Advances in Zika virus vaccines and therapeutics:A systematic review

Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.

Recent advances on vaccines against malaria: A review

This review aims to summarize the currently viable vaccine strategies including the approved vaccines and the those in trials for next-generation malaria vaccines.Data on malaria vaccine development was collected through a comprehensive review.The literature search was performed using databases including Google Scholar,PubMed,NIH,and Web of Science.Various novel approaches of vaccination are being developed,including those based on radiation-attenuated strategies,monoclonal antibodies,targeted immunogenic peptides,RNA and DNA vaccines,nanoparticle-based vaccines,protein-based vaccination protocols,and whole organism-based vaccination strategies.Trials on RTS,S have entered phase Ⅲtesting,and those based on blood-stage vaccines and vaccines to interrupt malarial transmission have advanced to higher stages of trials.Mathematical modeling,combined drug and vaccine strategies,mass drug administration,polyvalent vaccine formulations,and targeted vaccination campaigns is playing an important role in malarial prevention.Furthermore,assessing coverage,accessibility,acceptability,deployment,compilation,and adherence to specific vaccination strategies in endemic regions is essential for vaccination drives against malaria.

Hepatitis C virus in Pakistan:A systematic review of prevalence,genotypes and risk factors

In Pakistan more than 10 million people are living with Hepatitis C virus (HCV), with high morbidity and mortality. This article reviews the prevalence, genotypes and factors associated with HCV infection in the Pakistani population. A literature search was performed by using the keywords; HCV prevalence, genotypes and risk factors in a Pakistani population, in Pubmed, PakMediNet and Google scholar. Ninetyone different studies dating from 1994 to May 2009 were included in this study, and weighted mean and standard error of each population group was calculated. Percentage prevalence of HCV was 4.95% ± 0.53% in the general adult population, 1.72% ± 0.24% in the pediatric population and 3.64% ± 0.31% in a young population applying for recruitment, whereas a very high 57% ± 17.7% prevalence was observed in injecting drug users and 48.67% ± 1.75% in a multi-transfused population. Most prevalent genotype of HCV was 3a. HCV prevalence was moderate in the general population but very high in injecting drug users and multi-transfused populations. This data suggests that the major contributing factors towards increased HCV prevalence include unchecked blood transfusions and reuse of injection syringes. Awareness programs are required to decrease the future burden of HCV in the Pakistani population.

Molecular study of HCV detection,genotypes and their routes of transmission in North West Frontier Province,Pakistan

Objective:To determine hepatitis C virus(HCV) genotypes and explore the associated risk factors in chronic HCY patients.Methods:A total of 116 patients with chronic hepatitis C were subjected to polymerase chain reaction(PCR) based detection out of which 112 chronic HCV patients[53 male(47.32%),59 female(52.68%);mean age(43.76±16.40) years;mean BMI(23.8± 3.9)kg]were enrolled in this study.The frequency of 6 HCV genotypes and associated risk factors were evaluated from five districts of North West Frontier Province(NWFP).Results:Genotype 3was the most prevalent in 73 samples(65.17%) followed by genotype 1 in 24(21.42%) and genotype2 in 13(11.60%) samples.Genotype3 had significantly high prevalence(P=0.0002).The results showed that 48(42.85%) samples were infected with HCV 3a:25(22.32%) with 3b;14(12.50%) with 1a;10(8.92%)with 1b;11(9.82%) with 2a;2(1.78%) with 2b;and 2 were untypable.The distribution of HCV genotypes in Murdan.Charsadda,Peshawar.Sawabi and Nowshehra districts was different.Use of unsterile equipment lor medication,barbers and previous history of hospitalization were the main risk factors for HCV transmission.Conclusions:Cenotype 3a and 3b.1a.1b and 2a are the common genotypes in NWFP.Genotype 4.5.and 6 can not be found in a single sample.The level of awareness about various modes ot transmission of HCV among the population is found to be verv low.

Zika virus,a pathway to new challenges

The current Zika outbreak is largest of its kind with 1.4 million cases in Brazil alone.World Health Organization declared the current outbreak as the public health emergency of international concerns.The major route of Zika virus transmission is mosquito bites.Sexual transmission and monkey bites are also observed in few cases.There is dire need to evaluate the other routes of transmission like blood transfusion,lactation and contact with body fluids.Zika virus is infecting infants,not only causing microcephaly but also creating number of complications resulting in bad outcomes of pregnancy.In Brazil alone,4 000 cases of microcephaly have observed during the current outbreak.The incidence of Guillian-Barre(GB) syndrome is also observed during the current Zika virus outbreak.GB syndrome is acute medical condition leading the patients to death due to weakness of respiratory muscles or can cause the life time disability.There is no anti-viral drug or vaccine available for Zika virus.Zika infection can be prevented by using mosquito repellents,mosquito nets,cooling rooms by air conditions and wearing full sleeves or permethrin treated clothes.The current outbreak of Zika has not only affected the health care but also caused great economic loss.Estimated loss in Latin America and Caribbean is US$3.5 billion.United Nation's sustainable development goal 3.d stresses the strengthening of early warning,risk reduction and management of national and global health risks.The world will keep on facing new challenges in the form of Ebola or Zika;there is strong need to prepare ourselves for any disease outbreak.

Hepatitis elimination by 2030: Progress and challenges

Globally, over 300 million people are living with viral he-patitis with approximately 1.3 million deaths per year. In 2016, World Health Assembly adopted the Global Health Sector Strategy on viral hepatitis to eliminate hepatitis by 2030. Different World Health Organization member countries are working on hepatitis control strategies to achieve hepatitis elimination. So far, only 12 countries are on track to achieve hepatitis elimination targets. The aim of the study was to give an update about the progress and challenges to achieving hepatitis elimination by 2030. According to the latest data, 87% of infants had received the three doses of hepatitis B virus （HBV） vaccination in the frst year of their life and 46% of infants had received a timely birth dose of HBV vaccination.There is a strong need to improve blood and injection safety. Rates of hepatitis B and C diagnosis are very low and only 11% of hepatitis B and C cases are diagnosed. There is a dire need to speed up hepatitis diagnosis and find the missing millions of people living with viral hepatitis. Up to 2016, only 3 million hepatitis C cases have been treated. Pricing of hepatitis C virus drugs is also reduced in many countries. The major hurdle to ach-ieve hepatitis elimination is lack of finances to support hepatitis programs. None of the major global donors are committed to invest in the fght against hepatitis. It will be very diffcult for the low and middle-income countries to fund their hepatitis control program. Hepatitis elimination needs strong fnancial and political commitment, support from civil societies, and support from pharmaceutical and medical companies around the globe.

Clinical outcomes of moderate to severe COVID-19 patients receiving invasive vs. non-invasive ventilation

Objective:To evaluate the in-hospital outcome of moderate to severe COVID-19 patients admitted in High Dependency Unit(HDU)in relation to invasive vs.non-invasive mode of ventilation.Methods:In this study,the patients required either non-invasive[oxygen≤10 L/min or>10 L/min through mask or nasal prongs,rebreather masks and bilevel positive airway pressure(BiPAP)]or invasive ventilation.For analysis of 30-day in hospital mortality in relation to use of different modes of oxygen,Kaplan Meier and log rank analyses were used.In the end,independent predictors of survival were determined by Cox regression analysis.Results:Invasive ventilation was required by 15.1%patients while 84.9%patients needed non-invasive ventilation.Patients with evidence of thromboembolism,high inflammatory markers and hypoxemia mainly required invasive ventilation.The 30-day in hospital mortality was 72.7%for the invasive group and 12.9%for the non-invasive group(1.8%oxygen<10 L/min,0.9%oxygen>10 L/min,3.6%rebreather mask and 4.5%BiPAP).The median time from hospital admission to outcome was 7 days for the invasive group and 18 days for the non-invasive group(P<0.05).Age,presence of co-morbidities,number of days requiring oxygen,rebreather,BiPAP and invasive ventilation were independent predictors of outcome.Conclusions:Invasive mechanical ventilation is associated with adverse outcomes possibly due to ventilator associated lung injury.Thus,protective non-invasive ventilation remains the necessary and safe treatment for severely hypoxic COVID-19 patients.

眼血流的变化对青光眼病情进展的影响（英文）

青光眼是由多种因素引起的神经退行性疾病,眼压过高会损害视神经而导致永久性视力丧失。虽然青光眼的基本病理生理机制尚未确定,但眼组织如视神经,视网膜,脉络膜以及虹膜的血流改变是青光眼发病的重要危险因素。由于不同因素所引发的视神经损害的有限认知,测量方法和治疗方面缺乏,人们对青光眼的理解存在障碍。尽管研究人员在不断地积累证据,力证眼血流的变化在青光眼发病机制中起着重要的作用,但大部分情况下,对于眼血流的变化和青光眼的患病风险之间的关系,他们都持有多样甚至矛盾的结论。本文中,我们回顾了青光眼的不同方面以及眼血流在疾病发展中的影响。

Hepatitis C eradication: A long way to go

Hepatitis C virus(HCV) is a major global health problem with high morbidity and mortality. About 185 million people are living with HCV,of which 80% are living in low and middle income countries. With the development of new highly effective treatments for HCV,it is considered that the eradication of HCV may only be one step away. The major problem with new treatment options is its high price. The price of sofosbuvir-based treatment for one patient in the United States is US$85000-110000,while the actual production cost of a 12 wk direct-acting antiviral regimen is less than US$250. Another major hindrance in HCV eradication is the lack of quality management of blood transfusion screens. Due to the lack of HCV screening,75% of people in the United States with HCV infection are unaware of their positive HCV status. The control of massive HCV pandemic will require a significant financial investment,political will,and support from medical,pharmaceutical,and civil organizations around the globe.

Ebola in West Africa:an international medical emergency

West Africa is facing the worst Ebola outbreak with 3685 cases and 1841 deaths reported from Liberia,Cuinea,Senegal,Sierra Leona and Nigeria.There is no vaccine or direct treatment available to treat the patients with Ebola.World Health Organization(WHO) has approved the use of experimental drugs for Ebola patients.Health workers are at high risk.The governments and WHO are responsible to provide necessary protective equipment to health workers dealing with Ebola.There is a strong need to identify the invisible chains of virus transmission.World Bank pledges $200 million to fight against Ebola,while WHO said $430 million are needed to control the Ebola outbreak.Ebola can be contained by early detection and isolation of case,contact tracing,monitoring of contacts and adaptation of rigorous procedures for virus control.

Ledipasvir and sofosbuvir:Interferon free therapy for hepatitis C virus genotype 1 infection

Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited response with a number of side effects. Recently, results for phase III trials of ledipasvir and sofosbuvir combination therapy have been announced. In treatmentnave patients, 12 wk of therapy with ledipasvir and sofosbuvir showed a sustained virological response(SVR) rate of 99%. In treatment experienced patients, 12-24 wk of therapy with ledipasvir and sofosbuvir in the absence or presence of ribavirin showed an SVR rate of 94%-99%. In cirrhotic patients the rate of SVR was 86% and 99% for 12 and 24 wk of therapy, respectively. The ledipasvir and sofosbuvir therapy showed very good results in different subgroups of patients regardless of patient's race, alanine aminotransferase levels, sex and host genetic factors. The combination therapy was well tolerated with no emergence of resistant mutants. The most common adverse effects were nausea, headache and fatigue. With the availability of interferon free therapy with minimal adverse effects, it will be easy to decrease the future morbidity and mortality caused by HCV infection.

Prediction of promiscuous T-cell epitopes in the Zika virus polyprotein:An in silico approach

Objective:To predict immunogenic promiscuous T-cell epitopes from the polyprotein of the Zika virus using a range of bioinformatics tools.To date,no epitope data are available for the Zika virus in the IEDB database.Methods:We retrieved nearly 54 full length polyprotein sequences of the Zika virus from the NCBI database belonging to different outbreaks.A consensus sequence was then used to predict the promiscuous T cell epitopes that bind MHC 1 and MHC II alleles using Propred1 and Propred immunoinformatic algorithms respectively.The antigencity predicted score was also calculated for each predicted epitope using the Vaxi Jen 2.0 tool.Results:By using Pro Pred1,23 antigenic epitopes for HLA class I and 48 antigenic epitopes for HLA class II were predicted from the consensus polyprotein sequence of Zika virus.The greatest number of MHC class I binding epitopes were projected within the NS5(21%),followed by Envelope(17%).For MHC class II,greatest number of predicted epitopes were in NS5(19%) followed by the Envelope,NS1 and NS2(17% each).A variety of epitopes with good binding affinity,promiscuity and antigenicity were predicted for both the HLA classes.Conclusion:The predicted conserved promiscuous T-cell epitopes examined in this study were reported for the first time and will contribute to the imminent design of Zika virus vaccine candidates,which will be able to induce a broad range of immune responses in a heterogeneous HLA population.However,our results can be verified and employed in future efficacious vaccine formulations only after successful experimental studies.

Effect of interferon plus ribavirin therapy on hepatitis C virus genotype 3 patients from Pakistan:Treatment response,side effects and future prospective

More than 10 million people are suffering from hepatitis C virus(HCV) in Pakistan,The available treatment option is a combination of interferon and ribavirin.Treatment response is linked with several factors and also induces a number of side effects.We searched in Pubmed.Pak Medi Net and Coogle Scholar for the articles presenting the effect of interferon plus ribavirin therapy on HCV patients from Pakistan,their side effects and future prospects.The major prevalent HCV genotype in Pakistan is 3.Conventional interferon alpha plus ribavirin showed sustained virological response of 54%-64%while pegylaled interferon alpha plus ribavirin showed sustained virological response of 58%-75%.IL-28 B CC genotype is linked with better sustained virological response.Studies on patients with HCV genotype 3 infections showed no correlation between treatment response and interferon sensitivity determining region mutations.Interferon therapy is linked with a number of side effects like thyroid dysfuncton.hactnatological disorders,weight loss,gastrointestinal tract side effects and neuropsychiatric side effects.Unusual side effects of clubbing of fingers and seizures were also observed in a couple of patients.Interferon alpha plus ribavirin therapy showed better response rate in HCV genotype 3 patients from Pakistan with number of side effects.A couple of interferon free therapies are light of hope for the patients living with HCV.

Prediction of promiscuous T cell epitopes in RNA dependent RNA polymerase of Chikungunya virus

Objective: To explore RNA dependent RNA polymerase of Chikungunya virus(CHIKV) and develop T cell based epitopes with high antigenicity and good binding affinity for the human leukocyte antigen(HLA) classes as targets for epitopes based CHIKV vaccine. Methods: In this study we downloaded 371 non-structural protein 4 protein sequences of CHIKV belonging to different regions of the world from the US National Institute of Allergy and Infectious Diseases(NIAID) virus pathogen resource database. All the sequences were aligned by using CLUSTALW software and a consensus sequence was developed by using Uni Pro U Gene Software version 1.2.1. PropredⅠand Propred software were used to predict HLAⅠ and HLAⅡ binding promiscuous epitopes from the consensus sequence of non-structural protein 4 protein. The predicted epitopes were analyzed to determine their antigenicity through Vaxijen server version 2.0. All the HLAⅠ binding epitopes were scanned to determine their immunogenic potential through the Immune Epitope Database(IEDB). All the predicted epitopes of our study were fed to IEDB database to determine whether they had been tested earlier. Results: Twenty two HLA class Ⅱ epitopes and eight HLA classⅠepitopes were predicted. The promiscuous epitopes WMNMEVKII at position 486–494 and VRRLNAVLL at 331–339 were found to bind with 37 and 36 of the 51 HLA class Ⅱ alleles respectively. Epitope MANRSRYQS at position 58–66 and epitopes YQSRKVENM at positions 64–72 were predicted to bind with 12 and 9 HLAⅠI alleles with antigenicity scores of 0.754 9 and 1.013 0 respectively. Epitope YSPPINVRL was predicted to bind 18 HLAⅠ alleles and its antigenicity score was 1.425 9 and immunogenicity score was 0.173 83. This epitope is very useful in the preparation of a universal vaccine against CHIKV infection. Conclusions: Epitopes reported in this study showed promiscuity, antigenicity as well as good binding affinity for the HLA classes. These epitopes will provide the baseline for development of efficacious vaccine for CHIKV.

Progress on global hepatitis elimination targets

In 2016,the World Health Assembly adopted a Global Health Sector Strategy on viral hepatitis,with targets set for the years 2020 and 2030 to achieve hepatitis elimination.The main target of hepatitis elimination strategy is to reduce the incidence of hepatitis B virus(HBV)and hepatitis C virus(HCV)by 90%and mortality by 65%in 2030.In last 5 years,the number of people receiving HCV treatment has increased from 1 million to 9.4 million;however,this number is far from the 2030 target of 40 million people receiving HCV treatment.HBV and HCV incidence rates are down from 1.4 million to 1.1 million annual deaths but this is far from the 2030 target of<0.5 million deaths.The coronavirus disease 2019 pandemic has severely affected the efforts in the fight against hepatitis.No major donor has committed to investing in the fight against hepatitis.Time is running out.There is a need to speed up efforts in the fight against hepatitis to achieve hepatitis elimination by 2030.

