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BackgroundJoubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene–phenotype associations in JS.MethodsWe sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.ResultsWe identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a ‘pure JS’ phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.ConclusionsThis work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

Abstract Aim: This study aims to study the protective risk association between the breastfeeding pattern and acute leukemia in children. Materials and Methods: Retrospective study in Kidwai Institute of Oncology, Bangalore. One hundred and twenty cases and 120 controls were enrolled during April 1, 2015–July 31, 2015. Cases include children diagnosed with acute leukemia either ALL or AML, between the age group of 1–15 years, with an elderly sibling and availability of biologic mother for collecting data regarding breastfeeding pattern. Controls include the elder sibling of the cases, children on compassionate care toward end of life, and also whose mother denied to give consent were excluded from the study. Statistical Analysis Used: Pearson Chi-square test, conditional logistic regression models, and Fischer's extract tests were used to assess the association between breastfeeding patterns and risk of acute leukemia. Results: : The acute leukemia cases and controls were similar with respect to sex, birthweight, maternal education, and socioeconomic status. Frequency of ever breastfeeding was same 99% in both cases and controls, odds ratio of ever breastfed to never breastfed (odds ratio = 1;95% confidence interval = 0.13–7.21) was not associated with risk of acute leukemia. Exclusive breastfeeding ≤2, 2–4 and 4–6 months as compared to exclusive breastfeeding beyond 6 months were associated with significant risk of acute leukemia and the P value trend is 0.0026. Similarly, continued breastfeeding till 1 year of age as compared to beyond 1 year was also associated with highly significant risk of acute leukemia with P value trend of 0.0001. Whereas continued breastfeeding till 2 years as compared to beyond 2 years was not associated with any risk of acute leukemia with P value trend of 0.3433. Conclusion: Significant association between breastfeeding and risk of acute leukemia was observed.

Children with cerebral visual impairment (CVI) present with delayed developmental milestones. Pediatricians and pediatric neurologists are usually the first point of contact, and eye exam largely remains referral based. This study documented the visual concerns reported by parents of children with CVI visiting a pediatric neurology clinic. Additionally, we investigated the association between visual concerns, functional vision measures and visual functions. A cross-sectional study was undertaken in children with CVI (chronological age range: 7 months-7 years). Visual concerns reported by the parents/caregivers were documented as open-ended statements. Additionally, a functional vision assessment was conducted using the CVI Range instrument with phase 1, 2 and 3 indicating low, moderate and high visual functioning, respectively. Grating acuity and contrast sensitivity were measured using Teller acuity cards-II and Ohio contrast cards respectively. A total of 73 children (mean age of 2.84 ± 1.87 years) were recruited. Sixty-eight parents reported visual concerns that were broadly grouped into 14 unique concerns. Nineteen parents (27.9%) reported more than one visual concern. Difficulty maintaining eye contact and recognizing faces were the top two visual concerns in phases 1 and 2. Missing objects in the lower visual field was the top concern in phase 3. A larger number of visual concerns were reported in phase 1 (43%) than phase 2 (40.6%) and phase 3 (16.2%). Multiple regression analysis revealed that grating acuity, contrast sensitivity and chronological age were able to predict the functional vision, F (3, 55) = 63.0, p < 0.001, r = 0.77. Targeted questions enquiring about eye contact and face recognition can be included in history elicitation in children with CVI in pediatric neurology clinics. In the presence of visual concerns, it will be important to assess grating acuity and contrast sensitivity. A poor functional vision score requires referral for eye examination and vision rehabilitation services.

OBJECTIVE: To study the effect of a single dose of sodium bicarbonate given during neonatal resuscitation at birth on the acid–base status on the first day of life. SETTING: Tertiary care Level III NICU. STUDY DESIGN: A total of 55 consecutively born asphyxiated neonates continuing to receive positive pressure ventilation at 5 minutes of life were randomized to receive either 4 ml/kg (1.8 meq/kg) of sodium bicarbonate or 5% dextrose. RESULTS: The mean pH, base deficit and PaCO 2 were similar between the Base group and the Control group for the first 24 hours of life. The number of babies with persistent metabolic acidosis at 1, 6, 12 and 24 hours were comparable between the two groups. CONCLUSION: Sodium bicarbonate given during neonatal resuscitation did not change the acid–base status in the first 24 hours of life.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.

