Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.

The Urgent Need for Dengue Vaccination: Combating an Escalating Public Health Crisis in Pakistan.

Dengue fever, caused by the dengue virus (DENV), poses a significant global health threat, with a dramatic increase in cases driven by climate change, urbanization, and mosquito resistance. In Pakistan, a country with a population of 240 million, the world's fifth largest, dengue has emerged as an escalating public health crisis, with seasonal outbreaks severely straining the healthcare system. Despite decades of vector control efforts, there has not been much success, necessitating the introduction of dengue vaccination to boost population immunity. Recent advancements in vaccine development demonstrate promising efficacy and safety profiles, even in dengue-naive individuals. Implementing a dengue vaccination program in Pakistan could significantly reduce the disease burden, lower healthcare costs, and prevent future outbreaks. Integrating vaccination with existing public health initiatives can achieve high coverage and improve overall public health outcomes.

Effectiveness of early pharmaceutical interventions in symptomatic COVID-19 patients: A randomized clinical trial.

Objective: We assessed the effectiveness of oral Hydroxychloroquine (HC), Azithromycin (AZ) and Oseltamivir (OS), alone or combined, among patients hospitalized with mildly symptomatic coronavirus infectious disease (COVID-19). Methods: Following the approval of the National Bioethics Committee and prospective registration (clinicaltrials.gov NCT04338698), a multicenter randomized clinical trial of adaptive design was conducted at 10 multispecialty hospitals in Pakistan. Patients were randomized into seven treatment groups. Starting April 15, 2020, consenting, eligible, otherwise healthy adult patients or those with co-morbidities under control, were recruited if they presented with mildly symptomatic COVID-19 (scored 3 on a 7-point ordinal scale anchored between 1 = not hospitalized, able to undertake normal activities, to 7 = death) confirmed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Two primary outcomes were assessed by day seven: Turning qRT-PCR negative; and clinical improvement of two points from the baseline. Outcome rates were compared using a chi-square test. Multiple imputations were applied to handle missing data. An interim data analysis was carried out on July 19, 2020, following which the study continued without treatment group changes. Data Safety and Monitoring Board advised to stop recruitment due to its futility on January 18, 2021. Results: Of 471 patients randomized, a total of 426 (90.4%) completed the follow-up for primary outcomes. Based on imputed data analyses at day seven: Total qRT-PCR negative cases were 137/471 (29%, 95% CI 25.0 - 33.4). By day seven, a total of 111/471 (23.5%, 95% CI 19.8 - 27.6) showed clinical improvement. No serious or non-serious adverse event was reported. Conclusions: Among patients with mild COVID-19, there was no statistically significant difference in the effectiveness of oral antimalarial, antiviral, or antibiotic treatments.Clinicaltrials.gov ID: NCT04338698.

A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred.

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

Theoretical investigation of dynamics and concurrence of entangled [Formula: see text] and anti-[Formula: see text] symmetric polarized photons.

Non-Hermitian systems with parity-time [Formula: see text] symmetry and anti-parity-time [Formula: see text] symmetry have exceptional points (EPs) resulting from eigenvector co-coalescence with exceptional properties. In the quantum and classical domains, higher-order EPs for [Formula: see text] symmetry and [Formula: see text]-symmetry systems have been proposed and realized. Both two-qubits [Formula: see text]-[Formula: see text] and [Formula: see text]-[Formula: see text] symmetric systems have seen an increase in recent years, especially in the dynamics of quantum entanglement. However, to our knowledge, neither theoretical nor experimental investigations have been conducted for the dynamics of two-qubits entanglement in the [Formula: see text]-[Formula: see text] symmetric system. We investigate the [Formula: see text]-[Formula: see text] dynamics for the first time. Moreover, we examine the impact of different initial Bell-state conditions on entanglement dynamics in [Formula: see text]-[Formula: see text], [Formula: see text]-[Formula: see text] and [Formula: see text]-[Formula: see text] symmetric systems. Additionally, we conduct a comparative study of entanglement dynamics in the [Formula: see text]-[Formula: see text] symmetrical system, [Formula: see text]-[Formula: see text] symmetrical system, and [Formula: see text]-[Formula: see text] symmetrical systems in order to learn more about non-Hermitian quantum systems and their environments. Entangled qubits evolve in a [Formula: see text]-[Formula: see text] symmetric unbroken regime, the entanglement oscillates with two different oscillation frequencies, and the entanglement is well preserved for a long period of time for the case when non-Hermitian parts of both qubits are taken quite away from the exceptional points.

Protocol of Pakistan randomized and observational trial to evaluate coronavirus treatment among newly diagnosed patients with COVID-19: Azithromycin, Oseltamivir, and Hydroxychloquine.

