment areas, treating actinic will be authorized for the of cardiovascular death or each study achieving statistical keratosis treatment of symptomatic heart failure hospitalizations significance (p<0.0001) on this chronic heart failure in compared to background endpoint. Almirall SA announced adult patients with reduced therapy alone, following that the Committee for ejection fraction who are a worsening heart failure In the KX01-AK-003 Medicinal Products for Human stabilised after a recent event. study, complete clearance Use (CHMP) of the European decompensation event was observed in 44% of Medicines Agency (EMA) has requiring intravenous (IV) Vericiguat 2.5 mg, 5 the patients treated with issued a positive opinion for therapy. mg, and 10 mg is an oral tirbanibulin versus 5% for the regulatory approval of once-daily stimulator of vehicle-treated groups. In the tirbanibulin (Klisyri), indicated “Even when taking soluble sGC, an important KX01-AK-004 study, complete for the topical treatment of guideline-based therapy, enzyme in the nitric oxide clearance was observed in actinic keratosis (AK) on the many heart failure (NO) signalling pathway. 54% of the patients treated face or scalp. patients still experience When NO binds to sGC, with tirbanibulin versus 13% for progressive worsening the enzyme catalyzes the vehicle-treated groups. Local Tirbanibulin is a novel, of symptoms – meaning synthesis of intracellular reactions were mostly mild-to- topical first-in-class microtubule hospitalization or initiation cyclic guanosine moderate erythema, flaking or inhibitor with a selective of intravenous diuretics monophosphate (cGMP), scaling, application-site pruritus, antiproliferative mechanism is needed. This is one of a second messenger and application-site pain that of action that represents a the biggest challenges still that plays a role in the resolved spontaneously. significant step forward in the to be addressed in the regulation of vascular tone, treatment of AK due to its short management of chronic cardiac contractility, and Nivolumab treatment protocol - once daily heart failure, as sadly, one cardiac remodelling. as adjuvant application for 5 days-, proven in five do not survive for Heart failure is associated treatment of efficacy and safety profile longer than two years after with impaired synthesis GEJ cancer with very acceptable local a worsening heart failure of NO. tolerability. Bristol Myers Squibb announced that the US The CHMP opinion is FDA has approved nivolumab, based on two phase III studies (KX01-AK-003 and KX01- AK-004) positive results. These two double-blind, June 2021 / FUTURE MEDICINE / 33

an injection for intravenous Odevixibat to treat cholestasis in EU use (Opdivo) for the adjuvant treatment of completely Albireo Pharma, Inc announced that PFIC is pruritus, or intense itching, which resected esophageal or the European Medicines Agency’s often results in a severely diminished gastroesophageal junction (EMA) Committee for Medicinal Products quality of life. (GEJ) cancer with residual for Human Use (CHMP) issued a positive pathologic disease in patients opinion recommending approval of The positive opinion for odevixibat who have received neoadjuvant odevixibat (Bylvay) for the treatment was supported by data from PEDFIC 1 chemoradiotherapy (CRT). of progressive familial intrahepatic and PEDFIC 2, the largest, global, phase cholestasis (PFIC). 3 trials ever conducted in PFIC. In PEDFIC The approval is based 1, a randomized, double-blind study, on results from the phase Odevixibat is a potent, once-daily, placebo-controlled study, the drug met 3 CheckMate -577 trial that non-systemic ileal bile acid transport both its pruritus (p=0.004) and serum evaluated nivolumab(n=532) inhibitor (IBATi) and could be the bile acid (p=0.003) primary endpoints compared to placebo first non-surgical treatment for this and was well tolerated with a very low (n=262) in esophageal or GEJ rare disease. With this positive CHMP incidence of diarrhoea/frequent bowel cancer patients with residual opinion, odevixibat continues on the movements (9.5% of treated patients vs. pathologic disease following accelerated approval path for the 5.0% of placebo patients). neoadjuvant CRT and complete European Commission (EC) decision on resection. the marketing authorization application PEDFIC 2, a long-term, open-label (MAA) and an anticipated launch in the phase 3 extension study, reaffirmed In the trial, among patients second half of this year. odevixibat delivered sustained reductions who received nivolumab, in sBAs as well as improvements in median disease-free survival PFIC is a rare and devastating pruritus assessments, growth and other (DFS) was twice as long as in disorder affecting young children that markers of liver function in patients those who received placebo causes progressive, life-threatening liver treated up to 48 weeks. Across both (22.4 months [95% Confidence disease. In many cases, PFIC leads to studies, odevixibat was well tolerated Interval [CI]: 16.6 to 34.0] cirrhosis and liver failure within the first with diarrhoea/frequent stools being compared to 11.0 months [95% 10 years of life. The most prominent and the most common treatment-related CI: 8.3 to 14.3]). Nivolumab problematic ongoing manifestation of gastrointestinal adverse events. reduced the risk of disease recurrence or death by 31% surgery, had stage IV resectable with resected esophageal (NDA) for maribavir for the compared to placebo (Hazard disease, autoimmune disease, or GEJ cancer is 240 mg treatment of CMV infection in Ratio [HR] 0.69; 95% CI: 0.56 or any condition requiring intravenous infusion over 30 those that are refractory with to 0.85; P=0.0003). systemic treatment with either minutes every two weeks or or without resistance (R/R), in corticosteroids (>10 mg daily 480 mg intravenous infusion solid organ transplant (SOT) or In an exploratory prednisone or equivalent) or over 30 minutes every four hematopoietic cell transplant analysis, among patients with other immunosuppressive weeks until disease progression (HCT) recipients, Takeda adenocarcinoma (n=563, medications. or unacceptable toxicity for a Pharma said. 70.9%), mDFS was 19.4 total treatment duration of one months (95% CI: 15.9 to 29.4) The primary endpoint of year. The application is based on with nivolumab versus 11.1 the trial was DFS (investigator- the pivotal phase 3 TAK-620- months (95% CI: 8.3 to 16.8) assessed). Following Maribavir for 303 (SOLSTICE) trial. with placebo (unstratified HR neoadjuvant CRT and complete CMV infection 0.75; 95% CI: 0.59 to 0.96), tumour surgical resection (also Maribavir has been granted and among squamous cell known as trimodality therapy), The US FDA has accepted Orphan Drug Designation by carcinoma patients (n=230, a total of 794 patients were a New Drug Application the FDA for the treatment of 29%), mDFS was 29.7 months randomized to receive either clinically significant CMV viremia (95% CI: 14.4 to NE) with nivolumab 240 mg (n=532) and disease in at-risk patients. nivolumab versus 11.0 months or placebo (n=262) by The FDA has also granted (95% CI: 7.6 to 17.8) with intravenous infusion every two placebo (unstratified HR 0.61; weeks for 16 weeks, followed 95% CI: 0.42 to 0.88). by nivolumab 480 mg or placebo by intravenous infusion CheckMate -577 was a every four weeks beginning phase 3 randomized, placebo- at week 17. Treatment was controlled, double-blind, until disease recurrence, multi-centre trial, evaluating unacceptable toxicity, or for up nivolumab as an adjuvant to one year in total duration. treatment in patients with esophageal or GEJ cancer with The US FDA-approved residual pathologic disease dosing for nivolumab for following neoadjuvant CRT adjuvant treatment of patients and complete resection. The trial excluded patients who did not receive CRT prior to 34 / FUTURE MEDICINE / June 2021

