Casirivimab and Imdevimab Treatment in Seropositive, Hospitalized COVID-19 Patients With Non-neutralizing or Borderline Neutralizing Antibodies

We conducted a post-hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (nAbs) against SARS-CoV-2 at baseline from a phase 1/2/3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized COVID-19 patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline nAb status. At baseline, 20.6% (178/864) of seropositive patients were negative/borderline for nAbs. CAS+IMD reduced viral load in patients who were negative/borderline for nAbs versus placebo, but not in patients who were positive for nAbs. We observed a trend in reduction of the proportion of patients who died or required mechanical ventilation (MV), as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo in patients who were negative/borderline for nAbs. In those who were negative/borderline for nAbs, the proportions who died/needed MV from days 1-29 were 19.1% and 10.9%, and the proportions of patients who died from days 1-29 were 16.2% and 9.1%, in the placebo and CAS+IMD combined dose groups, respectively. No measurable harm or benefit in death/MV or all-cause mortality was observed in patients who were positive for nAbs. In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or MV, and all-cause mortality in seropositive patients who were negative/borderline for nAbs. ImportanceThe clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2 seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19, who have antibodies against SARS-CoV-2, who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post-hoc analysis demonstrates that there is a subset of hospitalized, seropositive patients with inadequate SARS-CoV-2 nAbs (ie, those who were negative or borderline for nAbs) who may still benefit from CAS+IMD treatment if infected with a susceptible variant. Therefore, utilizing seronegativity status alone to guide treatment decisions for patients with COVID-19 may fail to identify seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies which retain activity against circulating strains, depending on how effectively their endogenous antibodies neutralize SARS-CoV-2.

Effect of Green Space Environment on Air Pollutants PM2.5, PM10, CO, O3, and Incidence and Mortality of SARS-CoV-2 in Highly Green and Less-Green Countries.

Worldwide, over half of the global population is living in urban areas. The metropolitan areas are highly populated and environmentally non-green regions on the planet. In green space regions, plants, grass, and green vegetation prevent soil erosion, absorb air pollutants, provide fresh and clean air, and minimize the burden of diseases. Presently, the entire world is facing a turmoil situation due to the COVID-19 pandemic. This study investigates the effect of the green space environment on air pollutants particulate matter PM2.5, PM10, carbon monoxide (CO), ozone (O3), incidence and mortality of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in environmentally highly green and less-green countries. We randomly selected 17 countries based on the Environmental Performance Index (EPI) data. The 60% of the EPI score is based on seven categories: "biodiversity and habitat, ecosystem, fisheries, climate change, pollution emissions, agriculture, and water resources". However, 40% of the score is based on four categories: "air quality, sanitation and drinking water, heavy metals, and waste management". The air pollutants and SARS-CoV-2 cases and deaths were recorded from 25 January 2020, to 11 July 2021. The air pollutants "PM2.5, PM10, CO, and O3" were recorded from the metrological websites, Air Quality Index-AQI, 2021. The COVID-19 daily cases and deaths were obtained from the World Health Organization. The result reveals that air pollutants mean values for PM2.5 110.73 ± 1.09 vs. 31.35 ± 0.29; PM10 80.43 ± 1.11 vs. 17.78 ± 0.15; CO 7.92 ± 0.14 vs. 2.35 ± 0.03 were significantly decreased (p < 0.0001) in environmentally highly green space countries compared to less-green countries. Moreover, SARS-CoV-2 cases 15,713.61 ± 702.42 vs. 3445.59 ± 108.09; and deaths 297.56 ± 11.27 vs. 72.54 ± 2.61 were also significantly decreased in highly green countries compared to less-green countries. The green environment positively impacts human wellbeing. The policymakers must implement policies to keep the living areas, surroundings, towns, and cities clean and green to minimize air pollution and combat the present pandemic of COVID-19.

