Beyond expectations: investigating nilotinib's potential in attenuating neurodegeneration in alzheimer's disease.

Neurodegenerative diseases, such as Alzheimer's disease (AD), pose a formidable global challenge. While therapeutic options are available, their limitations are significant, necessitating the development of innovative treatment approaches. Here, we highlight the importance of repurposing drugs and discuss the future of drug treatments for AD.

Transitioning from night to day transplants: changing the transplant culture for optimisation through a province-wide quality improvement initiative.

Background: Organ transplants, some of the most complex operations, have historically been performed overnight due to logistical challenges in healthcare systems. Overnight transplants contribute to transplant team burnout and can compromise patient outcomes. A province-wide quality improvement (QI) initiative was launched to increase the daytime operation rate to ≥80%.

Ableism After Critical Illness: A Qualitative Translation of Key Concepts to the Post-ICU Context.

Objectives: Ableism-discrimination and social prejudice against people with disabilities-defines people by their disability and assumes that disabled people require fixing. We sought to characterize ableism after critical illness and to describe its relationship with care delivery.

Design: A secondary analysis of semi-structured individual interviews (n = 42) and ten group interviews (n = 68 participants) using modified grounded theory.

The left renal vein: the optimal interposition graft for pancreatic surgery?

Background: Porto-mesenteric venous resection (PMVR) is employed for advanced pancreatic cancer. When primary anastomosis is not feasible, an interposition graft can be used. At our centre, the left renal vein (LRV) is the preferred choice.

Evolution of Human Pair Bonds as a Consequence of Male-Biased Mating Sex Ratios?

Compared to our closest primate relatives, human life history involves greater longevity, which includes a distinctive postmenopausal life stage. Given mammalian reproductive physiology in which females build a finite stock of cells that can become oocytes early in life, which then continuously deplete mostly through cell death while males produce new sperm throughout adulthood, the postmenopausal stage makes the sex ratio in the fertile pool, called the adult sex ratio (ASR), male biased. Additionally, this affects a more fine-grained ratio, the operational sex ratio (OSR), defined as the ratio of males to females currently able to conceive.

Temporal trends of inflammatory bowel disease: Nationwide study from 2010 to 2020.

This study examined inflammatory bowel disease (IBD) trends over the last 10 years, including their nationwide patterns, and the outcomes of the utilization of total parental nutrition (TPN). Nationwide inpatient sample (NIS) database from 2010 to 2020, was used to identify IBD hospitalization and discharges and investigate outcomes, including in-hospital mortality and hospital resource utilization. The hospitalizations for IBD combining both Crohn's disease (CD) and ulcerative colitis (UC) initially noted a rising trend until 2016 followed by a decreasing trend with statistical significance ( < 0.

ACTIV trials: cross-trial lessons learned for master protocol implementation.

The United States Government (USG) public-private partnership "Accelerating COVID-19 Treatment Interventions and Vaccines" (ACTIV) was launched to identify safe, effective therapeutics to treat patients with Coronavirus Disease 2019 (COVID-19) and prevent hospitalization, progression of disease, and death. Eleven original master protocols were developed by ACTIV, and thirty-seven therapeutic agents entered evaluation for treatment benefit. Challenges encountered during trial implementation led to innovations enabling initiation and enrollment of over 26,000 participants in the trials.

Engineering a SARS-CoV-2 Vaccine Targeting the Receptor-Binding Domain Cryptic-Face via Immunofocusing.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target of neutralizing antibodies. Although they are infrequently elicited during infection or vaccination, antibodies that bind to the conformation-specific cryptic face of the RBD display remarkable breadth of binding and neutralization across . Here, we employed the immunofocusing technique PMD (protect, modify, deprotect) to create RBD immunogens (PMD-RBD) specifically designed to focus the antibody response toward the cryptic-face epitope recognized by the broadly neutralizing antibody S2X259.

Flexible Development Programs for Antibacterial Drugs to Address Unmet Medical Needs.

The US Food and Drug Administration recognizes the unmet medical need for antibacterial drugs to treat serious bacterial diseases caused by resistant pathogens for which effective therapies are limited or lacking. The agency also recognizes that designing and conducting clinical trials to assess the safety and efficacy of drugs to treat resistant infections is challenging, especially for drugs only active against a single or a few bacterial species, and that a more flexible development program might be appropriate. In this article, we discuss several regulatory considerations for flexible development programs for antibacterial drugs intended to meet an unmet medical need.

Acutely Modifying Phosphatidylinositol Phosphates on Endolysosomes Using Chemically Inducible Dimerization Systems.

Phosphoinositides are rare membrane lipids that mediate cell signaling and membrane dynamics. PI(4)P and PI(3)P are two major phosphoinositides crucial for endolysosomal functions and dynamics, making them the lipids of interest in many studies. The acute modulation of phosphoinositides at a given organelle membrane can reveal important insights into their cellular function.

A CD38/CD3xCD28 trispecific T-cell engager as a potentially active agent in multiple myeloma patients relapsed and/or refractory to anti-CD38 monoclonal antibodies.

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257.

Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39.

We previously reported that normothermic ex vivo kidney  perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS).

pHoenix score: development and validation of a novel approach to decrease the number of inconclusive GERD diagnoses.

Background: The Johnson-DeMeester composite score (DMS) is the historical gold standard for diagnosing gastroesophageal reflux disease (GERD). The Lyon Consensus outlines criteria for diagnosing GERD by pH monitoring, defining normal acid exposure time (AET) as < 4% and pathological as > 6%, presenting diagnostic uncertainty from 4 to 6%. We aimed to (i) calculate the proportion of borderline studies defined by total AET alone that are reclassified as normal or pathological by the DMS, (ii) determine the importance of supine AET for reclassification, and (iii) propose a new classification system using a composite score that considers positional changes.

Endoscopic assessment of failed fundoplications differs between endoscopists.

Background: Despite excellent long-term outcomes, a small proportion of patients who undergo fundoplication with hiatal hernia repair (laparoscopic antireflux surgery [ARS]) for treatment of gastroesophageal reflux disease (GERD) may require reoperation. Esophagogastroduodenoscopy (EGD) assessment in patients presenting with symptom recurrence plays a critical role in surgical planning of redo-ARS by confirming failure of the fundoplication and revealing the pattern of failure. We aimed to compare the findings documented by external endoscopists (i.

Dye-less quantification of tissue perfusion by laser speckle contrast imaging is equivalent to quantified indocyanine green in a porcine model.

Introduction: Subjective surgeon interpretation of near-infrared perfusion video is limited by low inter-observer agreement and poor correlation to clinical outcomes. In contrast, quantification of indocyanine green fluorescence video (Q-ICG) correlates with histologic level of perfusion as well as clinical outcomes. Measuring dye volume over time, however, has limitations, such as it is not on-demand, has poor spatial resolution, and is not easily repeatable.

Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles.

Peroxisomal cholesterol metabolism regulates yap-signaling, which maintains intestinal epithelial barrier function and is altered in Crohn's disease.

Intestinal epithelial cells line the luminal surface to establish the intestinal barrier, where the cells play essential roles in the digestion of food, absorption of nutrients and water, protection from microbial infections, and maintaining symbiotic interactions with the commensal microbial populations. Maintaining and coordinating all these functions requires tight regulatory signaling, which is essential for intestinal homeostasis and organismal health. Dysfunction of intestinal epithelial cells, indeed, is linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, and gluten-related enteropathies.

FDA, CDC, and NIH Co-sponsored Public Workshop Summary-Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.

There is an unmet need for developing drugs for the treatment of gonorrhea, due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets.

Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1.

Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC ranging from 0.

Unsupervised evolution of protein and antibody complexes with a structure-informed language model.

Large language models trained on sequence information alone can learn high-level principles of protein design. However, beyond sequence, the three-dimensional structures of proteins determine their specific function, activity, and evolvability. Here, we show that a general protein language model augmented with protein structure backbone coordinates can guide evolution for diverse proteins without the need to model individual functional tasks.