maribavir Breakthrough The trial’s primary endpoint diffuse large B-cell lymphoma CRR by PET-CT at the time of Therapy Designation as a was defined as the proportion (DLBCL). primary response assessment. treatment for CMV infection of patients who achieved Patients received six cycles of and disease in transplant confirmed CMV viremia The approval is based treatment, spaced three weeks patients resistant or refractory clearance (plasma CMV DNA on data including the results apart. to prior therapy. <137 IU/mL in two consecutive from a multicentre overseas tests =5 days apart at central phase Ib/II clinical study IDE supplement The TAK-620-303 laboratory) compared to IAT at (GO29365) that evaluated for phase 3 (SOLSTICE) trial is a multicentre, the end of Study Week 8. The the efficacy and safety of LUNAR trial to randomized, open-label, key secondary endpoint was polatuzumab in combination treat NSCLC active-controlled trial defined as achievement of CMV with bendamustine and comparing treatment with viremia clearance and symptom rituximab (BR therapy) NovoCure announced the either maribavir or investigator control at the end of Study compared to BR therapy alone, US FDA has approved assigned treatment, IAT, Week 8, maintained through and a multicentre, single- the company’s Investigational (conventional antiviral Study Week 16. arm Japanese phase II study Device Exemption (IDE) therapy) in hematopoietic (JO40762/P-DRIVE study) supplement, reducing the cell transplant and solid Chugai launches that evaluated the efficacy enrollment requirement for its organ transplant recipients polatuzumab IV and safety of polatuzumab in LUNAR trial to 276 patients with CMV infection refractory, to treat DLBCL combination with BR therapy in with 12 months follow-up. with or without resistance, to R/R DLBCL. one or a combination of the Chugai Pharmaceutical LUNAR is a phase 3 pivotal conventional antiviral therapies: has launched an A double-blind, placebo- trial testing the effectiveness ganciclovir, valganciclovir, antimicrotubule binding anti- controlled global phase III of Tumour Treating Fields in foscarnet or cidofovir. CD79b monoclonal antibody study (GO39942/POLARIX combination with immune intravenous infusion 30 mg and study) is ongoing for untreated checkpoint inhibitors or Patients underwent a 140 mg polatuzumab vedotin DLBCL to examine the efficacy docetaxel versus immune 2-week screening period, (Polivy) for the treatment of and safety of polatuzumab in checkpoint inhibitors or followed by randomization 2:1 relapsed or refractory (R/R) combination with rituximab docetaxel alone for patients to maribavir (n=235) (400 mg) plus cyclophosphamide, with stage 4 non-small cell or IAT (n=117) for an 8-week doxorubicin, prednisolone lung cancer (NSCLC) who treatment period, plus 12 (R-CHP) compared to rituximab progressed during or after weeks of follow-up. plus cyclophosphamide, platinum-based therapy. doxorubicin, vincristine, prednisolone (R-CHOP). The IDE supplement incorporates recommended JO40762 (P-DRIVE) is an changes from the interim open label, single-arm study analysis of the LUNAR trial investigating polatuzumab in conducted by an independent combination with BR therapy data monitoring committee in 35 patients with R/R DLBCL. (DMC). After review of the The primary endpoint is the interim analysis report earlier investigator’s assessment of this year, the DMC concluded that the LUNAR trial should continue with no evidence of increased systemic toxicity. LUNAR is a phase 3 pivotal trial testing the effectiveness of TTFields in combination with immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone for patients with stage 4 NSCLC who progressed during or after platinum-based therapy. It is estimated that approximately 46,000 patients receive second-line treatment for stage 4 NSCLC each year in the US. Tumour Treating Fields, or TTFields, are electric fields that disrupt cancer cell division. June 2021 / FUTURE MEDICINE / 35

Berotralstat pill to treat HAE in UK UK’s Medicines and attacks per month at baseline Healthcare products to a mean of 1.0 attack per Regulatory Agency (MHRA) month after 48 weeks of has granted marketing therapy. In the long-term open authorization for oral, once- label APeX-S trial, patients daily berotralstat (Orladeyo) completing 48 weeks of for the routine prevention therapy (150 mg) had a mean of recurrent hereditary attack rate of 0.8 attacks per angioedema (HAE) attacks month. in HAE patients 12 years and older, BioCryst Pharmaceuticals Berotralstat was safe said. and well tolerated in both trials. The most frequently In the pivotal phase 3 reported adverse reactions in APeX-2 trial, berotralstat patients receiving berotralstat significantly reduced attacks at compared with placebo were 24 weeks, and this reduction gastrointestinal reactions. was sustained through 48 weeks. HAE patients who Berotralstat is the first and completed 48 weeks of only oral therapy designed treatment (150 mg) saw specifically to prevent attacks reductions in their HAE attack of HAE in adult and paediatric rates, from a mean of 2.9 patients 12 years and older. Dostarlimab endometrial cancer who with recurrent low-grade mutant ORR at 70% (7 of for endometrial received dostarlimab in the serous ovarian cancer (LGSOC) 10 response evaluable cancer trial, 42.3% had a complete regardless of KRAS status patients), KRAS wild- response (disappearance of after one or more prior lines type ORR at 44% (4 US FDA has granted tumour) or a partial response of therapy, including platinum- of 9 response evaluable accelerated approval to (shrinkage of tumour) to based chemotherapy. dostarlimab (Jemperli) for treatment with dostarlimab. patients) and KRAS status treating patients with recurrent For 93% of responders, the The combination of VS- undetermined ORR at 0% (0 of or advanced endometrial response lasted for six months 6766 with defactinib is being 2 response evaluable patients). cancer that has progressed on or more. evaluated in the ongoing The most common side effects or following prior treatment investigator-initiated phase seen in the study were rash, with a platinum-containing Breakthrough 1/2 FRAME trial. In the most creatine kinase elevation, chemotherapy and whose desig VS-6766 recent read-out from the nausea, hyperbilirubinemia cancers have a specific genetic with defactinib FRAME LGSOC cohort (n=24), and diarrhoea, most being NCI feature known as dMMR (which in ovarian the overall response rate (ORR) CTC Grade 1/2 and all were contain abnormalities that cancer is 52% (11 of 21 response reversible. affect the proper repair of DNA evaluable patients), with KRAS inside the cell), as determined Verastem, Inc announced RAS is the most frequently by an FDA-approved test. that the US FDA mutated oncogene, occurring granted Breakthrough in 30% of human cancers. Dostarlimab works by Therapy designation for These cancers are typically targeting the cellular pathway the combination of its highly aggressive and recurrent, known as PD-1/PD-L1. investigational RAF/MEK sending signalling commands inhibitor VS-6766, with through the RAS pathway. VS- The safety and efficacy of defactinib, its FAK inhibitor, for 6766 is a novel dual inhibitor dostarlimab was studied in a the treatment of all patients of the RAF/MEK signalling single-arm, multi-cohort clinical pathway. With this unique trial. Of the 71 patients with dual mechanism of action, dMMR recurrent or advanced VS-6766 confers vertical inhibition of the RAS pathway in a single drug. 36 / FUTURE MEDICINE / June 2021

www.careonhealthcare.com QUALITY THAT MATTERS. Commitment to control hospital acquired infections with top quality single use medical disposables SCAN TO KNOW MORE

straight talk MUCORMYCOSIS CAN SPREAD RAPIDLY IN COVID-19 PATIENTS WITH UNCONTROLLED DIABETES Mucormycosis is the latest woe in India’s There is an assumption that certain drugs, including COVID fight. The fungal infection, which steroids, used for COVID treatment lead to the infection often turns fatal, is triggered by the overuse among diabetics. So is it right to say that diabetics are of steroids in severe COVID patients with more prone to the infection and if yes, which is the comorbidities such as diabetes, cancer or particular drug substance that causes the same? other immunocompromised conditions. Since the infection is highly dangerous, killing Steroids in general cause an acute increase in blood sugar between 46% to 96% of the patients, and levels by countering the action of insulin. It is known that often leads to complete blindness if not people who have high blood sugar levels are prone to all death, it is better to prevent it by taking due types of infections including bacterial, viral and fungal. So, care in treatment protocol and maintaining in a way it is important that special care is taken in case of diabetes patients while treating for COVID-19 where steroids proper hygiene in ICUs and the whole are used with no particular therapeutic regime yet evolved hospital environment, says DR V MOHAN, for critical cases. Director & Chief of Diabetes Research at Madras Diabetes Research Foundation, and What correlation do you see in patients with high blood Chairman & Chief Diabetologist, Dr. Mohan’s sugar levels and mucormycosis? Diabetes Specialities Centre, in Straight Talk High blood sugar reduces the immunity of the individuals with PRAPTI SHAH. and hence dangerous fungal infections like mucormycosis can spread rapidly in people with uncontrolled diabetes. At 38 / FUTURE MEDICINE / June 2021 the same time, I would also like to clarify that it is not the drugs used for diabetes which leads to the infection, but the use of steroids for COVID severity that causes the fungal infection. What are the key insights/experiences on the incidence of mucormycosis for immunocompromised patients? From past experience, it is people with uncontrolled diabetes who are most prone to mucormycosis. Other causes include the use of steroids, malignancies, chemotherapy drugs and drugs like deferoxamine which are used for iron overload conditions. All these have been linked to higher incidence of mucormycosis. In people who have diabetic ketoacidosis (coma), the risk of mucormycosis is very high. What are the particular symptoms of mucormycosis found in diabetics? The symptoms of mucormycosis in COVID patients with

Dr V Mohan underlying medical conditions are more or Most of the cases treat it after it occurs. less the same, whether it is in people with of mucormycosis diabetes or without diabetes. It starts off are immediately As a diabetologist and an avid like an ordinary cold and then the sinuses referred to the researcher in this area, do you have any get infected with blackish material. This ENT surgeons perspective or data about the size of the then spreads to the eye, which then gets or to the diabetic population currently suffering inflamed and becomes red. Later, there is ophthalmologists from mucormycosis post COVID recovery? swelling and protrusion of the eyeball and because flu if this is severe, it may lead to the need for and sinusitis or Most of the cases of mucormycosis are removal of the eye itself. Finally it can enter impaired sight and immediately referred to the ENT surgeons into the brain and if this occurs, it is usually blindness are the or to the ophthalmologists because flu and fatal. symptoms that are sinusitis or impaired sight and blindness manifested first. are the symptoms that are manifested What kind of special treatment first. If the sugars are uncontrolled, some is available for the treatment of of the patients get referred to us for the mucormycosis in diabetics? control of diabetes. Till COVID occurred, mucormycosis was extremely rare and The first thing to do is to get the one or two cases per year were seen. diabetes under very good control. Now, after COVID, a large number of cases Secondly, specific antifungal drugs like have been reported from Mumbai and Amphotericin B are used. These are Ahmedabad and they are also now being however quite toxic and also expensive. In seen in Delhi, Tamil Nadu, Andhra Pradesh, severe cases, removal of the jaw or the eye Karnataka and other states as well. Most may become necessary. Hence, it is always cases of mucormycosis occur in those with better to prevent mucormycosis than try to severe diabetes. June 2021 / FUTURE MEDICINE / 39

research snippets Peptide-based wound dressing Needle activated by to promote healing ultrasound enhances biopsy Saba Atefyekta et al fabricated against Staphylococcus a new antimicrobial peptide epidermidis, Staphylococcus Emanuele Perra et al demonstrated (AMP) based wound dressing aureus, Pseudomonas that adding ultrasound to a material that could reduce aeruginosa, methicillin-resistant conventional medical needle could infection and promote blood S. aureus (MRSA), and increase the sample yield during the coagulation and healing. The multidrug-resistant Escherichia fine-needle aspiration biopsy (FNAB) team found that AMPs could coli for up to 24 h. The AMP- application. The study showed that using get covalently immobilised onto hydrogels did not present any an ultrasound emission localised at a tip suitable substrates thereby toxicity to human fibroblasts of a conventional medical needle can helping form contact-killing and retained their antimicrobial act as an energy source for nonlinear surfaces with increased long- activity up to 48 h in human ultrasonics (NLU) around the needle term stability. The researchers blood serum. Studies performed tip. The sound emission could generate created the antibacterial on human whole blood showed NLU phenomena such as acoustic material by covalently linking that blood coagulated more radiation force, acoustic streaming the antimicrobial peptide, readily in the presence of and cavitation, extending to several RRPRPRPRPWWWW-NH2 AMP-hydrogels as compared millimetres from the physical needle (RRP9W4N), to amphiphilic to hydrogels without AMPs, boundary. This could help the physicians Pluronic F127 hydrogels. indicating potential hemostatic to quantitatively characterise the NLU The hydrogel was made of activity. The antibacterial wound effects from micrometer to millimetre cross-linked lyotropic liquid dressing could help reduce scale by spatially reaching beyond crystals composed of 1-ethyl- unnecessary drug intake by the currently used physical lancet. 3-(3-(dimethylamino)propyl) acting as a better alternative to The researchers defined the confined carbodiimide (EDC) and antibiotics. volume around the needle tip exhibiting N-hydroxysuccinimide (NHS). 40 / FUTURE MEDICINE / June 2021 Source: ACS Biomaterial Science & The AMP-hydrogels showed Engineering 2021, 7, 4, 1693–1702 high antibacterial |March 15, 2021 | https://doi. activity org/10.1021/acsbiomaterials.1c00029’’ pronounced nonlinear effects as the SonoLancet. The study showed that the SonoLancet contributed to obtaining tissue cores with an increase in tissue yield by 3–6× in different tissue types compared to conventional needle biopsy technique using the same 21 gauge needle. SonoLancet could be of interest to several other medical applications, including drug or gene delivery, cell modulation, and minimally invasive surgical procedures. Source: Scientific Reports volume 11, Article number: 8234 (2021) | 15 April 2021| https:// www.nature.com/articles/s41598-021-87303-x

Iontronic implant to ADenovirus (SHREAD) gene therapy, cells after which the tumour begins to targeted delivery of targets specific cells based on chosen eliminate itself through the production chemo for GBMs surface markers and converts them into of anti-cancer agents in high local biofactories secreting therapeutics. The concentrations by its own cells in a Linda Waldherr et al demonstrated team utilised a genetically modified paracrine fashion over an extended that electrically driven delivery of adenovirus to deliver genetic material duration. The study was carried out in chemotherapeutic drug gemcitabine that coded for an anti-cancer antibody. mice models in which the viral vector (Gem) has the potential to radically The virus then infects the tumour resulted in significant levels of antibody improve the efficacy of treatment of glioblastoma multiforme (GBM). Although Gem showed a high potency to kill GBM cells, its inability to travel across the blood-brain barrier (BBB) prompted the researchers to evaluate miniaturised capillary fibre-based organic electronic ion pumps (OEIPs) for delivery of the drug into the tumour cells. The study used a gemcitabine ion pump (GemIP) which is designed to transport the charged form of the chemotherapeutic Gem through a cation exchange Scientists develop siRNA therapy membrane (CEM) toward targeted for COVID-19 tumour cells. The research showed that GemIP could achieve controlled, Adi Idris et al have developed a one another. After encapsulation targeted Gem delivery to GBM cells. new therapeutic approach using of siRNAs in the lipid nanoparticle The GemIP-mediated Gem delivery was small-interfering RNAs (siRNAs) (LNP) formulation, it was delivered found to have pmol min−1 precision and targeted specifically to SARS-CoV-2, by in vivo injection into the lungs of its electric addressing was linked to the the virus causing the COVID-19 infected mice models. The research efficient killing of GBM cell monolayers infection. The siRNA molecules showed robust repression of the and disintegration of the targeted GBM were designed to be delivered via virus in the lungs and pronounced tumour spheroids. The study supports a novel lipid nanoparticle delivery survival advantage to the treated the development of new iontronic system devised by the researchers. mice. The LNP-siRNA approach implants for more targeted GBM therapy The team identified three highly may be developed to treat humans, using chemotherapeutics whose use is efficient candidate siRNAs that which could be used upon the first currently hampered by the BBB. target the highly conserved regions sign of SARS-CoV-2 infection. The of the SARS-CoV-2 virus where they therapeutic approach could also be Source: Advanced Materials technology| 12 April bind and disrupt the genome of the used as an adjunctive therapy to 2021 | https://doi.org/10.1002/admt.202001302 virus. The selected siRNA candidates current vaccine strategies. demonstrated an ability to inhibit Virus therapy helps the virus by greater than 90% Source: Molecular Therapy| May 13, self-destruction of either alone or in combination with 2021| DOI: https://doi.org/10.1016/j. tumours ymthe.2021.05.004 Sheena N Smith et al have developed a virus-based therapy that causes a tumour to destroy itself. The therapy, which is named SHielded, REtargeted June 2021 / FUTURE MEDICINE / 41

Implantable hydrogel helps neurons recover after TBI therapeutic production in Charles-Francois V Latchoumane et al enhanced cellular repair and gross motor target tissues. Using the passive showed that synthetic neurotrophic function recovery in 20 weeks. Animals CLARITY technique (PACT), the factor functionalised chondroitin sulfate subjected to M2 region injuries followed team could locally quantify the (eCS) matrices, when implanted into by eCS matrix implantations showed secreted therapeutic, and directly brain regions, mediated significant significant recovery of “reach-to-grasp” observe enhanced pore formation structural and functional recovery after function. The results were attributed to in the tumour and the destruction an increase in volumetric vascularisation, of the intact vasculature. The in situ severe traumatic brain injury (sTBI). activity-regulated cytoskeleton (Arc) production of the antibody increased The team analysed the long-term protein expression, and perilesional the tumour-to-serum antibody outcomes of implanting the sulfated sensorimotor connectivity. The findings concentration ratio by 1,800 folds eCS matrices which were laden with indicated that eCS matrices implanted compared to direct administration of acutely after sTBI supported complex the drug, thereby reducing systemic fibroblast growth factor 2 (FGF2) and cellular, vascular, and neuronal circuit toxicity and enhancing the efficacy of the brain-derived neurotrophic factor repair chronically after the injury. therapy. (BDNF). The study conducted in Source: Science Advances | 05 Mar 2021: Vol. 7, Source: PNAS May 25, 2021 118 (21) mice models showed that the no. 10, eabe0207 DOI: 10.1126/sciadv.abe0207| e2017925118; https://doi.org/10.1073/ brain-mimetic eCS matrices, https://advances.sciencemag.org/content/7/10/ pnas.2017925118 when implanted into M1 eabe0207?utm_content=buffera9ac6&utm_ region acutely after sTBI, medium= 3D bioprinting enables social&utm_source=twitter.com&utm_ cartilage-like implants cartilage. Using FRESH and in vitro campaign=buffer chondrogenesis, the team fabricated Xiaoyi Lan et al have developed tissue-engineered nasal cartilage from and histological characteristics helping in a method to 3D print cartilage- combining bovine type I collagen the reconstruction of the nose. like materials consisting of a hydrogel and human nasoseptal collagen hydrogel containing human chondrocytes. The printed structures Source: The FASEB Journal| February 2021| chondrocytes. Surgical resection of the mimicked human nasal cartilage in terms https://doi.org/10.1096/fj.202002081R tumorigenic lesions on the nose of skin of its mechanical, molecular cancer patients often resulted in nasal Male hormones play cartilage removal. Here, the researchers a role in stomach utilised the 3D bioprinting technology to inflammation engineer cartilages with customisable dimensions and anatomically shaped Jonathan T Busada et al determined configurations suitable for patients. that stomach inflammation is The team showed that using freeform reversible embedding of suspended hydrogel (FRESH), bioprinting strategy could generate customisable and homogeneously distributed functional cartilage matrix engineered nasal 42 / FUTURE MEDICINE / June 2021

regulated differently in male and female The ILC2s were depleted by treatment offer a flexible tool for image-guided mice after finding that androgens (male with CD90.2 antibodies which surgical removal of tumours. sex hormones) play an important role in protected the stomach from SPEM The imaging system is a six-channel preventing inflammation in the stomach. development. colour image sensor that could enable The team found that glucocorticoid near-infrared fluorescence image hormones are involved in suppressing Source: Gastroenterology| May 7, 2021| https://doi. guidance during surgery. The team could inflammation. In the absence of org/10.1053/j.gastro.2021.04.075 detect fluorescently labelled sentinel glucocorticoids, the lymph nodes with the help of the female mice developed gastric Hexachromatic camera sensor in breast cancer patients inflammation and spasmolytic for image-guided undergoing surgical resection. polypeptide-expressing metaplasia cancer surgery The image system could also help (SPEM) while the males did not. distinguish diseased prostate tumours However, depletion of both Steven Blair et al have developed a from healthy tissue in an estimated glucocorticoids and sex hormones hexachromatic camera that could 92% of cases in mice models. via adrenalectomy and castration did The image sensor also allowed trigger spontaneous pathogenic gastric to map the three-dimensional inflammation and SPEM in the male topography of tumours and mice. Treatment of female mice with surgical sites to within 5α-dihydrotestosterone (DHT) prevented 1.2-mm error by extracting the near- gastric inflammation and SPEM infrared structured illumination. By development and also reversed the seeing the entirety of the tumour pathology when administered and removing accurately around the after disease onset. Single cell- margins, the imaging sensor sequencing of gastric leukocytes should be able to minimise surgical revealed that type 2 innate lymphoid revisions and lower the chances of cells (ILC2s) expressed abundant levels cancer recurrence. of both the glucocorticoid receptor (Gr) and androgen receptor (Ar). The Source: Science Translational Medicine 05 May DHT treatment potently suppressed 2021: Vol. 13, Issue 592, eaaw7067 DOI: 10.1126/ the expression of the pro-inflammatory scitranslmed.aaw7067 cytokines Il13 and Csf2 by ILC2s. —Compiled by Divya Choyikutty Optical fibre device to treat cerebral aneurysms Jongkyeong Lim et al have developed a new technique to treat cerebral aneurysms. The treatment involves a catheter to deliver an alginate hydrogel microfibre that is crosslinked in place within the aneurysm using light. The light-responsive gel was developed using double-crosslinked alginate-based hydrogel with tantalum nanopowder (DAT) which rapidly underwent a covalent crosslinking reaction when exposed to light. The catheter delivery system which is an optical-fibre-integrated microfluidic device (OFI-MD) can deliver light as the gel is extruded, allowing fine control of gel deposition during the procedure. The gel is delivered as microfibres which fill the aneurysm and then undergo a further ionic crosslinking reaction once in place because of the presence of calcium in the blood. The hydrogel could reside within the body for extended periods and stabilise the aneurysm while reducing the chance of it bursting. Source: Advanced Materials| 04 February 2021| https://doi.org/10.1002/ adma.202006759 June 2021 / FUTURE MEDICINE / 43

column the cellview The third wave will be potentially about protecting our children In the first wave, less than 1% of the affected were children, but in the ongoing wave, it has increased ten-fold DR RAJANI KANTH India has one of the largest proportions The biggest challenge will then be about VANGALA of population in the younger age groups the capability of hospitals to take the load in the world. It is well known that SARS- of paediatric patients. The author is a medical CoV-2 infects everyone across all age scientist and former groups, but older age groups tend to have Another upcoming challenge will be director of SGRF, severe symptoms compared with younger to take precautions to keep our children Bangalore groups. The vaccination of people above the safe from emerging mutants or variants of age of 45 was the first step taken by the the virus. As several mutants have been Indian government and now some of the shown to evade the immune responses states have moved on to vaccinating people in adults, we do not know how they may above 18 years of age. This can really help affect children. In the first wave, less than reduce the spread of the virus, but it also 1% of the affected were children, but in the creates the very important problem of ongoing wave, it has increased ten-fold and tackling the younger population below the some of the children are having very serious age of 18 which cannot be vaccinated as conditions which is very worrisome. of yet. It was observed that infants below the age of 1 year are most vulnerable due COVID-19 infected children may recover to high hospitalization rates. The average quickly. However, the long-term effects incubation period for SARS CoV2 in children of the infection are less understood and is about 6.5 days in comparison to 5.4 days might really play a major role in their adult in adults. The severity of infection in children life. It was observed that a small percent of can vary based on the condition of the the children suffer from months of fatigue, immune system, pulmonary pathology, the rapid heart rate, memory loss, depression age of the infant and the presence of type 1 and other symptoms. These post-infection diabetes and other underlying diseases such symptoms are difficult to handle and impact as asthma or obesity. A vaccinated adult can the entire family. Young people also have to easily take home the virus, thus infecting go to colleges and schools where interactions children. Even though the symptoms of are bound to happen and, in such cases, paediatric patients are mild, virologic data infections will spread. The initial infection indicates that the viral load is almost the and associated symptoms may not always same. Several children below the age of 18 be the only thing to care about. Instead, the years tested positive in Maharastra’s Akola long-haul or lasting effects of COVID-19 will and Amravati districts, which account for have to be dealt with among the younger 10-12% of the total infections reported in population. This is not a fight for protecting India. Therefore, the imminent third wave elders anymore. It is a fight to protect our may be more about children than about the future generation from the upcoming third adults if vaccination targets are achieved. wave. India needs to gear up now to meet this imminent threat rather than wait for it to happen. 44 / FUTURE MEDICINE / June 2021



special feature BLACK FUNGUS THE NEW CRISIS The fast-rising incidents of mucormycosis casts a shadow over critical treatments in severe COVID-19 patients with underlying medical conditions, mostly diabetics. While treatment options are limited for critical and immunocompromised COVID patients, the misuse of steroids and unsterile hospital practices are blamed for the new healthcare calamity 46 / FUTURE MEDICINE / June 2021

When the worst does its INITIALLY FOUND WMTDHOIHTENAIGECTARTCTIOASEINS?BE best, even the rarest makes IN HOSPITALS IN it to the commonest. MAHARASHTRA, GUJARAT Dr. Dinoop K.P., Assistant An otherwise rare infection — AND DELHI, MUCORMYCOSIS Professor, Clinical Microbiology, mucormycosis — has emerged as a IS NOW BEING REPORTED at Sree Chitra Tirunal Institute for serious health crisis amid the ravaging FROM ALL OVER INDIA Medical Sciences & Technology second wave of COVID-19 in India. (SCTIMST), Thiruvananthapuram, and The ‘black fungus’ infection has hit now being reported from all over the Dr. R. Aravind, Head, Department the headlines after hundreds of cases country. Surat, a city of six million in of Infectious Diseases, Medical were reported among recovering and Gujarat, reported 40 cases in the last College, Thiruvananthapuram, recovered COVID-19 patients across week of April and out of these, eight have the following suggestions to the country. This rare but potentially lost their eyes within the first 15 days. manage the current crisis caused by fatal infection caused by a group of The health minister of Maharashtra, mucormycosis: molds called mucormycetes affects Rajesh Tope, said on May 11 “there the sinuses, the brain and the lungs. could be over 2,000 mucormycosis 1. Adequate sugar control should patients in the state” and the numbers be achieved in patients who are It is life-threatening in diabetic and would “increase for sure” given the already diabetic with or without severely immunocompromised rising number of COVID-19 cases. COVID-19, with or without steroid individuals, including cancer treatment, to reduce the overall patients and those people Meanwhile, the head of AIIMS, Delhi incidence. with HIV/AIDS. Initially found in 2. Early identification of the hospitals in Maharashtra, disease should be done via all Gujarat and Delhi, possible ways by the health staff if mucormycosis is the patient is in a hospital. Before a patient leaves the hospital, he/ she or the bystanders must be given an awareness about the early symptoms of the disease. Such awareness programmes done can also help those who are at home or quarantine centres. 3. The hygiene level of the hospital must be enhanced. Appropriate use of sterile saline or distilled water for humidifiers in ventilators is mandatory. There should be regular practice of disinfection. These actions can prevent infections having a hospital origin. 4. A judicious use of broad- spectrum antibiotics must be ensured, as this represents another possible risk factor for COVID-19 patients admitted to hospitals. June 2021 / FUTURE MEDICINE / 47

— India’s premier medical institution, Dr ENDOTHELIAL Randeep Gulleria, said 23 patients were INJURY AND treated in his institution for the infection MUCORMYCOSIS and 20 out of them are still COvid positive. “Many states have reported According to some more than 500 cases of mucormycosis experts, ‘endothelialitis’ as of now and there is an urgent need — seen along with to control and monitor blood sugar severe COVID-19 — levels among COVID-19 patients,” is another possible Gulleria said on May 15, adding that explanation for more than 90% of these mucormycosis the association of patients are diabetics. mucormycosis along with COVID-19. According to Maharashtra health Postmortem minister Tope, as many as 111 patients, observations have all COVID-19 survivors, are undergoing shown the presence treatment for mucormycosis in hospitals of more Severe in Mumbai and a couple of them have Pulmonary Vascular lost their eyesight due to the fungal Endothelial Injury and infection. new vessel growth in patients who have While Maharashtra has now decided died due to COVID-19 to create a separate database of cases than patients who died of mucormycosis to assess its actual of Influenza A (H1N1). spread and how to tackle it, AIIMS chief Another series of Dr Randeep Gulleria warned doctors autopsy observations that that the “misuse of steroids” during have revealed widespread endothelial MAHARASHTRA HAS NOW injury in patients who DECIDED TO CREATE A died of multi-organ SEPARATE DATABASE OF failure. CASES OF MUCORMYCOSIS TO ASSESS ITS ACTUAL SPREAD In a paper AND HOW TO TACKLE IT published in Clinical Infectious Diseases, COVID-19 treatment was a major cause endothelial adhesion of the infection. and penetration are referred to as the “The data clearly links the current critical early steps increase in mucormycosis cases with in mucormycosis diabetes and steroid intake,” he added. (Ibrahim, A.S., et al. 2012). Teny M. Referring to a recent meeting that John, et al., propose Dr Gulleria had with doctors from that acidemic states Gujarat where 500 cases of the fungal and hyperglycemia infection have been reported just from induce the endothelial government hospitals, he said hospitals receptor Glucose- in the state have set up special wards Regulated Protein for patients with mucormycosis and (GRP 78) and the are now forming combined teams Mucorales Adhesin with infectious disease specialists, Spore Coat Protein ENT surgeons, neurosurgeons and Homologs, resulting in an increased adhesion 48 / FUTURE MEDICINE / June 2021 and penetration of Mucorales-fungi to the endothelium. It is noteworthy that GRP 78 has been postulated as one of the receptors responsible for the entry of SARS-CoV-2.

CHALLENGES OF TREATMENT The possibility of infections caused the mucor structures. If mucormycosis is diluted Amphotericin B is recommended. by the fungus Aspergillus in people the case, histopathologic examinations The selection of the most appropriate with severe COVID-19 is still debated will be showing relatively broad non- systemic antifungal agents is also by scientists. In the past, Aspergillosis septate hyphae with right angle branches, important,” he says. was reported only from people with necrotizing granulomatous inflammation severely weakened immune systems. and vasculitis together with the presence Diabetes, COVID-19 and However, nowadays, Aspergillosis is also of mucor hyphae within the vascular wall mucormycosis reported from patients having severe and lumen. respiratory infections such as influenza, India has the highest burden of caused by viruses. Several recent reports Amph B - Drug of choice mucormycosis in the world with an alsodescribe COVID-19-Associated estimated prevalence of 140 cases Pulmonary Aspergillosis (CAPA). Among the different types of per million people. Diabetes mellitus mucormycosis, rhino-orbito-cerebral is seen associated with over 50% of As per available information, CAPA mucormycosis is relatively the most cases of mucormycosis in India. So, can occur in severe COVID-19 patients fatal infection and in cases of brain diabetes mellitus is considered as the who are on ventilators in ICUs. CDC involvement, the mortality can rise up to single most common risk factor for advises physicians to consider the 50%–85%. For mucormycosis of any kind, mucormycosis in India. It is a fact that possibility of Aspergillosis in severe systemic Amphotericin B and its liposomal patients with COVID-19 are predisposed COVID-19 patients who have worsening to diabetic ketoacidosis. And in patients respiratory function or sepsis, even if PHYSICIANS ARE ADVISED TO with Diabetes mellitus, mucormycosis is they are not having the classical risk CONSIDER THE POSSIBILITY associated with increased morbidity and factors for Aspergillosis. In such situations, OF ASPERGILLOSIS IN SEVERE mortality. testing for CAPA can be done. The test COVID-19 PATIENTS WHO HAVE usually involves obtaining specimens from WORSENING RESPIRATORY Researchers have proved that as patients’ lower respiratory tract which are FUNCTION OR SEPSIS with any other serious infection, SARS- tested for Aspergillus galacto-mannan CoV-2 induces damage of pancreatic antigen and subjected to fungal culture. formulation is the first drug of choice. islets resulting in acute diabetes and It can significantly improve the survival diabetic ketoacidosis. In a recent paper Diagnosis of mucormycosis rate of the patients. The antifungal agent published in the Journal of Fungi, this is Posaconazole can be used orally as step- presented as the possible explanation for CT and MRI scans along with regular down therapy after the initial control of the ‘diabetogenic state’ in SARS-CoV-2 examination are very important to detect the disease by Amphotericin B. infection, as there is a high expression mucormycosis at an early stage and of angiotensin-converting enzyme 2 know its propagation. Scan images of Surviving mucormycosis will be quite receptors in pancreatic islets, along the infected region are very crucial in easy if early diagnosis of the disease with increased insulin resistance due to the early diagnosis of the disease. The can be done, says Dr. R. Aravind, Head, cytokine storm. images can be useful in identifying the Infectious Diseases, Medical College, opacifications of involved paranasal Thiruvananthapuram, Kerala. In a study conducted in UK, the sinuses, bone destruction of sinus walls, prevalence of Diabetes mellitus and alterations of intraorbital tissue signal “Regular daily debridement of diabetic ketoacidosis was found to be with or without focal mass, cavernous necrotic tissues from paranasal sinuses higher in COVID-19 patients compared sinus filling defect, intracranial focal mass is necessary to prevent the propagation to the national prevalence of Diabetes and alteration of the meningeal signal. of mucormycosis. Also, irrigation of the mellitus type 2 and diabetic ketoacidosis sinuses and the involved regions with in the general population (Goldman, N. et However, mucormycosis is confirmed al., 2020). Recently, euglycemic diabetic if blackish necrotic tissues are detected ketoacidosis is also being reported in in the infected region and through COVID-19 patients (Oriot, P. et al., 2020). Researchers propose that the frequent histopathology. Stains such as use of corticosteroids can disrupt glucose Hematoxylin and Eosin, Periodic homeostasis, making patients more Acid-Schiff (PAS) and Gomori susceptible to Mucormycosis (Lionakis, Methenamine Silver (GMS) M.S. et al., 2003). can be used to identify 50% 0 61 140/244 976 3906 15625 62500 250000 1000000 million of cases of mucormycosis in India are associated with is the estimated current diabetes mellitus prevalence of cases in India which is the highest burden of mucormycosis in the world June 2021 / FUTURE MEDICINE / 49

plastic surgeons to operate upon these CIRFMOOISMRVKUIPDNOR-FI1OT9MLYTOUSRNCUEGOPAERPTDMRMYDEECSUNOSRTSIANIITSNGICOMRNEEDIANISCEINSES persons. DILIP GUDE “Almost all of the mucormycosis patients had taken steroids. More than Chief Consultant Physician, Diabetologist, Department of Internal Medicine, 90-95% were diabetics. COVID-19 itself Virinchi Hospitals, Hyderabad leads to lymphopenia, predisposing patients to opportunistic fungal What are the key substances Mucormycosis can be infections,” Guleria said. used in the COVID-19 treatment that prevented by strict sugar causes black fungus infection? control and in high risk He pointed out that steroid intake COVID-19 patients by giving can lead to a spike in blood sugar levels. High doses of immunity prophylactic drugs like suppressing medicines for posaconazole. The expert teams in Gujarat are prolonged duration in COVID-19 can now checking to see if tocilizumab — an increase risk of mucormycosis in Dilip Gude immunosuppressant being used to treat COVID. Drugs like steroids, at high COVID-19 by many doctors — also leads doses, immunosuppressants like Any data on the number of to fungal infections. Tociluzumab, baricitinib, diabetics suffering from mucormycosis bevacizumab and tofacitinib after recovery from COVID-19? Dr Yashdeep Gupta, Associate can predispose an individual to Professor with AIIMS’s department mucormycosis. It is hard to give a percentage as last of endocrinology and metabolism, year the mucor infection was relatively stressed the need for screening patients There is a direct link of rare, and it is only during the second being admitted to a COVID-19 care mucormycosis found with poorly wave that we are seeing increased facility. This, he pointed out, will help controlled sugar level (high sugars) numbers of this fungal infection. detect undiagnosed hyperglycemia for in patients, prolonged use of mucormycosis can be prevented by effective control of diabetes and its immunosuppressants and prolonged strict sugar control and in high risk consequences during treatment, as well hospital stay. COVID patients by giving prophylactic as constant monitoring of sugar levels drugs like posaconazole. for diabetic patients and keeping a low What are the key insights on threshold for administering insulin. the incidence of mucormycosis in diabetics? “Now, we are having two sets of patients: COVID-19 patients with Diabetes in itself is a disorder mucormycosis who we are kept in the with a weak immune response. COVID-19 ward, and those who become When sugars are very high, COVID-19 negative and continue to have the innate immunity is further hit mucormycosis. And the management and allows for opportunistic fungi strategy becomes even more like mucor to harbor and grow. challenging because of these two sets of Likewise diabetic patients with patients,” said Dr Gulleria. better controlled sugars have very less chance of getting black fungus A fatal fungus infection. Mucormycosis is an acute and potentially Invasion of sinuses may cause fatal fungal infection. It is caused by swelling in one side/or rarely both members of the fungal group commonly sides of the face. Drooping of eyelid called Mucorales. These fungi produce and eyeball, fever, drowsiness, altered asexual spores which can infect the oral sensorium, etc can be seen in case of and nasal cavities through inhalation. mucor infection. These fungi can be easily cultured from the nasal and oral mucosa of healthy As far as the treatment regime humans. In the presence of a normal is concerned, the experience so far immune system, these fungal spores are shows that liposomal amphoterisin removed by the action of the phagocytic and/or posaconazole coupled with leukocytes. aggressive debridement of sinuses may help save patients. However if such a defensive mechanism fails, the fungus spore gives out hyphae and begins to grow, leading to fatal consequences. This normally occurs in persons who have uncontrolled 50 / FUTURE MEDICINE / June 2021