Repeat Subcutaneous Administration of REGEN-COV(R) in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19

BackgroundData show that a single dose of casirivimab and imdevimab (REGEN-COV(R)) is effective in treating hospitalized individuals and outpatients with COVID-19 and in post-exposure prophylaxis. We present results from a phase 1, double-blind, placebo-controlled trial evaluating the safety, tolerability, and efficacy of repeat monthly doses of subcutaneous (SC) REGEN-COV in uninfected adult volunteers who were healthy or had chronic stable medical conditions. MethodsSubjects were randomized (3:1) to SC REGEN-COV 1200 mg or placebo dosed every 4 weeks for up to 6 doses. The primary and secondary endpoints evaluated the safety, pharmacokinetics, and immunogenicity of multiple-dose administration of REGEN-COV. Efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. ResultsIn total, 969 subjects were treated. Repeat monthly dosing of SC REGEN-COV led to a 92.4% relative risk reduction in clinically-defined COVID-19 compared to placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio: 0.07 [95% CI, 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies was low (<5% subjects). No grade [≥]3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. A slightly higher percentage of subjects reported TEAEs with REGEN-COV (54.9%) than placebo (48.3%), due to ISRs (all grade 1-2). Serious adverse events were rare and occurred at similar percentages in the REGEN-COV and placebo groups. No deaths were reported in the 6-month treatment period. ConclusionsRepeated monthly administration of 1200 mg SC REGEN-COV was well-tolerated with low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence. (ClinicalTrials.gov identifier, NCT04519437)

Phase 2 dose-ranging study of the virologic efficacy and safety of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting

BackgroundThe monoclonal antibody combination casirivimab and imdevimab (REGEN-COV(R)) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose [≥]1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. MethodsThis is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline. FindingsAll REGEN-COV treatments showed significant (p<0{middle dot}001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from -0{middle dot}56 to -0{middle dot}71 log10 copies/mL. Each REGEN-COV treatment showed significant (p<0{middle dot}001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade [≥]2 infusion related/hypersensitivity reactions, grade [≥]3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported. InterpretationIn asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses. FundingRegeneron Pharmaceuticals, Inc. and Hoffman-La Roche RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSEarly phase 1/2 data in coronavirus disease 2019 (COVID-19) outpatients (NCT04425629) found that the REGEN-COV(R) antibody combination, casirivimab and imdevimab, administered 1:1 as a single intravenous (IV) dose of 2400 mg or 8000 mg significantly reduced viral load over the first week compared to placebo. Enhanced viral clearance was more pronounced in patients who were seronegative for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or who had high viral load at baseline. The phase 3 portion of this outpatient treatment study subsequently evaluated 1200 mg IV and 2400 mg IV doses, demonstrating consistent virologic efficacy, further demonstrating that REGEN-COV treatment reduced risk of COVID-19-related hospitalisation or all-cause death, and shortened time to symptom resolution. Virologic clearance was similar among those treated with any of the three doses (8000 mg, 2400 mg, or 1200 mg); therefore, maximal virologic efficacy may have been achieved at the 1200 mg dose in this treatment setting. These results warranted investigation of lower dose regimens. Added value of this studyThe present dose-ranging study evaluated whether a lower dose regimen could demonstrate virologic efficacy similar to that observed with 1200 mg IV and 2400 mg IV doses in outpatient treatment study. Exploration of a wider dose range will provide further characterisation of the clinical effects of REGEN-COV. Moreover, identifying a lower efficacious dose could bolster the ability to provide an adequate therapeutic supply of REGEN-COV in the setting of a global pandemic. A 1200 mg subcutaneous (SC) dose of REGEN-COV also prevented COVID-19 in household contacts of SARS-CoV-2-infected individuals (NCT04452318). The availability of a SC regimen could improve access for patients who have confirmed SARS-CoV-2 infection but for who IV infusion is not feasible. Implications of all the available evidenceDespite the growing number of therapeutics with authorisation or approval for the treatment and/or prevention of COVID-19, there remains a significant global need for effective COVID-19 therapies. Additional therapeutics and dosing regimens will be required to meet demand and to meet the needs of specific patient populations. Lower IV doses of REGEN-COV, and the option of SC administration, should increase accessibility for patients. This increased availability needs to be weighed against several unanswered questions, including 1) whether the correlation between decreased viral load in the nasopharynx and improvement in clinical outcome holds at lower doses of REGEN-COV, and 2) whether the reduced drug exposure margins are sufficient to prevent viral escape and emergence of variants of concern.

REGEN-COV for the Treatment of Hospitalized Patients with Covid-19

BackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients. MethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2-74.0; nominal P = .0032). No safety concerns were noted. ConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.

Subcutaneous REGEN-COV Antibody Combination for Covid-19 Prevention

BackgroundCasirivimab and imdevimab (REGEN-COV) markedly reduces risk of hospitalization or death in high-risk individuals with Covid-19. Here we explore the possibility that subcutaneous REGEN-COV prevents SARS-CoV-2 infection and subsequent Covid-19 in individuals at high risk of contracting SARS-CoV-2 by close exposure in a household with a documented SARS-CoV-2-infected individual. MethodsIndividuals [≥]12 years were enrolled within 96 hours of a household contact being diagnosed with SARS-CoV-2 and randomized 1:1 to receive 1200 mg REGEN-COV or placebo via subcutaneous injection. The primary efficacy endpoint was the proportion of participants without evidence of infection (SARS-CoV-2 RT-qPCR- negative) or prior immunity (seronegative) who subsequently developed symptomatic SARS-CoV-2 infection during a 28-day efficacy assessment period. ResultsSubcutaneous REGEN-COV significantly prevented symptomatic SARS-CoV-2 infection compared with placebo (81.4% risk reduction; 11/753 [1.5%] vs. 59/752 [7.8%], respectively; P<0.0001), with 92.6% risk reduction after the first week (2/753 [0.3%] vs. 27/752 [3.6%], respectively). REGEN-COV also prevented overall infections, either symptomatic or asymptomatic (66.4% risk reduction). Among infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV vs. placebo (1.2 vs. 3.2 weeks, respectively), and the duration of time with high viral load (>104 copies/mL) was lower (0.4 vs. 1.3 weeks, respectively). REGEN-COV was generally well tolerated. ConclusionsAdministration of subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in uninfected household contacts of infected individuals. Among individuals who became infected, REGEN-COV reduced the duration of symptomatic disease, decreased maximal viral load, and reduced the duration of detectable virus. (ClinicalTrials.gov number, NCT04452318.)

Subcutaneous REGEN-COV Antibody Combination in Early SARS-CoV-2 Infection

ImportanceEasy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage. ObjectiveEvaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19. DesignRandomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2-infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR-positive at baseline were included in the analysis reported here. SettingMulticenter trial conducted at 112 sites in the United States, Romania, and Moldova. ParticipantsAsymptomatic individuals [≥]12 years of age were eligible if identified within 96 hours of collection of the index cases positive SARS-CoV-2 test sample. InterventionsA total of 314 asymptomatic, SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156). Main Outcome(s) and Measure(s)The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Safety was assessed in all treated participants. ResultsSubcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P=.0380). REGEN-COV reduced the overall population burden of high-viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P=.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19-related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had [≥]1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19. Conclusions and RelevanceSubcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated. Trial RegistrationClinicalTrials.gov Identifier, NCT04452318 KEY POINTSO_ST_ABSQuestionC_ST_ABSCan treatment with the anti-SARS-CoV-2 antibody combination REGEN-COV prevent COVID-19 and reduce viral load when given to recently exposed and asymptomatic individuals? FindingsIn this randomized, double-blind, phase 3 trial, subcutaneously administered REGEN-COV 1200 mg significantly reduced progression of asymptomatic SARS-CoV-2 infection to symptomatic infection (ie, COVID-19) by 31.5% compared with placebo. REGEN-COV also reduced the overall population burden of high viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010). MeaningIn the current pandemic, utilization of subcutaneous REGEN-COV prevents progression of early asymptomatic infection to COVID-19 and reduces viral carriage.

REGEN-COV Antibody Cocktail in Outpatients with Covid-19

BackgroundContinued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV(R) (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo. MethodsThis final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with [≥]1 COVID-19-related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2-positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients. ResultsData from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; P<.0001). This reduction was - 0.73 (P<.0001) and -0.36 (P=.0003) log10 copies/mL in serum antibody-negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with [≥]1 COVID-19-related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with [≥]1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups. ConclusionsIn COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19-related MAVs.

REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients

BackgroundREGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern. MethodsThe phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients. ResultsBoth REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200mg (1.1%) and 2400mg (1.3%) groups and grade [≥]2 infusion-related reactions were infrequent (<0.3% in all groups). ConclusionsTreatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

A Randomized Placebo-Controlled Trial of Sarilumab in Hospitalized Patients with Covid-19

BACKGROUNDSarilumab (anti-interleukin-6 receptor- monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODSWe performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with [≥]1-point improvement in clinical status from baseline to day 22. RESULTSFour-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with [≥]1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD -5.5%; 95% CI, -20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSIONIn hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit. (ClinicalTrials.gov number, NCT04315298)

Detection of malicious consumer interest packet with dynamic threshold values.

As a promising next-generation network architecture, named data networking (NDN) supports name-based routing and in-network caching to retrieve content in an efficient, fast, and reliable manner. Most of the studies on NDN have proposed innovative and efficient caching mechanisms and retrieval of content via efficient routing. However, very few studies have targeted addressing the vulnerabilities in NDN architecture, which a malicious node can exploit to perform a content poisoning attack (CPA). This potentially results in polluting the in-network caches, the routing of content, and consequently isolates the legitimate content in the network. In the past, several efforts have been made to propose the mitigation strategies for the content poisoning attack, but to the best of our knowledge, no specific work has been done to address an emerging attack-surface in NDN, which we call an interest flooding attack. Handling this attack-surface can potentially make content poisoning attack mitigation schemes more effective, secure, and robust. Hence, in this article, we propose the addition of a security mechanism in the CPA mitigation scheme that is, Name-Key Based Forwarding and Multipath Forwarding Based Inband Probe, in which we block the malicious face of compromised consumers by monitoring the Cache-Miss Ratio values and the Queue Capacity at the Edge Routers. The malicious face is blocked when the cache-miss ratio hits the threshold value, which is adjusted dynamically through monitoring the cache-miss ratio and queue capacity values. The experimental results show that we are successful in mitigating the vulnerability of the CPA mitigation scheme by detecting and blocking the flooding interface, at the cost of very little verification overhead at the NDN Routers.

Impact of lockdown on COVID-19 prevalence and mortality during 2020 pandemic: observational analysis of 27 countries.

BACKGROUND: This study aimed to assess the impact of 15 days before, 15 days during, and 15 days after the lockdown on the trends in the prevalence and mortality in 27 countries during COVID-19 pandemic. METHODS: Twenty-seven countries were randomly selected from the different continents. The information on the trends in the prevalence and mortality due to COVID-19 pandemic in 27 countries was obtained from World Health Organization and lockdown data were obtained from concerned countries and their ministries. The impact of lockdown for 15 days before, 15 days during, and 15 days after the lockdown on the prevalence and mortality due to the COVID-19 pandemic in 27 countries was analyzed. RESULTS: The findings showed that 15 days after the lockdown there was a trend toward a decline, but no significant decline in the mean prevalence and mean mortality rate due to the COVID-19 pandemic compared to 15 days before, and 15 days during the lockdown in 27 countries. The mean growth factor for number of cases was 1.18 and for mortality rate was 1.16. CONCLUSIONS: The findings indicate that 15 days after the lockdown, daily cases of COVID-19 and the growth factor of the disease showed a declined trend, but there was no significant decline in the prevalence and mortality.

Biological and epidemiological trends in the prevalence and mortality due to outbreaks of novel coronavirus COVID-19.

The novel coronavirus (Covid-19) infection outbreak has posed a major threat to the international health system and economy. This study is aimed at investigating the biological and epidemiological trends in the prevalence and mortality due to outbreaks of novel coronavirus (COVID-19) infections. The data on the global outbreak of COVID-19, were obtained from World Health Organization (WHO), Worldometer, Centers for Disease Control and Prevention (CDC), and research institutes. The information was also recorded from research documents published in global scientific journals indexed in Pub Med and Institute of Scientific Information (ISI) Web of Science on the trends in the prevalence and mortality due to COVID-19 infection outbreaks. The results show rising trends in the transmission, prevalence and mortality rate due to coronavirus COVID-19. During the period of December 29, 2019 through March 31, 2020, it has infected 750,890 people worldwide, resulting in 36,405 deaths with a mortality rate of 4.84%. The infections were more frequent among male gender over 60 years of age. The mean growth rate index for total number of cases from January 23 to March 31, 2020 was 1.20 and growth rate index for mortality rate was 1.12. There was a positive association between the prevalence and mortality rate (R2 = 0.996). The novel coronavirus COVID-19 is highly contagious and has affected a large number of people worldwide. It is still spreading with mutable prevalence and mortality outbreak trends. The global health officials have taken priority measures to prevent further outbreaks of this emerging pathogen across the globe. However, the rising number of cases and mortality risk estimates are demonstrating that enhanced public health mediations, good hygienic conditions, social distancing, and movement limitations may control the COVID-19 epidemics.

Progress and prospects of medical education research in Asian Countries.

BACKGROUND AND OBJECTIVES: Medical education has a profound impact on health care system. Progress in achieving medical education research goals varies over time and across countries. This study aimed to investigate the medical education research ambience in Asia during the period 1965-2015. METHODS: We investigated the bibliometric indicators of 49 Asian states in medical education research from 1965-2015. The data about Asian countries, their per capita GDP, expenditure on R&D, universities and indexed scientific journals were collected. We recorded medical education related research documents published in Institute of Scientific Information (ISI) Web of Science, Thomson Reuters during the period 1965-2015. RESULTS: Asian countries collectively published 12721799 research articles, among them 40628 (0.31%) publications were in medical education. China contributed total of 3351565 articles among which 5414 (0.16%) research articles were in medical education; India added 1328725 papers with 4563 (0.34%) in medical education; Japan produced 3080257 papers with 4199 (0.13%) in medical education; Israel 561531 with 3848 (0.68%) in medical education; and lastly, Georgia contributed a total of 296532 research articles with 2565 (0.86%) in medical education. CONCLUSIONS: In Asia, the top five countries in medical education research are China, Georgia, Israel, Japan and India. The countries at low ranking are Yemen, Palestine, Myanmar, Kazakhstan, Syria and Armenia. In Asian states, the overall performance in medical science research needs policies to enhance its impact globally. Medical universities should offer research programs for learning and understanding the challengeable issues in medical education research.

Effect of wearing cotton towel Ihram and plain Ihram on lung function among Hajj Pilgrims.

OBJECTIVES: Hajj is the world's largest gathering to Makkah, Saudi Arabia. Wearing cotton made Ihram is a basic and an essential component of Hajj. The aim of this study was to investigate the lung functions among Hajj pilgrims who were wearing cotton towel ihram (ihram with fibers) compared to those who were wearing plain cotton ihram (ihram without fibers). METHODS: Ninety male, non-smoker, Hajj pilgrim volunteers with age ranged 20-60 years were selected. Forty five of them wore cotton towel ihram and 45 wore plain ihram. A day before leaving for Hajj and wearing ihram (6th Dhu-al-Hijjah) lung function base line parameters of Hajj pilgrims were determined. Hajj Pilgrims continuously wear ihram from 7-10th Dhu-al-Hijjah. In the afternoon of 10th Dhu-al-Hijjah, after removal of ihram, all parameters were repeated and at the completion of Hajj when all pilgrims return to their homes at Riyadh, all parameters were recorded again. RESULTS: Before wearing Ihram, anthropometric and lung function baseline parameters were recorded, no significant difference was found between the study population. After wearing Ihram on the 7th Dhu-al-Hijjah and its removal on the 10th Dhu-al-Hijjah significant decline in the lung function test parameters was observed among Hajj pilgrims who were wearing cotton towel ihram. Forced Vital Capacity (FVC) 4.30±1.18 vs. 5.03±1.41 (p=0.01); Forced Expiratory Flow 25% (FEF-25%) 4.39±1.94 vs. 5.69±2.84 (p=0.03); Forced Expiratory Flow-50% (FEF-50%) 2.93±1.65 vs. 4.07±2.08 (p=0.01); Forced Expiratory Flow-75% (FEF-75%) 1.02±0.70 vs. 1.66±0.94 (p=0.002) compared to those who were wearing plain ihram. CONCLUSIONS: Lung function test parameters were decreased among the Hajj pilgrims who were wearing cotton towel ihram compared to those who were wearing plain cotton ihram. The pattern of impairment of lung function shows an obstructive peripheral airway lung involvement. It is suggested to conduct further large sample size studies to confirm the present study observations and reach at better conclusions.

Effectiveness of Cardiac Rehabilitation on Health-related Quality of Life in Patients with Myocardial Infarction in Pakistan.

OBJECTIVE: To find out the effectiveness of cardiac rehabilitation in patients with myocardial infarction in Pakistan. STUDY DESIGN: Randomised controlled trial. PLACE AND DURATION OF STUDY: Cardiac Rehabilitation Unit, Lady Reading Hospital, Peshawar, Pakistan, from July to December 2016. METHODOLOGY: Patients suffering first myocardial infarction (MI) were randomly allocated to usual care or cardiac rehabilitation in a 1:1 ratio. Cardiac rehabilitation comprised two phases: 1-2 weeks during hospital stay followed by 6-7 weeks outpatient structured exercise programme. Two generic health related quality of life (HRQoL) outcomes (General Health Questionnaire (GHQ) and Self-Rated Health (SRH)) and one post-MI specific tool (MacNew QLMI) were measured at baseline and at 8 weeks follow-up among both groups. Lower SRH and GHQ scores and higher MacNew QLMI scores indicate better health status. Data were analysed using STATA 14. RESULTS: Out of 206 participants, 195 (94.6%) were analysed at the end of trial. The mean age was 53 +8.3 years. In the cardiac rehabilitation group, the mean SRH score changed from 3.97 +0.9 at baseline to 2.36 +0.8 at follow-up (p<0.001). The mean GHQ of the cardiac rehabilitation group was 21.26 +5.5 at baseline and it decreased significantly to 7.43 +4.2 at follow-up (p<0.001). The MacNew QLMI of the cardiac rehabilitation group increased from 3.61 +1.07 to 5.62 +0.5 (p<0.001). The multivariate regression of all three HRQoL measures confirmed better HRQoL following cardiac rehabilitation compared with usual care (all p<0.001). CONCLUSION: Cardiac rehabilitation following MI was effective in terms of improving HRQoL and can be implement in Pakistan as it produced significant improvements in HRQoL.

Comparison of Subjective Responses to Oral and Intravenous Alcohol Administration Under Similar Systemic Exposures.

BACKGROUND: Individuals perceive the effects of alcohol differently, and the variation is commonly used in research assessing the risk for developing an alcohol use disorder. Such research is supported by both oral and intravenous (IV) alcohol administration techniques, and any differences attributable to the route employed should be understood. Our objective was to test whether an individual's subjective responses to alcohol are similar when the breath alcohol concentration (BrAC) trajectory resulting from oral administration is matched by IV administration. METHODS: We conducted a 2-session, within-subject study in 44 young adult, healthy, nondependent drinkers (22 females and 22 males). In the first session, subjects ingested a dose of alcohol which was individually calculated, on the basis of total body water, to yield a peak BrAC near 80 mg/dl, and the resulting BrAC trajectory was recorded. A few days later, subjects received an IV alcohol infusion rate profile, precomputed to replicate each individual's oral alcohol BrAC trajectory. In both sessions, we assessed 4 subjective responses to alcohol: SEDATION, SIMULATION, INTOXICATION, and HIGH; at baseline and frequently for 4 hours. We compared the individuals' baseline-corrected responses at peak BrAC and at half-peak BrAC on both the ascending and descending limbs. We also computed and compared Pearson-product moment correlations of responses by route of administration, the Mellanby measure of acute adaptation to alcohol, and the area under the entire response curve for each subjective response. RESULTS: No significant differences in any measure could be attributed to the route of alcohol administration. Eleven of 12 response comparisons were significantly correlated across the routes of alcohol administration, with 9 surviving correction for multiple measures, as did the Mellanby effect and area under the response curve correlations. CONCLUSIONS: The route of alcohol administration has a minimal effect on subjective responses to alcohol when an individual's BrAC exposure profiles are similar.

Effect of percutaneous transvenous mitral commissurotomy on brain natriuretic peptide in mitral stenosis in tertiary care hospitals of Peshawar.

The current study was planned to determine the effect of percutaneous transvenous mitral commissurotomy (PTMC) on brain natriuretic peptide (BNP) levels in mitral stenosis patients. It was conducted at the Postgraduate Medical Institute, Lady Reading Hospital, Peshawar, and Rehman Medical Institute Laboratory, Peshawar, Pakistan, from December 2013 to June 2014. Of the 100 patients, 63(63%) were females. The patients' age ranged from 14 to 58 years. Patients diagnosed with isolated mitral valve stenosis or with grade 1 or with grade 2 mitral regurgitation were randomly selected. BNP values before and after 24 hours of PTMC were calculated. The statistical analysis of the echocardiographic variables and BNP levels showed an increase in mitral valve area, drop in pulmonary artery systolic pressure, left atrium diameter and reduction in BNP levels (p<0,05 each) after PTMC that provides a concrete evidence for a successful PTMC procedure.

Medical education research in GCC countries.

BACKGROUND: Medical education is an essential domain to produce physicians with high standards of medical knowledge, skills and professionalism in medical practice. This study aimed to investigate the research progress and prospects of GCC countries in medical education during the period 1996-2013. METHODS: In this study, the research papers published in various global scientific journals during the period 1996-2013 were accessed. We recorded the total number of research documents having an affiliation with GCC Countries including Saudi Arabia, Bahrain, Kuwait, Qatar, United Arab Emirates and Oman. The main source for information was Institute of Scientific Information (ISI) Web of Science, Thomson Reuters. RESULTS: In ISI-Web of Science, Saudi Arabia contributed 40797 research papers, Kuwait 1666, United Arab Emirates 3045, Qatar 4265, Bahrain 1666 and Oman 4848 research papers. However, in Medical Education only Saudi Arabia contributed 323 (0.79%) research papers, Kuwait 52 (0.03%), United Arab Emirates 41(0.01%), Qatar 37(0.008%), Bahrain 28 (0.06%) and Oman 22 (0.45%) research papers in in ISI indexed journals. In medical education the Hirsch index (h-index) of Saudi Arabia is 14, United Arab Emirates 14, Kuwait 11, Qatar 8, Bahrain 8 and Oman 5. CONCLUSION: GCC countries produced very little research in medical education during the period 1996-2013. They must improve their research outcomes in medical education to produce better physicians to enhance the standards in medical practice in the region.

FREQUENCY OF ABDOMINAL OBESITY AND ITS ASSOCIATION WITH DIABETES MELLITUS AMONG PEOPLE OF PESHAWAR.

BACKGROUND: Increased body weight is a major risk factor for the metabolic syndrome which is a cluster of coronary heart disease risk factors, like: hypertension, diabetes mellitus and dyslipidaemia. This study was conducted to determine the frequency of abdominal obesity and diabetes mellitus in the population of Peshawar and association between them. METHODS: This was a cross sectional study, performed by the Cardiology Department, Lady Reading Hospital Peshawar, in the population of Peshawar. All participants were interviewed in detail regarding known risk factors for coronary artery disease. Waist circumference (≥102 cm in male and ≥88 cm in females) was used as the surrogate marker for abdominal obesity in already diagnosed patients of type-2 diabetes mellitus. RESULTS: A total of 2548 individuals were included, 71.1% were male. Mean age was 37.94±12.59 years. Mean waist circumference was 90.25±13.45cm in males and 90.52±12.52cm in females. Diabetes was present in 4.4% of the participants and abdominal obesity in 56.6% Among the male, abdominal obesity was present in 39.4% and diabetes in 2.9%. Out of 39.4% males with abdominal obesity, 2% were diabetic. Out of 38.6% males with no abdominal obesity, 0.9% was diabetic. Amongst the total 559 (21.1%) female subjects, 17.2% were having abdominal obesity and 1.4% was diabetics. Among 123 (4.8%) females with no abdominal obesity, 0.1% was diabetic. A positive association was established between abdominal obesity and diabetes mellitus with a significant p-valve (<0.05). CONCLUSION: Abdominal obesity is more common in the local population of Peshawar and associated with type-2 diabetes mellitus.