The human proton pump inhibitors inhibit rifampicin efflux and macrophage-induced rifampicin tolerance.

Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps.

Gaucher disease protects against tuberculosis.

Biallelic mutations in the glucocerebrosidase () gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis.

Larger gray matter volumes in neuropsychiatric long-COVID syndrome.

Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID. To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20).

Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in (), which regulates expression of the proinflammatory mediator leukotriene B (LTB). TT homozygotes, with increased expression of , have the highest survival when treated with dexamethasone and the lowest survival without.

A Bayesian analysis of the association between genotype and survival in tuberculous meningitis.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A hydrolase () gene encoding an enzyme that regulates inflammatory eicosanoids.

Machine Learning Approaches Reveal Metabolic Signatures of Incident Chronic Kidney Disease in Individuals With Prediabetes and Type 2 Diabetes.

Early and precise identification of individuals with prediabetes and type 2 diabetes (T2D) at risk for progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort by targeted metabolomics and machine learning approaches. Out of 125 targeted metabolites, sphingomyelin C18:1 and phosphatidylcholine diacyl C38:0 were identified as candidate metabolite biomarkers of incident CKD specifically in hyperglycemic individuals followed during 6.

Arrhythmic Gut Microbiome Signatures Predict Risk of Type 2 Diabetes.

Lifestyle, obesity, and the gut microbiome are important risk factors for metabolic disorders. We demonstrate in 1,976 subjects of a German population cohort (KORA) that specific microbiota members show 24-h oscillations in their relative abundance and identified 13 taxa with disrupted rhythmicity in type 2 diabetes (T2D). Cross-validated prediction models based on this signature similarly classified T2D.

Investigation of Adiposity Measures and Operational Taxonomic unit (OTU) Data Transformation Procedures in Stool Samples from a German Cohort Study Using Machine Learning Algorithms.

The analysis of the gut microbiome with respect to health care prevention and diagnostic purposes is increasingly the focus of current research. We analyzed around 2000 stool samples from the KORA (Cooperative Health Research in the Region of Augsburg) cohort using high-throughput 16S rRNA gene amplicon sequencing representing a total microbial diversity of 2089 operational taxonomic units (OTUs). We evaluated the combination of three different components to assess the reflection of obesity related to microbiota profiles: (i) four prediction methods (i.

The Reproduction Rate of Peptide Transporter PEPT-1 Deficient Is Dependent on Dietary Glutamate Supply.

Intestinal absorption of dietary amino acids is mediated via two routes. Free amino acids released by hydrolysis of dietary proteins are taken up by a multitude of amino acid transporters while di- and tripeptides released are taken up by the peptide transporter PEPT-1. Loss of PEPT-1 impairs growth, post-embryonic development and reproduction in , and supplementation with a mixture of all L-amino acids only partially rescues fertility.

Night Shift Work Affects Urine Metabolite Profiles of Nurses with Early Chronotype.

Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous urine samples.

Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues.

Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort.

Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.

Background: The application of metabolomics in prospective cohort studies is statistically challenging. Given the importance of appropriate statistical methods for selection of disease-associated metabolites in highly correlated complex data, we combined random survival forest (RSF) with an automated backward elimination procedure that addresses such issues.

Methods: Our RSF approach was illustrated with data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, with concentrations of 127 serum metabolites as exposure variables and time to development of type 2 diabetes mellitus (T2D) as outcome variable.

Measuring and explaining racial and ethnic differences in willingness to donate live kidneys in the United States.

Background: Reasons for US racial-ethnic minority ESRD patients' reported difficulties identifying live kidney donors are poorly understood.

Methods: We conducted a national study to develop scales measuring willingness to donate live kidneys among US adults (scores ranged from 0 [not willing] to 10 [extremely willing]), and we tested whether racial-ethnic differences exist in willingness to donate. We also examined whether clinical, sociodemographic, and attitudinal factors mediated potential racial-ethnic differences in willingness.

An in vivo platform for rapid high-throughput antitubercular drug discovery.

Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment.

Willingness of the United States general public to participate in kidney paired donation.

Background: Availability of kidney paired donation (KPD) is increasing in the United States, and a national system through UNOS is forthcoming. However, little is known about attitudes toward KPD among the general public, from which donors (particularly non-directed) are drawn.

Methods: In a national study, we assessed the public's attitudes regarding participation in KPD.

Donor designation: racial and ethnic differences in US nondesignators' preferred methods for disclosing intent to donate organs.

Little is known about racial/ethnic differences in preferred methods of disclosing deceased organ donation intentions among persons not previously designating their organ donation preferences publicly or the association of medical mistrust with preferences. We surveyed 307 United States (US) adults who had not yet designated their donation intentions via drivers' licenses or organ donor cards (nondesignators) to identify their preferred disclosure methods (personal discussions with family, physicians, or religious representatives or public registration via mail/telephone/computer, workplace, place of religious worship, or grocery store/bank/post office) and to assess the association of mistrust with preferences. In multivariable models, we assessed racial/ethnic differences in preferences and the influence of medical mistrust on preferences.

Protocol of a randomized controlled trial of culturally sensitive interventions to improve African Americans' and non-African Americans' early, shared, and informed consideration of live kidney transplantation: the Talking About Live Kidney Donation (TALK) Study.

Background: Live kidney transplantation (LKT) is underutilized, particularly among ethnic/racial minorities. The effectiveness of culturally sensitive educational and behavioral interventions to encourage patients' early, shared (with family and health care providers) and informed consideration of LKT and ameliorate disparities in consideration of LKT is unknown.

Methods/design: We report the protocol of the Talking About Live Kidney Donation (TALK) Study, a two-phase study utilizing qualitative and quantitative research methods to design and test culturally sensitive interventions to improve patients' shared and informed consideration of LKT.

Identifying and addressing barriers to African American and non-African American families' discussions about preemptive living related kidney transplantation.

Context: Ethnic/racial minority and nonminority families' perceived barriers to discussing preemptive living related kidney transplantation (LRKT) and their views on the potential value of health care professionals trained to address barriers are unknown. OBJECTIVE, SETTING, AND PARTICIPANTS: To collect pilot data for evaluating perceived barriers to preemptive LRKT and to inform the development of a culturally sensitive intervention to improve families' consideration of LRKT. In 4 structured group interviews of African American and non-African American patients (2 groups) with progressing chronic kidney disease and their family members (2 groups), participants' perceived barriers to initiating LRKT discussions and their views regarding the value of social workers to support discussions were explored.

Effect of primary care physicians' use of estimated glomerular filtration rate on the timing of their subspecialty referral decisions.

Background: Primary care providers' suboptimal recognition of the severity of chronic kidney disease (CKD) may contribute to untimely referrals of patients with CKD to subspecialty care. It is unknown whether U.S.

Primary care-specialist collaboration in the care of patients with chronic kidney disease.

Background And Objectives: Collaboration between primary care physicians (PCPs) and nephrologists in the care of patients with chronic kidney disease (CKD) is widely advocated, but physician preferences regarding collaboration are unknown. Physicians' desires to collaborate in the care of a hypothetical patient with CKD, their preferred content of collaboration, and their perceived barriers to collaboration were assessed.

Design, Setting, Participants, & Measurements: A questionnaire describing the care of a hypothetical patient with progressive CKD was administered to a national sample of U.

Perceived susceptibility to chronic kidney disease among high-risk patients seen in primary care practices.

Background: Patients' views of their risk for the development or progression of chronic kidney disease (CKD) are poorly characterized.

Objective: To assess perceived risk and concern regarding CKD development or progression among high-risk patients seen in primary care, identify predictors of perceptions, and correlate perceptions with adherence to high blood pressure management.

Design And Participants: Cross-sectional study of 195 patients enrolled in a randomized controlled trial on hypertension management in 40 Maryland primary care practices.

Clinical testing patterns and cost implications of variation in the evaluation of CKD among US physicians.

Background: Clinical practice guidelines were established to improve the diagnosis and management of chronic kidney disease (CKD), but the extent, determinants, and cost implications of guideline adherence and variation in adherence have not been evaluated.

Study Design: Cross-sectional survey.

Settings & Participants: The questionnaire was sent (on paper or through the internet) to a nationally representative sample of 1,200 US primary care physicians and nephrologists.

The association of state and national legislation with living kidney donation rates in the United States: a national study.

The effect of state legislation and federal policies supporting living donors on living kidney donation rates in the United States is unknown. We studied living kidney donation rates from 1988 to 2006, and we assessed changes in donation before and after the enactment of state legislation and the launch of federal initiatives supporting donors. During the study, 27 states enacted legislation.

Ionic current blockades from DNA and RNA molecules in the alpha-hemolysin nanopore.

We characterize the substate structure of current blockades produced when single-stranded polynucleotide molecules were electrophoretically driven into the alpha-hemolysin protein pore. We frequently observe substates where the ionic current is reduced by approximately 50%. Most of these substates can be associated with a molecular configuration where a polymer occupies only the vestibule region of the pore, though a few appear related to a polymer occupying only the transmembrane beta-barrel region of the pore.