Anomalies in Long-Crack Propagation at Low ΔK in Some Engineering Alloys.

In this article, we discuss an unusual pattern in long-crack behavior at low stress intensity factor ranges ΔK (below ΔK), characterized by an initial dip, followed by a plateau, and then an acceleration in fatigue crack growth (FCG) rate. This unanticipated FCG behavior was first observed experimentally in the IMI 834 alloy and reported by Marci in 1996. Such an anomaly is only reported from experimental observation but cannot be understood or explained using the plasticity, roughness, or oxide-induced crack closure assumptions.

Association of organ iron levels with type 2 diabetes mellitus and glycemic traits: A bidirectional two-sample Mendelian randomization study.

Introduction: Observational studies have found that higher iron levels are associated with an increased risk of diabetes mellitus. Given the limitations of causal inferences from observational studies and the expensive and time-consuming nature of randomized controlled trials, Mendelian randomization analysis presents a reasonable alternative to study causal relationships. Previous MR analyses studying iron levels and diabetes have used indirect markers of iron levels, such as serum ferritin, and found conflicting results.

IPNA clinical practice recommendations on care of pediatric patients with pre-existing kidney disease during seasonal outbreak of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, instigated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has profoundly impacted healthcare infrastructures around the globe. While children are usually asymptomatic or have mild symptoms, children with pre-existing kidney conditions require specialized attention. This pivotal report, championed by the International Pediatric Nephrology Association (IPNA), delivers precise and actionable recommendations tailored for pediatric patients with kidney ailments in this pandemic landscape.

Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: a multicenter real-world cohort study.

Background/aims: Upadacitinib is a novel selective Janus kinase inhibitor approved for use in ulcerative colitis. Clinical trials had rigorous criteria and excluded many patient subgroups. Given limited real-world effectiveness data, we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population.

Harnessing the FBXW7 somatic mutant R465C for targeted protein degradation.

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance the applicability of this strategy across various biological contexts. In this study, we discovered that a somatic mutant of FBXW7, R465C, can be exploited by heterobifunctional compounds for targeted protein degradation.

transplantation of intrahepatic cholangiocyte organoids with decellularized liver-derived hydrogels supports hepatic cellular proliferation and differentiation in chronic liver injury.

The limited replicative potential of primary hepatocytes (Hep) is a major hurdle for obtaining sufficient quantity and quality hepatocytes during cell therapy in patients with liver failure. Intrahepatic cholangiocyte organoids (ICOs) derived from intrahepatic bile ducts differentiate into both hepatocytes and cholangiocytes . Here, we studied effects of transplanting ICOs and Hep in chronic liver injury mice models.

C3 glomerulopathy in children: experience at a resource-limited center.

Background: In children, C3 glomerulopathy (C3G) is a heterogeneous disease characterized by diverse clinicopathological profiles and kidney outcomes. However, diagnostic work-up in resource-limited settings is challenging because of the unavailability of complement assays and limited access to electron microscopy or genetic testing.

Purpose: This study aimed to describe the clinicopathological features and response to immunosuppression and evaluate renal outcomes among children with C3G in a resource-limited setting.

Lipid nanoparticle delivery of TALEN mRNA targeting LPA causes gene disruption and plasma lipoprotein(a) reduction in transgenic mice.

Lipoprotein(a), or Lp(a), is encoded by the LPA gene and is a causal genetic risk factor for cardiovascular disease. Individuals with high Lp(a) are at risk for cardiovascular morbidity and are refractory to standard lipid-lowering agents. Lp(a)-lowering therapies currently in clinical development require repetitive dosing, while a gene editing approach presents an opportunity for a single-dose treatment.

Acceptability of Microbiota-Directed Complementary Foods in Treating Indian Children with Moderate Acute Malnutrition: eACT-MAM Pre-Proof-of-Concept Study.

Background: In India, currently, there are no standard guidelines for the management of moderate acute malnutrition (MAM). Previous research in Bangladesh has shown that children with MAM have impaired gut microbiota development, and microbiota-directed complementary foods (MDCF) can potentially repair their gut microbiota.

Objectives: The objectives of this study were to evaluate the acceptability and safety of supplementing shelf-stable formulation of MDCF in Indian children with MAM as compared with a locally prepared ready-to-use supplementary food (RUSF) in 3 geographically distinct Indian populations and to establish and pilot systems of intervention delivery, collection, transport, and storage of stool samples using stringent protocols.

