Fragment-based development of small molecule inhibitors targeting cholesterol metabolism.

( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.

PET/CT guided tuberculosis treatment shortening: a randomized trial.

Six months of chemotherapy using current agents is standard of care for pulmonary, drug-sensitive tuberculosis (TB), even though some are believed to be cured more rapidly and others require longer therapy. Understanding what factors determine the length of treatment required for durable cure in individual patients would allow individualization of treatment durations, provide better clinical tools to determine the of appropriate duration of new regimens, as well as reduce the cost of large Phase III studies to determine the optimal combinations to use in TB control programs. We conducted a randomized clinical trial in South Africa and China that recruited 704 participants with newly diagnosed, drug-sensitive pulmonary tuberculosis and stratified them based on radiographic disease characteristics as assessed by FDG PET/CT scan readers.

LGR5 as a diagnostic marker for dysplasia in serrated polyps.

Aims: WNT signalling pathway dysregulation is often a critical early component in colorectal neoplasia, particularly the chromosomal instability pathway. Using two WNT reporters, and , we sought to assess whether these polyps demonstrate predictable expression patterns and if these patterns show diagnostic value.

Methods: We evaluated 23 adenomas (TA), 23 sessile serrated lesions (SSLs), 14 SSL with dysplasia and 38 traditional serrated adenomas (TSA).

Genetic Ancestry-Based Differences in Biomarker-Based Eligibility for Precision Oncology Therapies.

Importance: Although differences in the prevalence of key cancer-specific somatic mutations as a function of genetic ancestry among patients with cancer has been well-established, few studies have addressed the practical clinical implications of these differences for the growing number of biomarker-driven treatments.

Objective: To determine if the approval of precision oncology therapies has benefited patients with cancer from various ancestral backgrounds equally over time.

Design, Setting, And Participants: A retrospective analysis of samples from patients with solid cancers who underwent clinical sequencing using the integrated mutation profiling of actionable cancer targets (MSK-IMPACT) assay between January 2014 and December 2022 was carried out.

Improved aquila optimizer for swarm-based solutions to complex engineering problems.

The traditional optimization approaches suffer from certain problems like getting stuck in local optima, low speed, susceptibility to local optima, and searching unknown search spaces, thus requiring reliance on single-based solutions. Herein, an Improved Aquila Optimizer (IAO) is proposed, which is a unique meta-heuristic optimization method motivated by the hunting behavior of Aquila. An improved version of Aquila optimizer seeks to increase effectiveness and productivity.

Beliefs and behaviors regarding abortion counseling among U.S. clinicians caring for adolescents.

Study Objective: To determine clinician factors associated with discussing abortion during pregnancy options counseling among adolescents.

Methods: We recruited and surveyed a convenience sample of U.S.

Patient and obstetrician-gynecologist perspectives on considering long-acting reversible contraception for postpartum patients who desire permanent contraception.

Objective(s): We sought to understand patients' and obstetrician-gynecologists' priorities in seeking or recommending long-acting reversible contraceptive methods (LARC; intrauterine devices and contraceptive implants) versus permanent contraception in the postpartum period when permanent contraception was the patient's initial contraceptive preference.

Study Design: We interviewed 81 postpartum patients who desired permanent contraception and their delivering obstetrician-gynecologist (n = 67) from four US institutions to explore patient and obstetrician-gynecologist (OBGYN) perspectives navigating permanent contraception counseling and decision-making. We used thematic content analysis to analyze interview transcripts using NVivo 12 Pro software.

Differences in Ancestry and Presence of Gastric Precursor Lesions in Individuals With Young- and Average-Onset Gastric Cancer.

Background: There has been a paradoxical rise in young-onset gastric cancer (YOGC), defined as gastric cancer (GC) diagnosed before age 50. Precursor lesions may contribute to pathogenesis, though their role in progression to different histologic subtypes is unclear. The impact of self-reported race is also poorly characterized and may be unreliable as a proxy for genetic differences.

Two siblings with triple A syndrome.

Triple A syndrome is a rare autosomal recessive disorder presenting as adrenal insufficiency, achalasia and alacrima, often accompanied by neurological complications. We present the cases of two siblings, a girl (patient 1) and a boy (patient 2) in their early adolescence, born from a consanguineous marriage. At the age of 4, patient 1 developed progressive dysphagia when consuming both solid and liquid foods, while patient 2 began displaying abnormal gait by 2 years.

Esophageal melanosis: Two case reports and review of literature.

Background: Esophageal melanosis (EM) is a rare condition characterized by melanin pigmentation in the esophageal mucosa. It is not well understood and has been documented in less than 100 cases worldwide.

Case Summary: We report two cases of African American patients who complained of significant weight loss (over 20 pounds in approximately six months) and abdominal pain during their first visit.

Successful combination of lactic acid bacteria and yeast fermentation and enzymatic treatment to re-cycle industrial bread by-products for bread making.

Bread industry generates significant amounts of by-products which are discarded every day with relevant economic and environmental repercussions, despite they still contain high concentrations of potentially exploitable nutrients. Aiming to develop new sustainable solutions, this study explored the synergistic application of enzymatic treatment and sourdough fermentation to re-cycle industrial bread by-products for new sourdough bread making. Lactiplantibacillus plantarum SD69.

Clinician Perspectives on Adolescent Contraceptive Counseling Following Dobbs v. Jackson: Implications for Young People's Contraceptive Autonomy.

Objective: The objective of this study is to understand whether clinicians who provide contraceptive counseling to adolescent patients perceive that the Dobbs decision has influenced their counseling.

Study Design: We conducted in-depth interviews with a convenience sample of 16 clinicians who provide contraceptive counseling to adolescents at the American Academy of Pediatrics annual conference in October 2022. We used thematic content analysis and an iterative process of constant comparison to identify themes inductively.

Long-Acting Reversible Contraception Use after Non-Receipt of Postpartum Permanent Contraception: A Retrospective Analysis.

To evaluate long-acting reversible contraception (LARC) use versus permanent contraception (PC) use at hospital discharge through 1 year postpartum after an unfulfilled immediate postpartum PC request. We present a secondary analysis of a retrospective cohort study of patients across four study sites between 2018 and 2019 with PC as their documented inpatient postpartum contraceptive plan. We abstracted demographic and clinical characteristics, contraceptive plans and time to contraceptive fulfillment, reasons for non-fulfillment, and pregnancy incidence up to 1 year postpartum from medical records.

Lipomatous Neoplasms of Soft Tissue: A Contemporary Review.

This review summarizes the clinicopathologic features of various lipomatous tumors of soft tissue and addresses some recent conceptual issues relating to adipocytic neoplasms, such as atypical spindle cell/pleomorphic lipomatous tumor and myxoid pleomorphic liposarcoma, and provides an update on the molecular aspects of these tumors. Recent advances in cytogenetic characterization and classification of lipomatous tumors are reviewed, and the genetic importance of distinct chromosomal aberrations are briefly discussed.

Probiotics, prebiotics, synbiotics and other microbiome-based innovative therapeutics to mitigate obesity and enhance longevity via the gut-brain axis.

The global prevalence of obesity currently exceeds 1 billion people and is accompanied by an increase in the aging population. Obesity and aging share many hallmarks and are leading risk factors for cardiometabolic disease and premature death. Current anti-obesity and pro-longevity pharmacotherapies are limited by side effects, warranting the development of novel therapies.

Unveiling Superior Solar-Blind Photodetection with a NiO/ZnGaO Heterojunction Diode.

This investigation presents a self-powered, solar-blind photodetector utilizing a low-temperature fabricated crystalline NiO/ZnGaO heterojunction with a staggered type-II band alignment. The device leverages the pyrophototronic effect (PPE), combining the photoelectric effect in the p-n junction and the pyroelectric effect in the non-centrosymmetric ZnGaO crystal. This synergistic effect enhances the photodetector's performance parameters, thereby outperforming traditional solar-blind photodetectors.

Pseudoactinomycotic Radiate Granules in the Gynecological Tract: A Case Report.

Actinomyces can cause severe infections in the gynecological tract, such as pelvic inflammatory disease (PID) and tubo-ovarian abscess. It's essential to accurately diagnose actinomycotic granules (AMGs) in gynecological specimens to ensure proper treatment, significantly differentiating them from pseudoactinomycotic radiate granules (PAMRAGs), a non-pathologic condition. This article describes a case of a 61-year-old postmenopausal woman with an intrauterine device (IUD) who was diagnosed with PAMRAGs in an endometrial biopsy specimen.

NIGMS Sandbox: a learning platform toward democratizing cloud computing for biomedical research.

Biomedical data are growing exponentially in both volume and levels of complexity, due to the rapid advancement of technologies and research methodologies. Analyzing these large datasets, referred to collectively as "big data," has become an integral component of research that guides experimentation-driven discovery and a new engine of discovery itself as it uncovers previously unknown connections through mining of existing data. To fully realize the potential of big data, biomedical researchers need access to high-performance-computing (HPC) resources.