Background & Objective: This study aimed to assess the clinical effectiveness of Hydroxychloroquine Sulfate (200 mg orally 8 hourlies thrice a day for 5 days), oseltamivir (75 mg orally twice a day for 5 days), and Azithromycin (500 mg orally daily on day 1, followed by 250 mg orally twice a day on days 2-5) alone and in combination (in seven groups). Methods & Analysis: An adaptive design is deployed, set within a comprehensive cohort study, to permit flexibility in fast-changing clinical and public health scenario. Primary outcomes include turning the test negative for coronavirus nucliec acid and in bringing about clinical improvement on day 7 of follow-up on a seven-point ordinal scale. The randomized study will recruit participants of either gender above 18 years of age who will test positive for SARS-CoV-2 on Quantitative Reverse Transcription Polymerase Chain Reaction (PCR). Pregnant or lactating females, and those with severe respiratory distress, or with serious comorbidities will be excluded. Randomization will be done maintaining concealment of allocation sequence using a computer-generated random number list. The sample size will be subjected to periodic reviews by National Data Safety and Monitoring Board. Ethics and Dissemination: The trial is approved by the National Bioethics Committee (No.4-87/NBC-471-COVID-19-05/20/) and institutional Ethical Review Committee. This clinical trial conducted under Good Clinical Practice is expected to inform patients clinical guidelines for the use of these drugs in newly diagnosed with SARS-CoV-2. Trial Registration: The trial was prospectively registered on April 08, 2020 at clinicaltrials.gov with ID: NCT04338698.

Epidemiology, Clinico-Pathological Characteristics, and Comorbidities of SARS-CoV-2-Infected Pakistani Patients.

SARS-CoV-2 is a causative agent for COVID-19 disease, initially reported from Wuhan, China. The infected patients experienced mild to severe symptoms, resulting in several fatalities due to a weak understanding of its pathogenesis, which is the same even to date. This cross-sectional study has been designed on 452 symptomatic mild-to-moderate and severe/critical patients to understand the epidemiology and clinical characteristics of COVID-19 patients with their comorbidities and response to treatment. The mean age of the studied patients was 58 ± 14.42 years, and the overall male to female ratio was 61.7 to 38.2%, respectively. In total, 27.3% of the patients had a history of exposure, and 11.9% had a travel history, while for 60% of patients, the source of infection was unknown. The most prevalent signs and symptoms in ICU patients were dry cough, myalgia, shortness of breath, gastrointestinal discomfort, and abnormal chest X-ray (p < 0.001), along with a high percentage of hypertension (p = 0.007) and chronic obstructive pulmonary disease (p = 0.029) as leading comorbidities. The complete blood count indicators were significantly disturbed in severe patients, while the coagulation profile and D-dimer values were significantly higher in mild-to-moderate (non-ICU) patients (p < 0.001). The serum creatinine (1.22 µmol L-1; p = 0.016) and lactate dehydrogenase (619 µmol L-1; p < 0.001) indicators were significantly high in non-ICU patients, while raised values of total bilirubin (0.91 µmol L-1; p = 0.054), C-reactive protein (84.68 mg L-1; p = 0.001), and ferritin (996.81 mg L-1; p < 0.001) were found in ICU patients. The drug dexamethasone was the leading prescribed and administrated medicine to COVID-19 patients, followed by remdesivir, meropenem, heparin, and tocilizumab, respectively. A characteristic pattern of ground glass opacities, consolidation, and interlobular septal thickening was prominent in severely infected patients. These findings could be used for future research, control, and prevention of SARS-CoV-2-infected patients.

Efficacy and Safety of the RBD-Dimer-Based Covid-19 Vaccine ZF2001 in Adults.

BACKGROUND: The ZF2001 vaccine, which contains a dimeric form of the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 and aluminum hydroxide as an adjuvant, was shown to be safe, with an acceptable side-effect profile, and immunogenic in adults in phase 1 and 2 clinical trials. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to investigate the efficacy and confirm the safety of ZF2001. The trial was performed at 31 clinical centers across Uzbekistan, Indonesia, Pakistan, and Ecuador; an additional center in China was included in the safety analysis only. Adult participants (≥18 years of age) were randomly assigned in a 1:1 ratio to receive a total of three 25-µg doses (30 days apart) of ZF2001 or placebo. The primary end point was the occurrence of symptomatic coronavirus disease 2019 (Covid-19), as confirmed on polymerase-chain-reaction assay, at least 7 days after receipt of the third dose. A key secondary efficacy end point was the occurrence of severe-to-critical Covid-19 (including Covid-19-related death) at least 7 days after receipt of the third dose. RESULTS: Between December 12, 2020, and December 15, 2021, a total of 28,873 participants received at least one dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who had completed the three-dose regimen, for whom there were approximately 6 months of follow-up data, were included in the updated primary efficacy analysis that was conducted at the second data cutoff date of December 15, 2021. In the updated analysis, primary end-point cases were reported in 158 of 12,625 participants in the ZF2001 group and in 580 of 12,568 participants in the placebo group, for a vaccine efficacy of 75.7% (95% confidence interval [CI], 71.0 to 79.8). Severe-to-critical Covid-19 occurred in 6 participants in the ZF2001 group and in 43 in the placebo group, for a vaccine efficacy of 87.6% (95% CI, 70.6 to 95.7); Covid-19-related death occurred in 2 and 12 participants, respectively, for a vaccine efficacy of 86.5% (95% CI, 38.9 to 98.5). The incidence of adverse events and serious adverse events was balanced in the two groups, and there were no vaccine-related deaths. Most adverse reactions (98.5%) were of grade 1 or 2. CONCLUSIONS: In a large cohort of adults, the ZF2001 vaccine was shown to be safe and effective against symptomatic and severe-to-critical Covid-19 for at least 6 months after full vaccination. (Funded by the National Science and Technology Major Project and others; ClinicalTrials.gov number, NCT04646590.).