Clinical and Technical Validation of OncoIndx Assay-A Comprehensive Genome Profiling Assay for Pan-Cancer Investigations.

Comprehensive next-generation sequencing (NGS) assays enable the identification of clinically relevant mutations, enhancing the capability for targeted therapeutic interventions. In addition, genomic alterations driving the oncogenic roadmap and leading to resistance mechanisms are reshaping precision oncology. We report the workflow and clinical and technical validation of the OncoIndx NGS platform-a comprehensive genomic profiling (CGP)-based assay for pan-cancer investigation.

Profiling Molecular Changes of Host Response to Predict Outcome in Children with Septic Shock.

Background: Septic shock is associated with high mortality and there is significant heterogeneity in the host response. The aim of this study was to understand the genome-wide expression transcriptomic signatures in children with septic shock and correlate them with outcomes.

Methods: This was a prospective study conducted on children (aged 1 month to 18 years) admitted to the PICU (June-December 2021) with septic shock.

Examining dietary interventions in Crohn's disease.

This editorial builds on the article by Shakhshir . We conducted an overview of evidence-based dietary interventions in adults with inflammatory bowel disease (IBD). In the IBD population, there may be a role for the Mediterranean diet due to its anti-inflammatory effects, long-term sustainability, and role in improving cardiovascular health.

A multicomponent nanosystem for capturing circulating tumor cells from cancer patients with PD-L1 as an immunotherapy oncotarget.

Capturing circulating tumor cells (CTCs) from the peripheral blood of cancer patients, where they are disseminated among billions of other blood cells, is one of the most daunting challenge. We report OncoDiscover®, a multicomponent nano-system consisting of iron oxide (FeO) nanoparticles (NPs), polyamidoamine generation 4 dendrimers (PAMAM-G4-NH), graphene oxide (GO) sheets and an anti-epithelial cell adhesion molecule (anti-EpCAM) antibody (Fe-GSH-PAMAM-GO-EpCAM) for the selective and precise capture of CTCs. We further evaluated this system for therapeutically important oncotargets, exemplifying overexpression of the programmed death ligand 1 (PD-L1) as a functional assay on CTCs in cancer patients.

Higher sodium in older individuals or after stroke/reperfusion, but not in migraine or Alzheimer's disease - a study in different preclinical models.

Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts.

Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study.

Background: The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision.

Objectives: This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis.

Methods: A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.

Long-Term Amino Acid Homeostasis, Neurodevelopmental and Growth Profiles Following Liver Transplantation in Maple Syrup Urine Disease.

Introduction: Maple syrup urine disease (MSUD) is caused by the deficiency of branched-chain keto acid dehydrogenase (BCKAD) and, it is well described that BCKAD contributed by an allograft following liver transplantation (LT) phenotypically normalizes this inborn error of metabolism (IEM). There is, however, a paucity of data especially with regards to the neurodevelopmental aspects and catch-up growth profiles after LT in a resource-challenged setting. We present our series of children under 6 years of age who underwent LT for MSUD particularly focusing on their amino acid homeostasis, neurodevelopmental and somatic growth profiles.

Effect of digital tools to promote hospital quality and safety on adverse events after discharge.

Objectives: Post-discharge adverse events (AEs) are common and heralded by new and worsening symptoms (NWS). We evaluated the effect of electronic health record (EHR)-integrated digital tools designed to promote quality and safety in hospitalized patients on NWS and AEs after discharge.

Materials And Methods: Adult general medicine patients at a community hospital were enrolled.

Secondary bile acids in portal blood contribute to liver regeneration in a rat model of partial hepatectomy.

Gut metabolites via the portal vein affect several liver functions, including regeneration. Here, we investigated gut microbiota-derived metabolites in portal and peripheral serum during liver regeneration. We developed rat models of 70% partial hepatectomy (PHx) with and without prior gut microbiota modulation by three-week antibiotic (Abx) treatment.

Physical presence of chemical synapses is necessary for turning behavior of anterograde synaptic vesicles at the branch point of PLM neurons in .

Neurons exhibit complex branched axonal morphologies in both vertebrate and invertebrate systems, and show heterogeneity in the distribution of synaptic cargo across multiple synapses. It is possible that differences in transport across multiple branches contribute to the heterogeneity in cargo distribution across multiple synapses. However, the regulation of transport at axonal branch points is not well understood.

Quantitative Measurement of Rate of Targeted Protein Degradation.

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects.

Approach to loss of response to advanced therapies in inflammatory bowel disease.

Background: Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem.