Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.

Background: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.

Methods: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk.

Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults.

Anti-CD19 chimeric antigen receptor T cells (CAR) are a well-established treatment option for children and young adults suffering from relapsed/refractory B-lineage acute lymphoblastic leukemia. Bridging therapy is used to control disease prior to start of lymphodepletion before CAR infusion and thereby improve efficacy of CAR therapy. However, the effect of different bridging strategies on outcome, side effects and response to CAR therapy is still poorly understood.

Exploring barriers to accessing health care services by young women in rural settings: a qualitative study in Australia, Canada, and Sweden.

Background: The aim of this study is to explore young rural women's perceived barriers in accessing healthcare services with a focus on the interrelation between three marginalization criteria: age (youth), gender (female), and place of residence (rural areas) in Australia, Canada, and Sweden.

Methods: Using a qualitative interpretive approach, we conducted semi-structured in-depth interviews with 31 young women aged 18 to 24 in selected rural communities. Data collection took place from May 2019 to January 2021, and the qualitative data were analyzed using NVivo software.

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.

Specific selection of stimulation-responsive γδ T-cells utilizing a short-term activation assay.

T cells expressing the γδ T-cell receptor (TCR) represent a numerically small proportion of total T cells. Unlike αβ T cells they are activated by non-peptide antigens independently of MHC-presentation. γδ T cells have been recognized as a favorable prognostic marker across different tumor entities.

SMC motor proteins extrude DNA asymmetrically and can switch directions.

Structural maintenance of chromosomes (SMC) complexes organize the genome via DNA loop extrusion. Although some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear.

Tail Tales: How Ecological Context Mediates Signal Effectiveness in a Lizard.

Animal signals are complex, comprising multiple components influenced by ecological factors and viewing perspectives that together impact their overall effectiveness. Our study explores how these factors affect the efficacy of multi-component signals in the Qinghai toad-headed agama, Phrynocephalus vlangalii. Using 3D animations, we simulated natural environments to evaluate how tail coiling and tail lashing-two primary tail displays-vary in effectiveness from both conspecific and predator perspectives under different ecological conditions.

Enhancing young people's pregnancy loss and fertility awareness and knowledge via schools: a way forward.

Pregnancy and infant loss, in the form of miscarriage, stillbirth or early neonatal death, occurs in 20-25% of all pregnancies. Despite its prevalence and associated physical and psychological impacts, there remains a lack of public awareness and understanding of pregnancy loss, including amongst people of reproductive age. Drawing on evidence from a preliminary review of peer-reviewed and grey literature, we make the case for enhancing pregnancy loss and (in)fertility awareness, specifically focusing on young people in second-level education.

Speech Perception in Noise After Cochlear Implantation for Single-Sided Deafness: A Randomized Clinical Trial.

Importance: There is a lack of high level of evidence studies comparing the effect of different treatment options for single-sided deafness (SSD).

Objective: To determine the effect of a cochlear implant (CI), bone conduction device (BCD), contralateral routing of signals hearing aid (CROS), and no treatment on speech perception in noise outcomes in patients with SSD.

Design, Setting, And Participants: In this single-center randomized clinical trial, adult patients with SSD were randomized into 3 groups: CI; a trial period with first a BCD on a headband and then a CROS; or a trial period with first a CROS and then a BCD on a headband.

Surveillance in inflammatory bowel disease: white light endoscopy with segmental re-inspection versus dye-based chromoendoscopy - a multi-arm randomised controlled trial (HELIOS).

Background: It remains unclear if the increased colorectal neoplasia detection rate in inflammatory bowel disease (IBD) by high-definition (HD) dye-based chromoendoscopy compared with HD white-light endoscopy is due to enhanced contrast or increased inspection times. Longer withdrawal times may yield similar neoplasia detection rates as found by HD chromoendoscopy.

Objective: To compare colorectal neoplasia detection rates for HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy, using single-pass HD white-light endoscopy as an additional control group.

A neurocomputational account of multi-line electronic gambling machines.

Multi-line electronic gambling machines (EGMs) are strongly associated with problem gambling. Dopamine (DA) plays a central role in substance-use disorders, which share clinical and behavioral features with disordered gambling. The structural design features of multi-line EGMs likely lead to the elicitation of various dopaminergic effects within their nested anticipation-outcome structure.

A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease.

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen.

Interplay of SHH, WNT and BMP4 signaling regulates the development of the lamina propria in the murine ureter.

In the mammalian ureters, the lamina propria presents as a prominent layer of connective tissue underneath the urothelium. Despite its important structural and signaling functions, little is known how the lamina propria develops. Here, we show that in the murine ureter, the lamina propria arises at late fetal stages and massively increases by fibrocyte proliferation and collagen deposition after birth.

Proteomic profiling of the large-vessel vasculitis spectrum identifies shared signatures of innate immune activation and stromal remodelling.

Background: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments.

Methods: Plasma proteomic profiling of 184 proteins was performed in two cohorts.

Cancer metastasis to the upper gastrointestinal tract-a case series.

Background: Metastasis of non-gastrointestinal (non-GI) cancers to the upper GI tract is a rare occurrence, with limited cases reported in the literature. Recognising this type of metastasis is crucial, as it presents unique diagnostic and therapeutic challenges. This case series adds to the literature by discussing seven rare cases of non-GI cancer metastasising to the upper GI tract, emphasising the complications and clinical manifestations.

A randomised phase III study of bevacizumab and carboplatin-pemetrexed chemotherapy with or without atezolizumab, as first-line treatment for advanced pleural mesothelioma: results of the ETOP 13 18 BEAT-meso trial.

Background: The currently approved frontline treatments for diffuse pleural mesothelioma (DPM) are ipilimumab-nivolumab or platinum-pemetrexed. The addition of bevacizumab to chemotherapy improves overall survival (OS). While single-agent immunotherapy or chemotherapy-immunotherapy combinations are superior to chemotherapy monotherapy, there is a potential for synergistic triple combination of chemotherapy, bevacizumab, and immunotherapy.

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis.

Polysarcosine emerges as a promising alternative to polyethylene glycol (PEG) in biomedical applications, boasting advantages in biocompatibility and degradability. While the self-assembly behavior of block copolymers containing polysarcosine-containing polymers has been reported, their potential for shape transformation remains largely untapped, limiting their versatility across various applications. In this study, we present a comprehensive methodology for synthesizing, self-assembling, and transforming polysarcosine-poly(benzyl glutamate) block copolymers, resulting in the formation of bowl-shaped vesicles, disks, and stomatocytes.

Cumulative blood pressure load and cognitive decline in older adults: An observational analysis of two large cohorts.

Introduction: Cumulative blood pressure metrics may provide greater precision for measuring temporal risk exposure, especially in later life where data are mixed regarding associations of high blood pressure (BP) on cognitive function. We examined the relationship between greater cumulative exposure to high BP in later life and several domains of cognitive function.

Methods: Individual cognitive assessment scores and BP measurements in older adults (age ≥70 years) at baseline and over approximately 8 years of follow-up were available in the population-based Canadian Victoria Longitudinal Study (VLS) and Swedish Gothenburg H70 Birth Cohort Studies (H70).

Impact of Frailty on Antihypertensive Treatment in Older Adults.

Background: The association between systolic blood pressure and all-cause mortality differs between frail and nonfrail individuals, highlighting uncertainties about the effectiveness of antihypertensive treatments in frail populations.

Methods: Using data from the SHEP trial (Systolic Hypertension in the Elderly Program), a baseline frailty index (FI), including 55 variables, was constructed. Fine-Gray subdistribution hazard models and Cox proportional hazards regression models were used to explore the association between baseline FI and the risks of stroke, cardiovascular disease, and all-cause death, as well as to examine whether the impact of antihypertensive treatment on these outcomes was modified by baseline FI.

Subgroups varying in risk and density highlight the potential for stratified breast cancer screening.

Most breast cancer screening programs rely only on demographic data without considering individual risk factors of the population, which might limit their effectiveness by over- and underscreening specific subgroups. Therefore, the aim of this study is to highlight health and economic disparities in outcomes from such a uniform screening strategy. With the microsimulation model MISCAN, we simulated outcomes of the Dutch screening program considering 16 subgroups varying by their 5-year breast cancer risk and breast density.

Severity of Impaired Oxygenation and Conservative Oxygenation Targets in Mechanically Ventilated Children: A Post Hoc Subgroup Analysis of the Oxy-PICU Trial of Conservative Oxygenation.

Objectives: A conservative oxygenation strategy is recommended in adult and pediatric guidelines for the management of acute respiratory distress syndrome to reduce iatrogenic lung damage. In the recently reported Oxy-PICU trial, targeting peripheral oxygen saturations (Spo2) between 88% and 92% was associated with a shorter duration of organ support and greater survival, compared with Spo2 greater than 94%, in mechanically ventilated children following unplanned admission to PICU. We investigated whether this benefit was greater in those who had severely impaired oxygenation at randomization.

The predictive power of baseline metabolic and volumetric [F]FDG PET parameters with different thresholds for early therapy failure and mortality risk in DLBCL patients undergoing CAR-T-cell therapy.

Objective: [F]FDG imaging is an integral part of patient management in CAR-T-cell therapy for recurrent or therapy-refractory DLBCL. The calculation methods of predictive power of specific imaging parameters still remains elusive. With this retrospective study, we sought to evaluate the predictive power of the baseline metabolic parameters and tumor burden calculated with automated segmentation via different thresholding methods for early therapy failure and mortality risk in DLBCL patients.

Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease.

Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from the earliest stages of Alzheimer's disease onwards and has been associated with symptoms of agitation. It is hypothesized that compensatory locus coeruleus-noradrenaline system overactivity and impaired emotion regulation could underlie agitation propensity, but to our knowledge this has not previously been investigated. A better understanding of the neurobiological underpinnings of agitation would help the development of targeted prevention and treatment strategies.

Maintaining level of modifiable dementia risk scores is associated with better cognitive outcomes than increasing risk scores: A population-based prospective cohort study.

Background: A brain healthy lifestyle, consisting of good cardiometabolic health and being cognitively and socially active in midlife, is associated with a lower risk of cognitive decline years later. However, it is unclear whether lifestyle changes over time also affect the risk for mild cognitive impairment (MCI)/dementia, and rate of cognitive decline.

Objectives: To investigate if lifestyle changes over time are associated with incident MCI/dementia risk and rate of cognitive decline.