Delineating the mechanistic relevance of the TP53 gene and its mutational impact on gene expression and patients' survival in bladder cancer.

Bladder carcinoma (BLCA) is a widespread urological malignancy causing significant global mortality, often hindered by delayed diagnosis and limited treatments. BLCA frequently exhibits TP53 mutations, playing a pivotal role in its pathogenesis and underscoring the potential of targeting TP53 as a therapeutic approach for this prevalent urological malignancy. Tumor tissues from 50 bladder cancer patients were used for mutational analysis in TP53's mutation-rich exons (5, 7, & 8). The gene expression of the TP53 gene, along with a TP53-target gene B-cell translocation gene 2 (BTG2) was also assessed in the cDNA samples from the same BLCA tissues and 15 urine controls of healthy people. The analysis revealed 22 % of patients with somatic hotspot mutations, 18 % with pathogenic missense mutations, and 12 % with intronic variants. Patients with somatic mutations exhibited the worst prognosis, supported by survival analysis from The Cancer Genome Atlas (TCGA) BLCA data. Interestingly, H296Y missense mutation correlated with higher TP53 expression and improved survival, while intronic SNPs were linked to worse outcomes. Additionally, upregulated BTG2 expression in mutated patients was observed which was correlated with poor prognosis, emphasizing the role of TP53 mutations in bladder cancer progression. The multivariate analysis highlighted the predictive power of TP53 mutations, with a high frequency of high-grade tumors (78.57 %) in mutated patients, underscoring their role in cancer progression. In conclusion, this study emphasizes the crucial role of TP53 mutations in bladder cancer patients from Bangladesh.

Computational exploration of SLC14A1 genetic variants through structure modeling, protein-ligand docking, and molecular dynamics simulation.

The urea transporter UT-B1, encoded by the SLC14A1 gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the SLC14A1 (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the SLC14A1 gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. SLC14A1 missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of SLC14A1 gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive in-silico study of SLC14A1 gene variants may serve as a springboard for future large-scale investigations examining SLC14A1 polymorphisms.

A Case Report on Fever of Unknown Origin in a 10-Year-Old: Tubercular Liver Abscess.

The liver, which presents as a focal point for tuberculosis in pediatric cases, is rarely encountered, and reported instances are scarce. This atypical manifestation underscores the management of tuberculosis affecting this particular organ in the context of pediatric patients. The treatment of solitary tubercular liver abscesses in children necessitates a collaborative approach, engaging pediatricians, infectious disease specialists, and interventional radiologists. It also needs awareness among physicians to explore and treat early and to complete further assessments for a better outcome. In our instance, investigating the cause of fever led us to diagnose a tubercular liver abscess in a previously healthy 10-year-old male. The substantiation of this diagnosis was accomplished through a meticulous liver biopsy, wherein immunohistochemistry was employed to detect tubercular pathogens. Following the confirmation of the diagnosis, the initiation of a targeted therapeutic regimen resulted in the subsequent resolution of the fever.

Effectiveness of bubble continuous positive airway pressure for treatment of children aged 1-59 months with severe pneumonia and hypoxaemia in Ethiopia: a pragmatic cluster-randomised controlled trial.

BACKGROUND: The safety and efficacy of bubble continuous positive airway pressure (bCPAP) for treatment of childhood severe pneumonia outside tertiary care hospitals is uncertain. We did a cluster-randomised effectiveness trial of locally made bCPAP compared with WHO-recommended low-flow oxygen therapy in children with severe pneumonia and hypoxaemia in general hospitals in Ethiopia. METHODS: This open, cluster-randomised trial was done in 12 general (secondary) hospitals in Ethiopia. We randomly assigned six hospitals to bCPAP as first-line respiratory support for children aged 1-59 months who presented with severe pneumonia and hypoxaemia and six hospitals to standard low-flow oxygen therapy. Cluster (hospital) randomisation was stratified by availability of mechanical ventilation. All children received treatment in paediatric wards (in a dedicated corner in front of a nursing station) with a similar level of facilities (equipment for oxygen therapy and medications) and staffing (overall, one nurse per six patients and one general practitioner per 18 patients) in all hospitals. All children received additional care according to WHO guidelines, supervised by paediatricians and general practitioners. The primary outcome was treatment failure (defined as any of the following: peripheral oxygen saturation <85% at any time after at least 1 h of intervention plus signs of respiratory distress; indication for mechanical ventilation; death during hospital stay or within 72 h of leaving hospital against medical advice; or leaving hospital against medical advice during intervention). The analysis included all children enrolled in the trial. We performed both unadjusted and adjusted analyses of the primary outcome, with the latter adjusted for the stratification variable and for the design effect of cluster randomisation, as well as selected potentially confounding variables, including age. We calculated effectiveness as the relative risk (RR) of the outcomes in the bCPAP group versus low-flow oxygen group. This trial is registered with ClinicalTrial.gov, NCT03870243, and is completed. FINDINGS: From June 8, 2021, to July 27, 2022, 1240 children were enrolled (620 in hospitals allocated to bCPAP and 620 in hospitals allocated to low-flow oxygen). Cluster sizes ranged from 103 to 104 children. Five (0·8%) of 620 children in the bCPAP group had treatment failure compared with 21 (3·4%) of 620 children in the low-flow oxygen group (unadjusted RR 0·24, 95% CI 0·09-0·63, p=0·0015; adjusted RR 0·24, 0·07-0·87, p=0·030). Six children died during hospital stay, all of whom were in the low-flow oxygen group (p=0·031). No serious adverse events were attributable to bCPAP. INTERPRETATION: In Ethiopian general hospitals, introduction of locally made bCPAP, supervised by general practitioners and paediatricians, was associated with reduced risk of treatment failure and in-hospital mortality in children with severe pneumonia and hypoxaemia compared with use of standard low-flow oxygen therapy. Implementation research is required in higher mortality settings to consolidate our findings. FUNDING: SIDA Sweden and Grand Challenges Ethiopia.

Latitude and seasons influence the prevalence of Theileria orientalis and affect the hematology of non-grazed dairy cows in Korea.

This pilot study aimed to investigate the effects of regional and seasonal variations on the prevalence of Theileria orientalis and the hematological profile of non-grazed dairy cows in Korea. A total of 365 clinically healthy lactating Holstein Friesian cows from 26 dairy farms in 7 provinces that were categorized into northern, central, and southern regions were sampled during the warm period from July to August and the cold period from October to December. The detection of T. orientalis major piroplasm surface protein gene and the hematology non-grazed dairy cows were analyzed using peripheral blood samples. The T. orientalis prevalence was 20.0% (73/365). The prevalence in the southern region was 35.9%, which was significantly higher than that in the central (21.6%) and northern (12.9%) regions (P < 0.05). The prevalence during warm period was higher (43.0%) than that during the cold season (13.5%). The infected cows showed significantly lower erythrocyte counts in the southern region (5.8 ± 0.6 M/µl) and during the warm period (5.8 ± 0.7 M/µl) compared with those in the central and northern regions and during the cold season, which affected the extended RBC parameters, including hematocrit and hemoglobin concentrations. Our findings revealed the prevalence of T. orientalis in Korea, highlighting its high occurrence during warm periods and in certain geographical regions. Climatic factors could contribute to the health and productivity of cattle, as evidenced by the prevalence of T. orientalis and its negative impact on animals.

Asymmetric Synthesis of Nidulalin A and Nidulaxanthone A: Selective Carbonyl Desaturation Using an Oxoammonium Salt.

Nidulaxanthone A is a dimeric, dihydroxanthone natural product that was isolated in 2020 from Aspergillus sp. Structurally, the compound features an unprecedented heptacyclic 6/6/6/6/6/6/6 ring system which is unusual for natural xanthone dimers. Biosynthetically, nidulaxanthone A originates from the monomer nidulalin A via stereoselective Diels-Alder dimerization. To expedite the synthesis of nidulalin A and study the proposed dimerization, we developed methodology involving the use of allyl triflate for chromone ester activation, followed by vinylogous addition, to rapidly forge the nidulalin A scaffold in a four-step sequence which also features ketone desaturation using Bobbitt's oxoammonium salt. An asymmetric synthesis of nidulalin A was achieved using acylative kinetic resolution (AKR) of chiral, racemic 2H-nidulalin A. Dimerization of enantioenriched nidulalin A to nidulaxanthone A was achieved using solvent-free, thermolytic conditions. Computational studies have been conducted to probe both the oxoammonium-mediated desaturation and (4 + 2) dimerization events.

Comprehensive characterization of coding and non-coding single nucleotide polymorphisms of the Myoneurin (MYNN) gene using molecular dynamics simulation and docking approaches.

Genome-wide association studies (GWAS) identified a coding single nucleotide polymorphism, MYNN rs10936599, at chromosome 3q. MYNN gene encodes myoneurin protein, which has been associated with several cancer pathogenesis and disease development processes. However, there needed to be a more detailed characterization of this polymorphism's (and other coding and non-coding polymorphisms) structural, functional, and molecular impact. The current study addressed this gap and analyzed different properties of rs10936599 and non-coding SNPs of MYNN via a thorough computational method. The variant, rs10936599, was predicted functionally deleterious by nine functionality prediction approaches, like SIFT, PolyPhen-2, and REVEL, etc. Following that, structural modifications were estimated through the HOPE server and Mutation3D. Moreover, the mutation was found in a conserved and active residue, according to ConSurf and CPORT. Further, the secondary structures were predicted, followed by tertiary structures, and there was a significant deviation between the native and variant models. Similarly, molecular simulation also showed considerable differences in the dynamic pattern of the wildtype and mutant structures. Molecular docking revealed that the variant binds with better docking scores with ligand NOTCH2. In addition to that, non-coding SNPs located at the MYNN locus were retrieved from the ENSEMBL database. These were found to disrupt the transcription factor binding regulatory regions; nonetheless, only two affect miRNA target sites. Again, eight non-coding variants were detected in the testes with normalized expression, whereas HaploReg v4.1 unveiled annotations for non-coding variants. In summary, in silico comprehensive characterization of coding and non-coding single nucleotide polymorphisms of MYNN gene will assist researchers to work on MYNN gene and establish their association with certain types of cancers.

Identification and validation of prognostic signature genes of bladder cancer by integrating methylation and transcriptomic analysis.

Being a frequent malignant tumor of the genitourinary system, Bladder Urothelial Carcinoma (BLCA) has a poor prognosis. This study focused on identifying and validating prognostic biomarkers utilizing methylation, transcriptomics, and clinical data from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA BLCA) cohort. The impact of altered differentially methylated hallmark pathway genes was subjected to clustering analysis to observe changes in the transcriptional landscape on BLCA patients and identify two subtypes of patients from the TCGA BLCA population where Subtype 2 was associated with the worst prognosis with a p-value of 0.00032. Differential expression and enrichment analysis showed that subtype 2 was enriched in immune-responsive and cancer-progressive pathways, whereas subtype 1 was enriched in biosynthetic pathways. Following, regression and network analyses revealed Epidermal Growth Factor Receptor (EGFR), Fos-related antigen 1 (FOSL1), Nuclear Factor Erythroid 2 (NFE2), ADP-ribosylation factor-like protein 4D (ARL4D), SH3 domain containing ring finger 2 (SH3RF2), and Cadherin 3 (CDH3) genes to be the most significant prognostic gene markers. These genes were used to construct a risk model that separated the BLCA patients into high and low-risk groups. The risk model was also validated in an external dataset by performing survival analysis between high and low-risk groups with a p-value < 0.001 and the result showed the high group was significantly associated with poor prognosis compared to the low group. Single-cell analyses revealed the elevated level of these genes in the tumor microenvironment and associated with immune response. High-grade patients also tend to have a high expression of these genes compared to low-grade patients. In conclusion, this research developed a six-gene signature that is pertinent to the prediction of overall survival (OS) and might contribute to the advancement of precision medicine in the management of bladder cancer.

Evaluating Gut Microbiota Modification as a Next-Generation Therapy for Obesity and Diabetes.

The human body is a complex ecosystem that thrives on symbiosis. It is estimated that around 10^14 commensal microorganisms inhabit the human body, with the gut microbiota being one of the most diverse and complex populations of bacteria. This community is thought to comprise over a thousand different species that play a crucial role in the development of critical human diseases such as cancer, obesity, diabetes, mental depression, hypertension, and others. The gut microbiota has been identified as one of the most recent contributors to these metabolic disorders. With the emergence of inexpensive and high-performance sequence technology, our understanding of the function of the intestinal microbiome in host metabolism regulation and the development of (cardio) metabolic diseases has increased significantly. The symbiotic relationship between the gut microbiota and the host is essential for properly developing the human metabolic system. However, if this balance is disrupted by various factors such as infection, diet, exercise, sleep patterns, or exposure to antibiotics, it can lead to the development of various diseases in the body, including obesity and diabetes type 1 and 2. While many approaches and medications have been developed globally to treat these diseases, none have proven to be entirely effective, and many show side effects. Therefore, scientists believe that treating the gut microbiota using tried-and-true methods is the best option for combating obesity and diabetes. In this study, we aim to identify several feasible ways and prospects for gut microbiota therapy that can shape a new format for the treatment of obesity and diabetes.

Testing the effectiveness and acceptability of online supportive supervision for mental health practitioners in humanitarian settings: a study protocol for the caring for carers project.

BACKGROUND: Local humanitarian workers in low and middle-income countries must often contend with potentially morally injurious situations, often with limited resources. This creates barriers to providing sustainable mental health and psychosocial support (MHPSS) to displaced individuals. Clinical supervision is an often neglected part of ensuring high-quality, sustainable care. The Caring for Carers (C4C) project aims to test the effectiveness and acceptability of online group-based supportive supervision on the well-being of MHPSS practitioners, as well as service-user-reported service satisfaction and quality when working with displaced communities in Türkiye, Syria, and Bangladesh. This protocol paper describes the aim, design, and methodology of the C4C project. METHOD: A quasi-experimental, mixed-method, community-based participatory research study will be conducted to test the effectiveness of online group-based supportive clinical supervision provided to 50 Syrian and 50 Bangladeshi MHPSS practitioners working with Syrian and Rohingya displaced communities. Monthly data will be collected from the practitioners and their beneficiaries during the active control (six months) and supervision period (16 months over two terms). Outcomes are psychological distress (Kessler-6), burnout (the Copenhagen Burnout Inventory), compassion fatigue, compassion satisfaction, and secondary traumatic stress (Professional Quality of Life Scale), perceived injustice, clinical self-efficacy (Counseling Activity Self-Efficacy Scale), service satisfaction, and quality (Client Satisfaction Questionnaire and an 18-item measure developed in this project). A realist evaluation framework will be used to elucidate the contextual factors, mechanisms, and outcomes of the supervision intervention. DISCUSSION: There is a scarcity of evidence on the role of clinical supervision in improving the well-being of MHPSS practitioners and the quality of service they provide to displaced people. By combining qualitative and quantitative data collection, the C4C project will address the long-standing question of the effectiveness and acceptability of clinical supervision in humanitarian settings.

Mental illness stigma in Bangladesh: Findings from a cross-sectional survey.

Background: Mental illness stigma is universally prevalent and a significant barrier to achieving global mental health goals. Mental illness stigma in Bangladesh has gained little attention despite its widespread impact on seeking mental health care in rural and urban areas. This study aimed to investigate mental illness stigma and the associated factors in rural and urban areas of Bangladesh. Methods: The study areas were divided into several clusters from which 325 participants (≥18 years) were recruited with systematic random sampling. The Bangla version of the Days' Mental Illness Stigma Scale was used to collect data. Independent-samples t-test, ANOVA, and multiple regression were performed. Results: Results suggest that gender, age, geographical location, socioeconomic status, and occupation significantly differed across subscales of stigma. Age, gender, seeking treatment of mental illness, having knowledge on mental health, and socioeconomic status were predictive factors of mental illness stigma. The results also showed a high treatment gap in both rural and urban areas. Conclusion: This study supports that mental illness stigma is prevalent in Bangladesh, requiring coordinated efforts. Results can inform the development of contextually tailored mental health strategies to reduce stigma and contribute to the promotion of mental health of individuals and communities across Bangladesh.

Comparative safety analysis of newly prepackaged backed food products and those approaching the expiry date in Bangladesh.

PURPOSE: The enrichment of microbial growth in prepackaged, frozen food goods from the day of manufacturing to the day of expiration has been the subject of recurrent concerns. These fortified foods are widely consumed by individuals of all ages in poor nations due to their ability to satisfy even the smallest of appetites. People often disregard the expiration dates printed on food packaging despite the fact that manufacturers are required by law to do so. This research looked into whether or not it was safe to consume packaged foods that were getting close to their expiration date. Finding out if people are exposed to hazardous microorganisms and how much bacteria is created daily on them. MATERIALS AND METHODS: We collected six prepackaged backed food products samples of three types separately, where three were collected around manufacturing days and three were nearly expired days from different companies. We have assayed and identified the foodborne microbial communities among the samples by morphological study and different types of biochemical tests. After that, we tested how well various popular antibiotics worked against those isolates. RESULTS: It showed that there are more bacterial communities that grow gradually day by day on prepackaged backed food products and nearly expired products that contain a large number of food-borne disease-causing bacteria that show mostly resistance against commonly used antibiotics. CONCLUSION: Although nowadays the demand for prepackaged backed food products is increasing as ready-to-eat processed foods, mostly in developing countries, there's a serious health risk if we take the products that were produced a long time ago.

Mental illness stigma among indigenous communities in Bangladesh: a cross-sectional study.

BACKGROUND: Mental illnesses stigma is a universal and transcultural phenomenon. While mental illnesses stigma is pervasive in Bangladesh, very little research exists on stigma toward mental illnesses among indigenous communities. This study aimed to investigate the prevailing stigma and the risk factors among different indigenous communities in the Chattogram Hill Tracts (CHT) in Bangladesh. METHODS: A cross-sectional survey was carried out and participants were recruited purposively from Rangamati, a South-Eastern district of Bangladesh in the CHT. Participants from various indigenous communities including Chakma, Marma, Rakhine, Tripura, and Pangkhua were recruited. The 28- item Bangla translated version of the Mental Illnesses Stigma Scale was used. Independent-samples t-test, ANOVA, and multiple regression were performed. RESULTS: The results indicate evidence of a gender difference with females reporting more stigma than their male counterparts. Age, gender, socioeconomic status, and monthly income are associated with stigma among indigenous people. Further analyses of the subscales indicated significant differences among sociodemographic variables. CONCLUSIONS: The results provide an insight into the prevailing stigma and associate risk factors among indigenous communities. The results may help inform anti-stigma interventions targeting indigenous communities in Bangladesh.

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders.

Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., "Critical-Exon Genes (CEGs)"] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package. Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients' pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit (p = 0.014) and overall ASD symptoms severity (p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.

Determinants of minimum dietary diversity of lactating mothers in rural northern region of Bangladesh: A community-based cross-sectional study.

Background: Breastfeeding requires additional diversified foods for the nutritional requirements of mothers and children, especially in preventing micronutrient deficiencies. The minimum dietary diversity for women (MDD-W) is a proxy indicator of micronutrient adequacy for women. Objectives: This study aimed to identify the determinants associated with MDD in lactating women. Methods: A community-based cross-sectional study was conducted among lactating mothers having at least one live birth in last three years from two districts of Bangladesh between 31st May 2021 and 9th June 2021. Dietary and socio-demographic information was obtained using a single 24-h recall and socio-economic status questionnaires. MDD was defined as at least four food groups consumed in the last 24 hours. In binary logistic regression, adjusted models were used to assess the relationship between MDD and socio-economic factors. Results: The mean Dietary Diversity Score (DDS) was 3.9 ± 1.2. The MDD was met by 29.7% of women. Respondent's ages 20-24 years [Adjusted Odds Ratio (AOR) = 0.5; 95% CI: 0.3-0.9], 25-34 years [AOR = 0.5; 95% CI: 0.3-0.8], and 35-49 years [AOR = 0.5; 95% CI: 0.2-0.9], husband's academic qualifications more than 12 years [AOR = 1.9; 95% CI: 1.0-3.7], family income more than 15000 BDT per month [AOR = 2.3; 95% CI: 1.2-4.3], and husband's profession as a day labor [AOR = 0.5; 95% CI: 0.3-0.7] were significant factors to have MDD. Conclusions: DDS and MDD were very poor among the mothers, whereas women's age, husband's education, and the family's monthly income were independent determinants of MDD. Special interventions may be needed to improve MDD.

Perception and experience of clinicians and caregivers in treating childhood severe pneumonia and hypoxemia using bubble continuous positive airway pressure in Ethiopian tertiary and general hospitals.

BACKGROUND: In low and middle-income countries (LMICs), severe pneumonia with hypoxemia is the leading cause of child deaths, even with the provision of WHO-recommended antibiotic therapy, oxygen therapy and other supportive care. Previous studies found positive outcomes from the use of bubble continuous positive airway pressure (bCPAP) for treating these children compared to the standard oxygen therapy. Due to lack of data on the perceptions and experiences of hospital health care workers and caregivers of children on the feasibility and acceptability of bCPAP in treating children with severe pneumonia and hypoxemia in real-life settings, we examined these issues in tertiary and general hospitals in Ethiopia. METHODS: As part of a three-stages clinical trial, this qualitative study was conducted in two tertiary (stage I) and two general (stage II) hospitals from September 2019 to July 2020. During stages I and II, we have consecutively enrolled children with severe pneumonia and hypoxemia and put them on bCPAP to examine its feasibility and acceptability by clinicians and parents. A total of 89 children were enrolled (49 from two tertiary and 40 from two general hospitals). Then qualitative data were collected through 75 repeated in-depth interviews by social-science experts with purposively selected 30 hospital health workers and 15 parents of 12 children who received bCPAP oxygen therapy in the hospitals. Interview data were supplemented by 6 observations in the hospitals. Data were analyzed using a thematic approach. RESULTS: Identified structural and functional challenges for the introduction of bCPAP in treating childhood severe pneumonia and hypoxemia in the study hospitals include: inadequate number of pulse oximeters; unavailability of nasal prongs with age-specific size; inadequate and non-functioning oxygen flow meters, concentrator, and cylinders; disruption in power-supply; and inadequate number of staff. The opportunities in introducing bCPAP oxygen therapy included the availability of a dedicated corner for the study patients situated in front of nurse's station, required medicines and satisfactory level of clinicians' knowledge and skills for treating severe pneumonia patients. Additionally, the identified operational challenges were occasional lack of bubbling in the water-filled plastic bottle, lack of stand for holding the water-filled plastic bottle, and delayed shifting of oxygen source from an oxygen concentrator to a cylinder, particularly during electricity disruption. Participants (clinicians and parents) expressed their satisfaction as bCPAP oxygen therapy was found to be simple to handle, children had ease of breathing and recovered fast without major ill effects. CONCLUSION: Our study identified some important structural, functional, and operational challenges that need to be addressed before implementation of bCPAP oxygen therapy especially in frontline general hospitals with limited resources. In spite of these observed challenges, the clinicians and caregivers were highly satisfied with the overall performance of bCPAP oxygen therapy.

Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior.

Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.

Effectiveness of Bubble Continuous Positive Airway Pressure (BCPAP) for Treatment of Children Aged 1-59 Months with Severe Pneumonia and Hypoxemia in Ethiopia: A Pragmatic Cluster Randomized Controlled Clinical Trial.

Despite the beneficial effect of bubble continuous positive airway pressure (BCPAP) oxygen therapy for children with severe pneumonia under the supervision of physicians that has been shown in different studies, effectiveness trials in developing country settings where low-flow oxygen therapy is the standard of care are still needed. Thus, the aim of this study is to assess the effectiveness of bubble CPAP oxygen therapy compared to the WHO standard low-flow oxygen therapy among children hospitalized with severe pneumonia and hypoxemia in Ethiopia. This is a cluster randomized controlled trial where six district hospitals are randomized to BCPAP and six to standard WHO low-flow oxygen therapy. The total sample size is 620 per arm. Currently, recruitment of the patients is still ongoing where the management and follow-up of the enrolled patients are performed by general physicians and nurses under the supervision of pediatricians. The primary outcome is treatment failure and main secondary outcome is death. We anticipate to complete enrollment by September 2022 and data analysis followed by manuscript writing by December 2022. Findings will also be disseminated in December 2022. Our study will provide data on the effectiveness of BCPAP in treating childhood severe pneumonia and hypoxemia in a real-world setting.

Death in severely malnourished hospitalized children presenting with diarrhea and vomiting.

INTRODUCTION: There is lack of data on outcomes of severely malnourished children who are hospitalized with concomitant diarrhea and vomiting. We sought to evaluate outcomes of such children. METHODOLOGY: In this retrospective chart review, we used electronic databases to evaluate children aged 0-59 months and admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, with diarrhea and severe malnutrition between April 2011 and August 2012. Outcomes of children with and without vomiting were compared. The primary outcome was death. A probability of ≤ 0.05 was considered statistically significant. RESULTS: Out of 306 enrolled children, 51 (17%) had vomiting and 255 (83%) did not have vomiting. A total of 31 (10%) children died, 12 (24%) of them had vomiting and 19 (8%) did not have vomiting. Death was significantly higher in severely malnourished diarrheal children with vomiting (12/51 (24%)) compared to those without vomiting (19/255 (8%)) (Relative risk [RR] 2.73, 95% confidence interval [CI] 1.61-4.64; p < 0.001). We used Log linear bi-nominal regression after adjusting for potential confounders such as metabolic acidosis and hypoglycemia, and found that vomiting was significantly associated with deaths in severely malnourished diarrheal children (RR 1∙89, 95% CI 1.01-1.33; p = 0.05). CONCLUSIONS: Our analysis showed that children with diarrhea and severe malnutrition who had vomiting during hospitalization were at a higher risk of death compared to those without vomiting. The results underscore the importance of prompt identification and management of vomiting to reduce deaths in such children.