Sensorineural hearing loss is genetically heterogeneous. Here we report that mutations in CIB2, encoding a Ca2+- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). There is one mutation of CIB2 that is a prevalent cause of DFNB48 deafness in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In rodents, CIB2 is localized in the mechanosensory stereocilia of inner ear hair cells and in retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of Ca2+ binding, CIB2 significantly decreased the ATP-induced Ca2+ responses in heterologous cells, while DFNB48 mutations altered CIB2 effects on Ca2+ responses. Furthermore, in zebrafish and Drosophila, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We show that CIB2 is a new member of the vertebrate Usher interactome.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

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 .)

ObjectiveThe aim of this study was to explore inequities in knowledge, attitudes and practices regarding tuberculosis (TB) among the urban and rural populations.DesignA cross-sectional study was conducted in two districts of Pakistan's Punjab province. The 1080 subjects aged 20 years and above, including 432 urban and 648 rural respondents, were randomly selected using multistage cluster sampling and interviewed after taking verbal informed consent. Logistic regression was used to calculate the crude odds ratio (OR) with 95% confidence interval (CI) for the urban area. The differences in knowledge, attitudes, practices and information sources between the urban and rural respondents were highlighted using Pearson chi-square test and Fisher's exact test.ResultsThe study revealed poor knowledge regarding TB. The deficit was greater in the rural areas in all aspects. The knowledge regarding symptoms (OR 2.03, 95% CI 1.59-2.61), transmission (OR 1.93, 95% CI 1.44-2.59), prevention (OR 2.24, 95% CI 1.70-2.96), duration of standard treatment (OR 1.88, 95% 1.41-2.49) and DOTS (OR 1.84, 95% CI 1.43-2.38) was significantly higher in the urban areas (all P < 0.001). Although a majority of the subjects (urban 83.8%, rural 81.2%) were aware of the correct treatment for TB, less than half (urban 48.1%, rural 49.2%) were aware of the availability of the diagnostic facility and treatment free of cost. The practice of seeking treatment at a health facility (P = 0.030; OR 2.01, 95% CI 1.06-3.82), as soon as they realized that they had TB symptoms (P < 0.001; OR 1.72, 95% CI 1.26-2.35), was significantly higher in the urban areas. People in the urban areas were more likely to feel ashamed and embarrassed being a TB patient (P < 0.001; OR 2.03, 95% CI 1.50-2.76); however, they seem to be supportive in case their family member suffered from TB (P = 0.005; OR 1.53, 95% CI 1.13-2.06). Nearly half of the respondents, irrespective of the area of residence, believed that the community rejects the TB patient (urban 49.8%, rural 46.4%). Television (urban 80.1%, rural 68.1%) and health workers (urban 30.6%, rural 41.4%) were the main sources for people to acquire the TB related information.ConclusionRespondents' knowledge regarding TB was deficient in all aspects, particularly in the rural areas. Intended health seeking behavior was better in the urban areas. Television and health workers were the main sources for TB related information in both the urban as well as the rural areas. Therefore, the area of residence should be considered in tailoring communication strategies and designing future interventions for TB prevention and control.

BackgroundKnowledge about coronary heart disease (CHD) and its risk factors is an important pre-requisite for an individual to implement behavioral changes leading towards CHD prevention. There is scant data on the status of knowledge about CHD in the general population of Pakistan. The objective of this study was to assess knowledge of CHD in a broad Pakistani population and identify the factors associated with knowledge.MethodsCross sectional study was carried out at four tertiary care hospitals in Pakistan using convenience sampling. Standard questionnaire was used to interview 792 patient attendants (persons accompanying patients). Knowledge was computed as a continuous variable based on correct answers to fifteen questions. Multivariable linear regression was conducted to determine the factors independently associated with knowledge.ResultsThe mean age was 38.1 (±13) years. 27.1% had received no formal education. The median knowledge score was 3.0 out of a possible maximum of 15. Only 14% were able to correctly describe CHD as a condition involving limitation in blood flow to the heart. Majority of respondents could identify only up to two risk factors for CHD. Most commonly identified risk factors were stress (43.4%), dietary fat (39.1%), smoking (31.9%) and lack of exercise (17.4%). About 20% were not able to identify even a single risk factor for CHD. Factors significantly associated with knowledge included age (p = 0.023), income (p < 0.001), education level (p < 0.001), residence (p < 0.001), a family history of CHD (p < 0.001) and a past history of diabetes (p = 0.004). Preventive practices were significantly lacking; 35%, 65.3% and 84.6% had never undergone assessment of blood pressure, glucose or cholesterol respectively. Only a minority felt that they would modify their diet, stop smoking or start exercising if a family member was to develop CHD.ConclusionThis is the first study assessing the state of CHD knowledge in a relatively diverse non-patient population in Pakistan. There are striking gaps in knowledge about CHD, its risk factors and symptoms. These translate to inadequate preventive behavior patterns. Educational programs are urgently required to improve the level of understanding of CHD in the Pakistani population.