Disruptions of vaginal microbiota might increase women's susceptibility to HIV infection. Advances in molecular microbiology have enabled detailed examination of associations between vaginal bacteria and HIV acquisition. Therefore, this study aimed to evaluate the association between the concentrations of specific vaginal bacteria and increased risk of HIV acquisition in African women. We did a nested case-control study of participants from eastern and southern Africa. Data from five cohorts of African women (female sex workers, pregnant and post-partum women, and women in serodiscordant relationships) were used to form a nested case-control analysis between women who acquired HIV infection versus those who remained seronegative. Deep sequence analysis of broad-range 16S rRNA gene PCR products was applied to a subset of 55 cases and 55 controls. From these data, 20 taxa were selected for bacterium-specific real-time PCR assays, which were examined in the full cohort as a four-category exposure (undetectable, first tertile, second tertile, and third tertile of concentrations). Conditional logistic regression was used to generate odds ratios (ORs) and 95% CIs. Regression models were stratified by cohort, and adjusted ORs (aORs) were generated from a multivariable model controlling for confounding variables. The Shannon Diversity Index was used to measure bacterial diversity. The primary analyses were the associations between bacterial concentrations and risk of HIV acquisition. Between November, 2004, and August, 2014, we identified 87 women who acquired HIV infection (cases) and 262 controls who did not acquire HIV infection. Vaginal bacterial community diversity was higher in women who acquired HIV infection (median 1·3, IQR 0·4–2·3) than in seronegative controls (0·7, 0·1–1·5; p=0·03). Seven of the 20 taxa showed significant concentration-dependent associations with increased odds of HIV acquisition: Parvimonas species type 1 (first tertile aOR 1·67, 95% CI 0·61–4·57; second tertile 3·01, 1·13–7·99; third tertile 4·64, 1·73–12·46; p=0·005) and type 2 (first tertile 3·52, 1·63–7·61; second tertile 0·85, 0·36–2·02; third tertile 2·18, 1·01–4·72; p=0·004), Gemella asaccharolytica (first tertile 2·09, 1·01–4·36; second tertile 2·02, 0·98–4·17; third tertile 3·03, 1·46–6·30; p=0·010), Mycoplasma hominis (first tertile 1·46, 0·69–3·11; second tertile 1·40, 0·66–2·98; third tertile 2·76, 1·36–5·63; p=0·048), Leptotrichia/Sneathia (first tertile 2·04, 1·02–4·10; second tertile 1·45, 0·70–3·00; third tertile 2·59, 1·26–5·34; p=0·046), Eggerthella species type 1 (first tertile 1·79, 0·88–3·64; second tertile 2·62, 1·31–5·22; third tertile 1·53, 0·72–3·28; p=0·041), and vaginal Megasphaera species (first tertile 3·15, 1·45–6·81; second tertile 1·43, 0·65–3·14; third tertile 1·32, 0·57–3·05; p=0·038). Differences in the vaginal microbial diversity and concentrations of key bacteria were associated with greater risk of HIV acquisition in women. Defining vaginal bacterial taxa associated with HIV risk could point to mechanisms that influence HIV susceptibility and provide important targets for future prevention research. National Institute of Child Health and Human Development.

In this study of 4758 HIV-1–serodiscordant heterosexual couples in Kenya and Uganda, daily antiretroviral prophylaxis (with tenofovir or emtricitabine–tenofovir) in the HIV-1–negative partner significantly decreased the risk of HIV infection. The use of antiretroviral medications for the prevention of HIV type 1 (HIV-1) transmission is a promising strategy for reducing the spread of HIV-1. 1 – 4 Antiretroviral treatment for persons infected with HIV-1 provides important clinical benefits and substantially reduces infectiousness. 5 – 7 Antiretroviral prophylaxis is a potential HIV-1–prevention strategy for those not yet infected with HIV-1, administered either as postexposure prophylaxis after high-risk occupational or nonoccupational exposure or as preexposure prophylaxis in those with ongoing HIV-1 exposure. 8 , 9 The rationale for antiretroviral prophylaxis in persons with ongoing exposure is based on its efficacy in infants exposed to HIV-1 during birth and . . .

