Defects of renal tubular homeostasis and cystogenesis in the Pkhd1 knockout.

Loss of PKHD1-gene function causes autosomal recessive polycystic kidney disease (ARPKD) characterized by bilateral severely enlarged kidneys and congenital liver fibrosis requiring kidney replacement therapy most frequently during childhood. Studies using renal tissue from ARPKD patients suggest cyst promotion by suppressed hippo activity and enhanced Src/STAT3-signaling. We address renal homeostasis in female Pkhd1-knockout mice, aged 3 to 9 months, and observe features in common with late-onset ARPKD. Pkhd1-knockout animals show significant increase in kidney and liver weight with preserved organ function. Kidney cyst formation of the S3 segment is accompanied by macrophage recruitment and fibrotic remodeling. Cystic epithelia display increased proliferation, high levels of nuclear YAP/TAZ, and enhanced apoptosis. Y705-phosphorylated STAT3 is strongly enhanced in nuclei of cyst-lining epithelia. In this Pkhd1-deficiency model, stressed cystic epithelia expose the altered signaling pattern and disease-related mechanisms deemed relevant to human ARPKD, and thus may allow identification of therapeutic targets of this disease.

A small survey of introduced Zaprionus indianus (Diptera: Drosophilidae) in orchards of the eastern United States.

The African fig fly, Zaprionus indianus (Gupta), is a generalist fruit fly that typically breeds in decaying fruits from over 70 plant species. The species has spread globally from its native range in tropical Africa, becoming an invasive pest on ripening figs in Brazil. First reported in the United States in 2005 in Florida, Z. indianus has since been documented as far north as Canada and is hypothesized to recolonize northwards from southern refugia each year. We sampled drosophilid communities over the growing season at 2 orchards in Virginia from 2020 to 2022 and 11 orchards along the East Coast during the fall of 2022 to quantify the abundance of Z. indianus relative to other drosophilids across locations, seasons, and fruit crops. Massachusetts had the northernmost population, with no Z. indianus detected in Maine and no correlation between latitude and relative abundance. Variation in Z. indianus relative abundance was high between nearby orchards and abundance was higher on peaches relative to apples within orchards. Comparisons of seasonal abundance curves between 2 Virginia orchards showed similar dynamics across years with individuals first detected around July and becoming absent around December, with peaks in late summer and mid-fall. The variation in seasonal and latitudinal abundance shown here highlights a need for broader sampling to accurately characterize the range, spread, and environmental tolerances of Z. indianus in North America.

Opportunities and challenges of leveraging COVID-19 vaccine innovation and technologies for developing sustainable vaccine manufacturing capabilities in Africa.

The COVID-19 pandemic heralded unprecedented resource mobilisation and global scientific collaboration to rapidly develop effective vaccines. Regrettably, vaccine distribution has been inequitable, particularly in Africa where manufacturing capacity remains nominal. To address this, several initiatives are underway to develop and manufacture COVID-19 vaccines in Africa. Nevertheless, diminishing demand for COVID-19 vaccines, the cost competitiveness of producing goods locally, intellectual property rights issues, and complex regulatory environments among other challenges can undermine these ventures. We outline how extending COVID-19 vaccine manufacturing in Africa to include diverse products, multiple vaccine platforms, and advanced delivery systems will ensure sustainability. Possible models, including leveraging public-academic-private partnerships to enhance success of vaccine manufacturing capacity in Africa are also discussed. Intensifying research in vaccine discovery on the continent could yield vaccines that further bolster sustainability of local production, ensuring greater pandemic preparedness in resource-constrained environments, and long-term health systems security.

Neurokinin 1/3 receptor antagonists for menopausal women: A current systematic review and insights into the investigational non-hormonal therapy.

BACKGROUND: Over 75% of menopausal women experience vasomotor symptoms (VMS), such as night sweats and hot flashes. Despite the prevalence of these symptoms, there is limited data on non-hormonal therapies to alleviate them. METHODS: PubMed, Cochrane, Scopus, Ovid, Web of Science, and ClinicalTrials.Gov were searched for relevant studies. The search was performed using the following keywords, which were customized to suit the specific databases/registers: menopause, women, neurokinin 3, and/or Fezolinetant. The search was conducted until December 20, 2022. This systematic review was conducted in compliance with the PRISMA Statement 2020 guidelines. RESULTS: A total of 326 records were found, with 10 studies (enrolling 1993 women) selected for inclusion. The women received 40-mg doses of NK1/3 receptor antagonists twice daily, with follow-ups at 1 to 3 weeks. Moderately strong evidence was found suggesting that NK1/3 receptor antagonists can help limit the frequency and severity of hot flashes in menopausal women. CONCLUSION: While the results should be interpreted with caution until further clinical trials validate the efficacy and safety of NK1/3 receptor antagonists among menopausal women, these findings suggest that they are promising targets for future pharmacological and clinical studies in addressing vasomotor symptoms.

An in-silico approach leads to explore six genes as a molecular signatures of lung adenocarcinoma.

Due to heterogenetic-specific nature of the available biomarkers, the incidence of lung adenocarcinoma (LUAD) is on the rise worldwide. Previously reported LUAD-related hub genes were searched from the medical literature via literature mining and were processed to identify few top genes via degree method. Later, a comprehensive in silico methodology was applied on the selected real hub genes to identify their tumor driving, diagnostic, and prognostic roles in LUAD patients with divers clinicopathological variables. Out of total 145 extracted hub genes, six genes including CDC6, PBK, AURKA, KIF2C, OIP5, and PRC1 were identified as real hub genes. The expression analysis showed that all these genes were significantly up-regulated across LUAD samples of different clinicopathological variables. In addition, a variety of unique correlations among the expression and of real hub genes and some other parameters including promoter methylation status, overall survival (OS), genetic changes, tumor purity, and immune cell infiltration have also been explored in the present study. Moreover, via TFS-miRNA-mRNA regulatory network, one important TF (E2F1) and one important miRNAs (hsa-mir-34a-5p) that targeted all the real hub genes were also identified. Finally, a variety of drugs also predicted to be very useful in treating LUAD. The discovery of the real hub genes, TFS-miRNA-mRNA network, and chemotherapeutic drugs associated with LUAD provides new insights into underlying mechanisms and treatment of LUAD overcoming heterogeneity barriers.

Spatial and temporal variation in abundance of introduced African fig fly (Zaprionus indianus) (Diptera: Drosophilidae) in the eastern United States.

The African fig fly, Zaprionus indianus (Gupta), has spread globally from its native range in tropical Africa, becoming an invasive crop pest in select areas such as Brazil. Z. indianus was first reported in the United States in 2005 and has since been documented as far north as Canada. As a tropical species, Z. indianus is expected to have low cold tolerance, likely limiting its ability to persist at northern latitudes. In North America, the geographic regions where Z. indianus can thrive and seasonal fluctuations in its abundance are not well understood. The purpose of this study was to characterize the temporal and spatial variation in Z. indianus abundance to better understand its invasion of the eastern United States. We sampled drosophilid communities over the growing season at two orchards in Virginia from 2020-2022 and several locations along the East Coast during the fall of 2022. Virginia abundance curves showed similar seasonal dynamics across years with individuals first detected around July and becoming absent around December. Massachusetts was the northernmost population and no Z. indianus were detected in Maine. Variation in Z. indianus relative abundance was high between nearby orchards and across different fruits within orchards but was not correlated with latitude. Fitness of wild-caught females decreased later in the season and at higher latitudes. The patterns of Z. indianus abundance shown here demonstrate an apparent susceptibility to cold and highlight a need for systematic sampling to accurately characterize the range and spread of Z. indianus.

Latent Autoimmune Diabetes in an Adult Male Presenting With Diabetic Ketoacidosis (DKA).

Latent autoimmune diabetes in adults (LADA) is a common but not well-studied entity and its features overlap between type 1 and type 2 diabetes mellitus (T1D, T2D). Although autoimmunity is a well-known factor associated with this diabetes subtype, environmental factors including excessive weight, physical inactivity, and smoking may also be associated with it. It is commonly misdiagnosed as T2D and generally treated by oral anti-diabetes medications that cause a delay in commencing insulin therapy. There are few cases mentioned in the literature of LADA presenting first time as diabetic ketoacidosis (DKA). Here, we report a case of latent autoimmune diabetes in an adult male who presented with DKA.

Epileptic Seizure Detection Using a Hybrid 1D CNN-Machine Learning Approach from EEG Data.

Electroencephalography (EEG) is a widely used technique for the detection of epileptic seizures. It can be recorded in a noninvasive manner to present the electrical activity of the brain. The visual inspection of nonlinear and highly complex EEG signals is both costly and time-consuming. Therefore, an effective automatic detection system is needed to assist in the long-term evaluation and treatment of patients. Traditional approaches based on machine learning require feature extraction, while deep learning approaches are time-consuming and require more layers for effective feature learning and processing of complex EEG waveforms. Deep learning-based approaches also have weak generalization ability. This paper proposes a solution based on the combination of convolution neural networks (CNN) and machine learning classifiers. It preprocesses the EEG signal using the Butterworth filter and performs feature extraction using CNN. From the extracted set of features, the approach selects only the relevant features using mutual information-based estimators to reduce the curse of dimensionality and improve classification accuracy. The selected features are then passed as input to different machine learning classifiers. The suggested solution is evaluated on the University of Bonn dataset and CHB-MIT datasets. Our model effectively predicts 2, 3, 4, and 5 classes with accuracy of 100%, 99%, 94.6%, and 94%, respectively, for the Bonn dataset and 98% for CHB-MIT datasets.

Verbal fluency in Lebanese children: Preliminary normative data, sociodemographic determinants, and patterns of clustering and switching.

This study assessed the quantitative and qualitative performance of Lebanese-speaking children on verbal fluency (VF) tasks and investigated the effects of sociodemographic characteristics. This study included 219 Lebanese children aged between 5 and 12 years and 11 months, whose native language is Lebanese-Arabic. Semantic and letter VF tasks were assessed using a range of categories and letters. Switching and clustering strategies were analyzed for 177 Lebanese children. The number of words produced presented a significant increase with age (p < .004) in semantic (SVF), while in letter (LVF), the differences were significant between extreme age groups. Females generated more words in the clothes (p = .003) and household items (p = .002) categories. The total number of switches and clusters showed a significantly increasing pattern with age (p < .05). The number of switches was higher for participants with high maternal (p < .001) and paternal (p < .013) educational levels. Regression analyses showed that the total number of switches and clusters, and the mean cluster size had a significant effect on SVF performance (p < .001). The current study generated preliminary norms for VF tasks for Lebanese-speaking children. The results of the current study have an important contribution to neuropsychology research and clinical practice.

Same day discharge after structural heart disease interventions in the era of the coronavirus-19 pandemic and beyond.

With recent advancements in imaging modalities and techniques and increased recognition of the long-term impact of several structural heart disease interventions, the number of procedures has significantly increased. With the increase in procedures, also comes an increase in cost. In view of this, efficient and cost-effective methods to facilitate and manage structural heart disease interventions are a necessity. Same-day discharge (SDD) after invasive cardiac procedures improves resource utilization and patient satisfaction. SDD in appropriately selected patients has become the standard of care for some invasive cardiac procedures such as percutaneous coronary interventions. This is not the case for the majority of structural heart procedures. With the coronavirus disease 2019 pandemic, safely reducing the duration of time spent within the hospital to prevent unnecessary exposure to pathogens has become a priority. In light of this, it is prudent to assess the feasibility of SDD in several structural heart procedures. In this review we highlight the feasibility of SDD in a carefully selected population, by reviewing and summarizing studies on SDD among patients undergoing left atrial appendage occlusion, patent foramen ovale/atrial septal defect closure, Mitra-clip, and trans-catheter aortic valve replacement procedures.

Potential Role of Inflammation-Promoting Biliary Microbiome in Primary Sclerosing Cholangitis and Cholangiocarcinoma.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. METHODS: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. RESULTS: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups. CONCLUSIONS: We identified a unique microbial signature in the bile of patients with increased duration of PSC or with CCA, suggesting a role for microbiota-driven inflammation in the pathogenesis and or progression to perihilar CCA. Further studies are needed to test this hypothesis.

Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases.

BACKGROUND: In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient's genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. RESULTS: UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids-a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both-patients and healthy controls-in order to eliminate restrictions in cell number and availability of primary URECs. CONCLUSIONS: Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

Mind-Body Connection: Cardiovascular Sequelae of Psychiatric Illness.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the world. Mental health disorders are associated with the onset and progression of cardiac disease. The adverse sequelae of this association include worsened quality of life, adverse cardiovascular outcomes, and heightened mortality. The increased prevalence of CVD is partly explained by increased rates of traditional cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus, obesity, and smoking, but mental illness is an independent risk factor for CVD and mortality. Given the association between mental health disorders and poor cardiovascular health, it is vital to have an early and accurate identification and treatment of these disorders. Our review article shares the current literature on the adverse cardiovascular events associated with psychiatric disorders. We present a review on depression, anxiety, bipolar disorder, schizophrenia, type A and D personality disorders, obsessive-compulsive disorder, and stress.

Share vaccine know-how.

Leaders of the world's major economies, representing 80% of the world's gross domestic product, will meet at the end of this month at the G20 meeting in Rome to address issues of global importance, including how to increase the worldwide supply of COVID-19 vaccines. How the world addresses the current state of vaccine inequity will affect how we meet future global disease challenges.

Hepatitis B Screening of At-Risk Immigrants Seen at Primary Care Clinics: A Quality Improvement Project.

OBJECTIVE: To test an intervention to increase screening for hepatitis B (HBV) in at-risk immigrants in the primary care setting. PATIENTS AND METHODS: From a Mayo Clinic primary care panel, we identified approximately 19,000 immigrant patients from 9 high-risk countries/ethnic groups with intermediate or high prevalences of chronic HBV. Eligible patients with no record of prior HBV testing scheduled for primary care visits within the study period spanning October 1, 2017, through October 31, 2018, were identified. During the intervention period, the primary health care professional was notified by email 1 week prior to each primary care visit and encouraged to discuss screening for HBV infection and order screening tests at the appointment. We assessed rates of HBV screening during control and intervention periods. RESULTS: We identified 597 patients in the control period and 212 patients in the intervention period who had not been screened previously for HBV. During the intervention period, 31.4% (58) of the 185 eligible patients were screened for HBV vs 7.2% (43) of the 597 eligible patients in the control period. Thus, the intervention resulted in a 4.3-fold increase in screening (P<.00001). Of the 101 patients screened in the at-risk population, 22 (21.8%) screened positive for prior exposure to HBV (hepatitis B core antibody-positive) and 6 (5.9%) for chronic HBV infection (hepatitis B surface antigen-positive). CONCLUSION: Notifying primary care physicians of the high-risk status of immigrant patients substantially increased screening for HBV. Identifying patients with HBV is important for monitoring disease prevalence, preventing transmission, and initiating treatment and cancer surveillance, allowing earlier recognition and prevention of chronic hepatitis, disease reactivation, cirrhosis, and hepatocellular carcinoma.