Pakistan needs to speed up its human immunodeficiency virus control strategy to achieve targets in fast-track acquired immune deficiency syndrome response

In last fifteen years remarkable success in the fight against human immunodeficiency virus(HIV) is achieved globally. The number of HIV infections has decreased and the number of people on antiretroviral therapy is increased. This all is possible by strong political commitments and heavy investments in the fight against HIV. Pakistan is among few Asian countries in which HIV cases are increasing year by year since 1990. There are 94000 cases of HIV in Pakistan and only 14000 are registered with government. The main source of HIV infection in Pakistan is the use of contaminated injection equipment among people who inject drugs(PWID). The overall prevalence of HIV among PWID in Pakistan is 27.2%. There are five cities in Pakistan in which HIV prevalence is above 40% in PWIDs. In June 2016, United Nations political declaration on acquired immune deficiency syndrome(AIDS) provided a global mandate to fast-track the AIDS response over the next five years to achieve the targets in Sustainable Development Goals. To achieve the targets in fasttrack AIDS response, the global leaders showed strong commitments to invest $ 26 billion per year by 2020. Pakistan needs to speed up its HIV control program. There is a dire need to locate all HIV positive people and enroll them in the treatment program. Pakistan also needs to calculate exact number of people living with HIV, increase HIV treatment centers and increase HIV awareness. Recently, Global Fund invested handsome money in the fight against HIV. Let's hope the country will have effective HIV control strategy to achieve the HIV elimination target by 2030.

Identification of novel silent HIV propagation routes in Pakistan

Human immunodeficiency virus(HIV) is rapidly increasing in both high risk groups and the general population.In this study, silent routes of propagation in teenaged Pakistanis are discussed. In order to promote sexual activity in youths, regular clients write contact details of sex workers on the doors of public washrooms. HIV prevalence is much higher among Hijra sex workers.Hijra sex workers have apparently stepped into the profession of begging at public places, where they earn money by both begging and distributing visiting cards offering unsafe sex. In many educational institutes, sex education is lacking or absent; if delivered via teachers,government agencies and nongovernmental organizations this could prevent a future epidemic of sexually transmitted infections in Pakistan.

Predictors of response to antiviral therapy in patients with chronic hepatitis C from Pakistani population

Background Hepatitis C virus （HCV） constitutes a major public health issue around the world, especially in developing countries like Pakistan. In this study, we assessed outcome of interferon （INF） treatment in chronic hepatitis C patients categorized by gender, age, and viral load.Methods In this study, 750 HCV positive patients with genotype 3 were selected, out of which 616 completed the entire treatment. Their personal history, pro-treatment HCV RNA and serum alanine transaminase （ALT） was quantified.Patients were treated with combination therapy of INF-α 2b three million units （thrice a week） plus ribavirin （1000-1200mg per day） for 24 weeks. After 24 weeks their HCV RNA and serum ALT level was quantified.Results Out of the 616 patients, 391 （63.5%） responded to therapeutic regimen （INF-α 2b plus ribavirin）. Among the responders, 27.1% were men and 36.4% were women. Best treatment response was observed in patients having Iow viral load ＜8×105 IU/ml and age ≤40 years than patients having Iow viral load and age ＞40 years （73.2% vs. 60.3%, P=0.05）.Conclusions Better response to IFN-α 2b plus ribavirin was observed in patients with lower viral RNA and younger age.It suggests that all patients considered for treatment should have quantification of serum HCV RNA level. The result can be used to counsel patients on the likelihood of response and may influence the patient＇s decision on treatment.

Elimination of hepatitis from Pakistan by 2030: is it possible?

Globally 71 million people are living with hepatitis C virus (HCV) out which 7.1 million (10%) are present in Pakistan. Genotype 3 is the most common HCV type in the country. World Health Organization is working with health authorities in different countries for effective control of HCV, to reduce its incidence by 90% and to reduce hepatitis related mortality by 65% by the year 2030. There are several challenges that hinder elimination of HCV from Pakistan including the lack of patient awareness about the causes and transmission of disease, lack of affordability for investigations and drug treatment and lack of experienced healthcare professionals. Other major contributors to achieve HCV elimination are lack of effective drugs and delayed regulatory approvals combined with compromised monitoring by health authorities and lack of robust epidemiological data. Efforts are needed to educate the public about the modes of transmission and prevention of HCV infection, and massively upscale screening along with treatment. There is a dire need to prevent more than 200,000 new infections that occur each year in Pakistan. Given the scale of the problem, it is very unlikely that the government alone can handle it.