Quantitative estimation of the extent to which the immune system's protective effect against one herpes simplex virus type 2 (HSV-2) infection protects against infection with additional HSV-2 strains is important for understanding the potential for HSV-2 vaccine development. Using viral genotyping, we estimated the prevalence of HSV-2 dual-strain infection and identified risk factors. People with and without HIV infection participating in HSV-2 natural history studies (University of Washington Virology Research Clinic) and HIV prevention trials (HIV Prevention Trials Network 039 and Partners in Prevention HSV/HIV Transmission Study) in the US, Africa, and Peru with 2 genital specimens each containing ≥105 copies herpes simplex virus DNA/ml collected a median of 5 months apart (IQR: 2-11 months) were included. It is unlikely that 2 strains would be detected in the same sample simultaneously; therefore, 2 samples were required to detect dual-strain infection. We identified 85 HSV-2 SNPs that, in aggregate, could determine whether paired HSV-2 strains were the same or different with >90% probability. These SNPs were then used to create a customized high-throughput array-based genotyping assay. Participants were considered to be infected with more than 1 strain of HSV-2 if their samples differed by ≥5 SNPs between the paired samples, and dual-strain infection was confirmed using high-throughput sequencing (HTS). We genotyped pairs of genital specimens from 459 people; 213 (46%) were men, the median age was 34 years (IQR: 27-44), and 130 (28%) were HIV seropositive. Overall, 272 (59%) people were from the US, 59 (13%) were from Peru, and 128 (28%) were from 8 countries in Africa. Of the 459 people, 18 (3.9%) met the criteria for dual-strain infection. HTS and phylogenetic analysis of paired specimens confirmed shedding of 2 distinct HSV-2 strains collected at different times in 17 pairs, giving an estimated dual-strain infection prevalence of 3.7% (95% CI = 2.0%-5.4%). Paired samples with dual-strain infection differed by a median of 274 SNPs in the UL_US region (range 129-413). Matching our observed dual-strain infection frequency to simulated data of varying prevalences and allowing only 2 samples per person, we inferred the true prevalence of dual-strain infection to be 7%. In multivariable analysis, controlling for HIV status and continent of origin, people from Africa had a higher risk for dual-strain infection (risk ratio [RR] = 9.20, 95% CI = 2.05-41.32), as did people who were HIV seropositive (RR = 4.06, 95% CI = 1.42-11.56). HSV-2 dual-strain infection was detected in 3.7% of paired samples from individual participants, and was more frequent among people with HIV infection. Simulations suggest that the true prevalence of dual-strain infection is 7%. Our data indicate that naturally occurring immunity to HSV-2 may be protective against infection with a second strain. This study is limited by the inability to determine the timing of acquisition of the second strain.

Manganese (Mn) is an abundant redox-active metal that cycles in many of Earth’s biomes. While diverse bacteria and archaea have been demonstrated to respire Mn(III/IV), only recently have bacteria been implicated in Mn(II) oxidation-dependent growth. Chemolithoautotrophic manganese oxidation has long been theorized but only recently demonstrated in a bacterial coculture. The majority member of the coculture, “ Candidatus Manganitrophus noduliformans,” is a distinct but not yet isolated lineage in the phylum Nitrospirota ( Nitrospirae ). Here, we established two additional MnCO 3 -oxidizing cultures using inocula from Santa Barbara (California) and Boetsap (South Africa). Both cultures were dominated by strains of a new species, designated “ Candidatus Manganitrophus morganii.” The next most abundant members differed in the available cultures, suggesting that while “ Ca. Manganitrophus” species have not been isolated in pure culture, they may not require a specific syntrophic relationship with another species. Phylogeny of cultivated “ Ca. Manganitrophus” and related metagenome-assembled genomes revealed a coherent taxonomic family, “ Candidatus Manganitrophaceae,” from both freshwater and marine environments and distributed globally. Comparative genomic analyses support this family being Mn(II)-oxidizing chemolithoautotrophs. Among the 895 shared genes were a subset of those hypothesized for Mn(II) oxidation (Cyc2 and PCC_1) and oxygen reduction (TO_1 and TO_2) that could facilitate Mn(II) lithotrophy. An unusual, plausibly reverse complex 1 containing 2 additional pumping subunits was also shared by the family, as were genes for the reverse tricarboxylic acid carbon fixation cycle, which could enable Mn(II) autotrophy. All members of the family lacked genes for nitrification found in Nitrospira species. The results suggest that “ Ca. Manganitrophaceae” share a core set of candidate genes for the newly discovered manganese-dependent chemolithoautotrophic lifestyle and likely have a broad, global distribution. IMPORTANCE Manganese (Mn) is an abundant redox-active metal that cycles in many of Earth’s biomes. While diverse bacteria and archaea have been demonstrated to respire Mn(III/IV), only recently have bacteria been implicated in Mn(II) oxidation-dependent growth. Here, two new Mn(II)-oxidizing enrichment cultures originating from two continents and hemispheres were examined. By comparing the community composition of the enrichments and performing phylogenomic analysis on the abundant Nitrospirota therein, new insights are gleaned on cell interactions, taxonomy, and machineries that may underlie Mn(II)-based lithotrophy and autotrophy.

The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy (ART), therapeutic vaccines, and other non-ART interventions. We use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log(10) plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log(10) copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1-related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels ≥4 log(10) copies/mL. This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels.