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Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage. [ABSTRACT FROM AUTHOR]

The timely enrollment of study participants is critical to the success of clinical trials. Understanding factors that contribute to patients' decision to participate in trials involving online cognitive behavioural therapy for pain management should prove helpful to optimize the design of study protocols. Fracture patients from an orthopaedic clinic who declined to participate in the Cognitive behavioural therapy to Optimize Post-operative rEcovery (COPE) trial were asked to complete a Research Participation Questionnaire that asked them about their previous experiences with clinical research and mental health therapy and their reasons for declining to participate in the COPE trial. At the end of the questionnaire, a subset of participants was offered the opportunity to participate in a telephone interview to further discuss why they declined to participate in the COPE trial. Sixty-four patients who declined to participate in the COPE trial completed the questionnaire and twenty of these participants agreed to take part in a telephone interview (31%). Twenty-two participants (34%) had previous experience with clinical research and six participants (9%) had received cognitive behavioural therapy (CBT) in the past. Excessive time commitment (41%) was the most commonly selected reason for not participating in the COPE trial, followed by a disinclination to participate in clinical research (19%). Four themes emerged from the interviews with participants: 1) belief that they could overcome mental health challenges after their fracture without external help; 2) belief that CBT might be helpful for some fracture patients, but not for themselves; 3) preference for online or in-person CBT; and 4) concerns regarding time commitment. To maximize enrollment, trials exploring the role of psychotherapy in recovery from orthopedic trauma should optimize time commitment of psychotherapy. Providing information in the patient consent process regarding evidence for psychotherapy and recovery from orthopedic trauma may also prove helpful in promoting patient enrollment. [ABSTRACT FROM AUTHOR]

Background: Urine is an attractive biospecimen for nutritional status and population health surveys. It is an excellent non-invasive alternative to blood for appropriate biomarkers in young children and is suitable for home-based collection, enabling representative collections across a population. However, the bulk of literature in this population is restricted to collection in primary care settings. Feasibility of home-based collection at scale has not been tested. Here, we describe a mixed method approach to collect urine samples in a large cohort study with children under 5 years. Methods: The ORIGINS Project is an ongoing birth cohort investigating early life influences on child health outcomes in Perth, Australia. Recruitment began in 2017, with 3713 children consented by December 2022. Urine is collected longitudinally from children between 2 months and 5 years of age. Mixed methods for sample collection and return accommodates requirements across various ages and study timepoints. Uniquely, courier collection and postal kit deliveries were established in response to participant feedback regarding difficulty with in-person sample drop-offs with young children. Results: Over half of all eligible caregivers (1929/3713, 52%) returned a sample, 91% meeting quality standards. A third of all samples were returned by courier, with the highest uptake at 2–6 months of age, and increased uptake across all ages during COVID lockdowns. Caregivers cited being time-poor as the greatest barrier to sample completion and very few participants indicated difficulty with study methods. Conclusion: Our data suggests that home-based urine collection using a mixed method approach is acceptable to caregivers at a large scale, supporting the use of urine for biomarker studies and population surveys with young children. Key messages: • Urine from young children is an attractive non-invasive sample that has great potential for use in population-based health surveys and biomarker research. • Most researchers using child urine have performed the collections in a primary care setting, however, suitable methods for home collection must be developed to enable more widely representative sample collections across a population. • The ORIGINS Project has incorporated participant feedback to develop a mixed-methods strategy for urine collection and sample return in a large cohort of young children aged 2 months to 5 years. • More than half of all eligible children in The ORIGINS Project had caregivers return at least one child urine sample between 2017 and 2022. • To enable large scale urine home collections, particularly from children aged under 6 months, The ORIGINS Project recommends offering mixed methods and a courier service to increase compliance and allow continuity during periods of public health restrictions such as COVID lockdowns. [ABSTRACT FROM AUTHOR]

Background: Outcomes following surgery to operatively manage extremity fractures are variable, and up to two-thirds of patients report chronic post-surgical pain. Preliminary evidence suggests that psychotherapy directed at improving coping skills and reducing somatic vigilance may improve outcomes among fracture patients. The objective of this pilot study was to test the feasibility and acceptability of a randomized controlled trial comparing an online cognitive behavioural therapy (CBT) program versus usual care in patients with an operatively managed open or closed extremity fracture. Methods: We conducted a single-centre internal pilot study over a 10-month period in patients with at least one operatively managed open or closed fracture of the appendicular skeleton. Participants were randomized to an online CBT program or usual care and followed for 12 months. The goals of our pilot study were to determine an acceptable rate of recruitment, the degree to which participants randomized to CBT were compliant with treatment, the site investigator's ability to adhere to study protocol and data collection procedures, and our ability to achieve high follow-up rates. Feasibility criteria were evaluated using a graded "traffic light" approach, in which "green light" indicates moving forward with the definitive trial, "yellow light" indicates proceeding with modifications to the protocol and trial procedures, and "red light" indicates a definitive trial is not feasible without significant protocol and trial procedure modifications. Results: We enrolled 94 participants over 10 months, which resulted in a "yellow light" for recruitment. Participant compliance with completion of the online CBT program received a "yellow light", with 60% of participants who were randomized to CBT completing all seven modules. However, 40% of participants in the CBT-arm withdrew from the program, resulting in a "red light". Adherence with the study protocol activities at baseline was relatively high (88%) which resulted in a "yellow light". Follow-up was 85% (80 of 94) at 12 months, resulting in a "yellow light". Conclusions: These results suggest feasibility of a definitive, multi-centre trial to compare CBT versus usual care in the management of persistent post-operative pain in fracture patients despite the pilot phase identifying some challenges with enrollment timelines, compliance with the CBT program, and participant follow-up. For the definitive trial, we will expand participant recruitment to additional centres and implement strategies to optimize participant engagement and compliance with the CBT program and follow-up. Trial registration: ClincialTrials.gov (NCT04274530). Registered February 18, 2020, https://classic.clinicaltrials.gov/ct2/show/NCT04274530. [ABSTRACT FROM AUTHOR]

Fatigue is prevalent in immune-mediated inflammatory and neurodegenerative diseases, yet its assessment relies largely on patient-reported outcomes, which capture perception but not fluctuations over time. Wearable sensors, like inertial measurement units (IMUs), offer a way to monitor daily activities and evaluate functional capacity. This study investigates the relationship between sit-to-stand and stand-to-sit transitions and self-reported physical and mental fatigue in participants with Parkinson's, Huntington's, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory bowel disease. Over 4 weeks, participants wore an IMU and reported fatigue levels four times daily. Using mixed-effects models, associations were identified between fatigue and specific kinematic features, such as 5th and 95th percentiles of sit-to-stand performance, suggesting that fatigue alters the control and effort of movement. These kinematic features show promise as indicators for fatigue in these patient populations. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is produced and secreted by skeletal muscle cells during exercise and plays an important role in mediating metabolic responses to exercise. The promoter region of the IL-6 gene contains a common genetic variant (−174 G/C, rs1800795), which may alter responses to exercise training. To isolate the impact of this gene variant on exercise-induced IL-6 expression and skeletal muscle transcription responses following exercise, we generated knock-in mice with a GG or variant CC genotype for the murine homolog of rs1800795. The overall gross metabolic phenotype of resting mice was similar between genotypes; however, following acute treadmill running, the variant CC genotype was associated with a greater increase in skeletal muscle Il6 mRNA and circulating IL-6. Furthermore, we observed that mice with the variant CC genotype exhibited sex-specific differences in skeletal muscle master metabolism regulatory genes and had greater increases in genes controlling mitochondrial biogenesis in skeletal muscle post exercise. However, there was no effect of genotype on exercise-induced skeletal muscle glycogen depletion, circulating free fatty acids, blood glucose and lactate production, or exercise-responsive gene expression in subcutaneous fat. These findings suggest that the IL-6 promoter variant −174 G/C may result in enhanced skeletal muscle adaptations in response to exercise training and could mean that individuals with the "C" allele may more readily gain improvements in metabolic health in response to exercise training. NEW & NOTEWORTHY: Interleukin-6 (IL-6) is produced and secreted by skeletal muscle during exercise and mediates metabolic responses to exercise. A common variant in the IL-6 promoter region (−174G/C) may alter responses to exercise training. Mice with the variant "CC" genotype exhibited higher skeletal muscle IL-6 mRNA and circulating IL-6 levels post exercise, as well as altered skeletal muscle gene transcription. This suggests that this variant might enhance muscle adaptations to exercise, potentially benefiting metabolic health. [ABSTRACT FROM AUTHOR]

Vocalizations are potential indicators of pain in animals. We recorded and analyzed spectrographically the vocalizations of harbor seal pups (Phoca vitulina) before, during, and after the routine procedures of flipper tagging and microchipping prior to release from a rehabilitation facility in British Columbia, Canada. It is standard practice for these procedures to be done without analgesia. In Experiment 1, we compared vocalizations before and after the procedures (n = 21); in Experiment 2, we compared vocalizations in response to real and sham procedures (n = 10). In Experiment 1, seals produced more vocalizations, and peak frequency was higher, after tagging and after microchipping. In Experiment 2, seals also produced more vocalizations after real but not after sham tagging and microchipping. The average peak frequency was higher after each procedure, but not after each sham procedure. These results suggest that an increase in the number and peak frequency of vocalizations are indicators of pain in seal pups. The results also suggest that analgesia, when feasible, should be considered for harbor seal pups undergoing routine flipper tagging and microchipping. [ABSTRACT FROM AUTHOR]

Neonatal calf diarrhea is a frequent disease of calves and may result in dehydration and metabolic acidosis. The disease causes mortality and reduces growth and future productivity. Early identification of disease improves calf outcomes and thus there is increasing interest in technological methods for detecting disease. Dehydration leads to the blood becoming more concentrated and this can be measured using serum osmolality. Research in humans has shown that saliva conductivity is correlated with serum osmolality. Saliva conductivity may therefore offer a non-invasive opportunity to assess hydration status in calves. Furthermore, as blood pH is a prognostic indicator and there is ion exchange in the salivary ducts, saliva pH may act as an indicator of metabolic acidosis. This observational study aimed to assess the relationship of saliva conductivity and pH with the clinical and biochemical parameters of calves suffering from neonatal calf diarrhea. One hundred and forty-one dairy-bred calves were recruited onto the study at approximately 1 week of age. The health of the calves was assessed daily. Calves had blood and saliva samples taken weekly until 25 days of age or the development of neonatal calf diarrhea. When calves developed diarrhea, they were sampled for three consecutive days. Hematocrit, plasma total protein, saliva pH and saliva conductivity were measured at each sampling. Saliva pH and saliva conductivity were measured using portable meters (LAQUAtwin-pH-33 and LAQUAtwin-EC22). In a subset of 30 matched samples, serum proteins and electrolytes were also measured. Saliva conductivity was not associated with diarrhea or dehydration. Saliva pH was lower in calves with diarrhea, regardless of hydration status. The Lin's concordance correlation coefficients between saliva variables and hematocrit and strong ion difference were negligible. Dehydrated calves with diarrhea had a higher hematocrit and albumin and the lowest sodium and SID. Calves with diarrhea and no dehydration had a lower plasma total protein. While saliva conductivity has been associated with measures of dehydration in humans, this does not appear to be the case in calves. Saliva pH has not previously been considered for disease detection; however as it is associated with diarrhea, further research is warranted. [ABSTRACT FROM AUTHOR]

Objectives: System-wide learning for patient safety is a core challenge for the health care sector, despite the prevalence of localised reporting and learning approaches. There is growing interest in how health care services could emulate other safety-critical sectors with the introduction of specialist safety investigation agencies to inform sector-wide safety. This paper reports on a study of the introduction and early operation of one such agency in the English health and care system. Methods: This was a qualitative interview study carried out between 2019 and 2021 and co-designed through a partnership between University researchers and the Executive Team from the Healthcare Safety Investigation Branch (HSIB) to explore the organisational development of this 'first of type' organisation. The study involved interviews with 33 internal and external stakeholders and documentary analysis of HSIB reports. Results: The study findings highlight the organisational competencies and developmental challenges experienced in the early years of HSIB operations focusing on (i) independence and fit within the wider system; (ii) the selection and scope of investigations; (iii) the methodology and investigation approach; and (iv) the skill and competencies of investigators. Conclusions: This study offers practical learning to health care decision-makers about the importance of securing independence and integration, about the production of system-wide learning, the standardisation of robust methodologies and the support for a multidisciplinary specialist workforce. [ABSTRACT FROM AUTHOR]

BAY 2413555 is a novel selective and reversible positive allosteric modulator of the type 2 muscarinic acetylcholine (M2) receptor, aimed at enhancing parasympathetic signaling and restoring cardiac autonomic balance for the treatment of heart failure (HF). This study tested the safety, tolerability and pharmacokinetics of this novel therapeutic option. REMOTE-HF was a multicenter, double-blind, randomized, placebo-controlled, phase Ib dose-titration study with two active arms. Study participants had an established diagnosis of HF with NYHA Class I-III and LVEF ≤ 45%. Patients were required to have an implanted cardiac defibrillator (ICD) or cardiac resynchronization therapy (CRT) device because of the potential for bradycardia or AV conduction delay, which may be induced by BAY 2413555. The study period included a screening and run-in period, followed by a treatment period of over 28 days, consisting of two parts, A and B, comprising 14 days each. Participants were randomized into 1 of 3 arms: a placebo arm and two BAY 2413555 arms—one receiving 1.25 mg in both Part A and Part B (BAY 1.25 mg–1.25 mg) and the other receiving 1.25 mg in Part A followed by 5 mg in Part B (BAY 1.25 mg–5 mg). The primary safety endpoint was the number of participants with treatment-emergent adverse events (TEAEs). Secondary endpoints included number of participants with high degree AV block or symptomatic pauses/ bradycardia and changes from baseline in resting heart rate after 2 and 4 weeks of dosing with BAY 2413555. Changes from baseline in heart rate recovery (HRR) at 1 and 2 min after exercise testing and chronotropic reserve (CR) were also assessed. Of the anticipated 129 participants, 22 participants were randomized: 7 to placebo, 8 to BAY 1.25 mg–1.25 mg, and 7 to BAY 1.25 mg–5 mg. The study was terminated early based on new and unexpected preclinical findings from a chronic animal toxicology study in monkeys in which evidence of increased vascular inflammation was observed, leading to a no longer favorable risk-benefit balance for the intended long-term (i.e., life-long) treatment of heart failure patients. Comparable adverse events were not encountered in REMOTE-HF. Overall, until the termination of the study, BAY 2413555 was safe and well tolerated, with no deaths or TEAEs leading to discontinuation, and no symptomatic bradycardia or AV blocks observed. There was a larger change in the mean HRR at 60 s in the pooled BAY 2413555 treatment arms in Part A (1.25 mg) compared to the placebo (+ 7.3 vs. −6.7 bpm), indicating enhanced cardiac parasympathetic activity. Administration of 1.25 mg and 5 mg BAY 2413555 was safe and well tolerated in both active treatment arms, with no concerning safety findings observed. However, due to the limited number of subjects resulting from early termination, the results should be considered with caution and viewed as exploratory. There were promising signs of target engagement, providing grounds for further exploration of the mechanism [ABSTRACT FROM AUTHOR]

We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T892.64 as important in the ELA binding site, and R1684.64 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H1684.64 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement. This study explores apelin receptor's role in cardiovascular function, identifying residues critical for binding through genetic variants, AlphaFold2 modelling and base editing in cardiomyocytes. Co-crystallization with biased agonist CMF-019 shows a unique binding mode versus endogenous peptides. [ABSTRACT FROM AUTHOR]

While corticosteroids have led to significant reduction in ASUC mortality over the last few decades, they are associated with significant side effects and up to 30% of patients have steroid refractory ASUC, which means we require safer and better therapies for patients with ASUC. Several salvage therapies have been proposed in guidelines; however, we lack high quality head-to-head randomised controlled trials to assess effectiveness and safety of these agents. Furthermore, the role of newer novel agents in ASUC management is unclear. We aim to present an up to date review and envisage future treatment of ASUC without steroids based on current trials and data. In summary, we conclude that ASUC treatment still heavily relies on corticosteroids despite the side effect profile. While infliximab and cyclosporine have extensive data, there are no prospective studies comparing them with corticosteroids as initial therapy. Novel therapies open up the possibility of oral options but require prospective data before any conclusion can be made. [ABSTRACT FROM AUTHOR]

The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis. Editor's summary: Germinal center B cells proliferate at an almost unparalleled rate, yet the metabolic pathways that fuel GC B cell proliferation are not fully understood. By metabolic profiling in murine GC B cells, Yazicioglu et al. identify that the amino acid asparagine (Asn) was up-regulated. Asn metabolism was required to regulate GC B cell metabolic homeostasis and GC function, including antibody affinity maturation and humoral immune response. When environmental Asn was limited, GC B cells used the enzyme asparagine synthetase (ASNS) for Asn production, which was up-regulated by the integrated stress response sensor GCN2. These findings implicate Asn metabolism in GC function and humoral immunity. —Hannah Isles [ABSTRACT FROM AUTHOR]

We present a portable polarimeter capable of real-time visualization of partial and fully polarized light over a broad band of wavelengths. Our system utilizes a Raspberry Pi computer with a low-cost data acquisition "HAT" and an integrated photodetection circuit. Wide bandwidth operation is achieved through digital calibration of an arbitrary retardance waveplate presented herein. All mechanical, electrical, and software components are open source and available on a GitHub repository. This completely integrated approach provides an efficient tool for modern optics research laboratories and is well-suited for educational demonstrations. [ABSTRACT FROM AUTHOR]

Aims: This study aims to evaluate the current state of endoscopy services in Pacific Island Countries (PICs) by quantifying human and material resources, including the number of trained endoscopists and nurses, the types of procedures performed, and the availability and maintenance of endoscopic equipment. Methods and Results: A mixed methods survey was conducted in 2023, targeting doctors and nurses who participated in the WGO‐FNU‐ANZGITA endoscopy training program as well as non‐participants. Survey invitations were sent through email, WhatsApp, and Facebook Messenger. Data were collected from 16 sites across 12 PICs, achieving an 85% response rate. Survey results indicated a total of 58 endoscopists (2.1/100000 population) and 52 nurses (1.9/100000 population), with a majority having received training through international partnerships. Basic endoscopy services, such as gastroscopy and colonoscopy, were widely available, but advanced procedures were limited to a few sites. Most sites reported using donated equipment, with significant challenges in equipment maintenance and repair. The availability of functional endoscopes averaged four per site. Common issues included outdated equipment, lack of qualified personnel, and insufficient funding for new equipment. Conclusion: Despite efforts to enhance endoscopy services in PICs through international collaborations, significant gaps remain, particularly in terms of advanced procedural capacity and equipment maintenance. Recommendations include expanding training programs, improving equipment maintenance infrastructure, securing funding for new equipment, and fostering stronger partnerships to support the sustainability of endoscopy services. Addressing these areas can enhance the quality and availability of endoscopy services, ultimately improving healthcare outcomes for populations in PICs. [ABSTRACT FROM AUTHOR]

This paper presents a novel genetic algorithm (GA) design for current profiling in switched reluctance machines that eliminates torque ripple (TR) while inherently guaranteeing minimal RMS currents across the machines speed range. Minimising RMS current provides an increase to machine efficiency and the elimination of TR is required for potential SRM applications such as traction vehicles. This paper proposes a novel method for intentional greater‐than‐two‐phase overlap in the algorithm design. This allows any SRM configuration capable of three or more phase conduction to utilise its full speed range with zero torque ripple, in the case where it is limited using two‐phase torque sharing. An optimal set of current profiles is created using the algorithm across the full speed range of an exemplary 8/6 SRM and these are analysed. A current profiling‐based control scheme using these results is then proposed and simulated for the 8/6 SRM. This is then compared to classical and recently published SRM control methods to highlight the merits of the overall GA design and its resultant control scheme. [ABSTRACT FROM AUTHOR]

Aims: LMNA‐related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM‐DCM trial evaluated a potential disease‐modifying therapy for LMNA‐related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM‐DCM to descriptively characterize the phenotype and progression of LMNA‐related DCM in a contemporary cohort of patients using common heart failure (HF) measures. Methods: REALM‐DCM enrolled patients with stable LMNA‐related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Results: Between 2018 and 2022, 77 patients took part in REALM‐DCM. The median patient age was 53 years (range: 23–72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentration at baseline were 42% (23–62), 403 m (173–481), 67 (18–97) and 866 pg/mL (57–5248), respectively. LVEF, 6MWT distance and KCCQ‐OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ‐OS score: 43 vs. 70), whereas NT‐proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow‐up was 73 weeks (range: 0.4–218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ‐OS and NT‐proBNP values during follow‐up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF‐related hospitalization or urgent care visit) or all‐cause death; six had NYHA Class II and four had NYHA Class III at baseline. All‐cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Conclusions: Findings confirm the significant morbidity and mortality associated with LMNA‐related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ‐OS score and NT‐proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA‐related DCM. NCT03439514. [ABSTRACT FROM AUTHOR]

Purpose: There has been concern that a shift in disability funding to the National Disability Insurance Scheme (NDIS) in Australia may have influenced paediatric speech and language intervention to involve parents less in service delivery. This study aimed to describe paediatric speech-language pathologists' (SLPs) practices and perceptions of parent involvement in NDIS-funded speech and/or language intervention. Method: Seventy-two paediatric SLPs currently practicing in Australia with NDIS-funded speech and/or language clients completed an online survey. The survey assessed SLPs' self-reported practices supporting parent involvement through Likert scale responses and included open-text questions about perceived barriers and facilitators in NDIS-funded intervention services. Results from the survey were analysed using descriptive statistics, significance testing, and thematic analysis. Result: The majority of SLPs indicated commitment to involving parents in intervention. Experienced SLPs used more family-centred practices and Department of Education (DE)-based SLPs used fewer. Barriers arose from SLP, parent, and workplace characteristics. Facilitators included communication and rapport building, utilising a family-centred model of service delivery, and parent characteristics. Conclusion: This self-selected sample of Australian SLPs utilised many techniques to facilitate parent involvement within NDIS-funded paediatric speech and language intervention. Results indicate NDIS-funded SLP services for families are family focused. [ABSTRACT FROM AUTHOR]

Background: Cancer survivors can be at risk of cardiovascular disease (CVD) because of either their malignancy or its treatment. Although studies linking cancer and CVD exist, few examine risk in older adults, the impact of cancer treatment, or the effect of aspirin on reducing risk in this cohort. Methods: The authors conducted a secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial to investigate the impact of cancer and cancer treatment on a composite CVD end point comprising hospitalization for heart failure (HHF), myocardial infarction (MI), and stroke. Results: Of 15,454 Australian and US ASPREE participants, 1392 had an incident cancer diagnosis. Rates of CVD were greater in the cancer risk‐set compared to the cancer‐free risk‐set (20.8 vs. 10.3 events per 1000 person‐years; incidence rate ratio, 2.03; 95% confidence interval, 1.51–2.66), with increased incidence seen across MI, HHF, overall stroke, and ischemic stroke. Increased incidence remained after adjustment for clinically significant risk factors for CVD. Incidence was greatest in metastatic, hematological, and lung cancer. Chemotherapy was associated with increased risk of CVD. Similar rates of CVD were seen across aspirin and placebo groups. Conclusions: Incidence of CVD, including MI, HHF, and ischemic stroke, was increased in older adults with cancer. Aspirin did not impact CVD incidence. Risk may be higher in those with metastatic, hematological, and lung cancer, and following chemotherapy. Cancer and its treatment may predispose patients to cardiovascular disease. In the study, the authors demonstrated increased risk of cardiovascular disease in older adults with cancer, particularly following chemotherapy. [ABSTRACT FROM AUTHOR]

This paper compares the performance of fin plate joints designed with and without seismic considerations under gravity loading and fire conditions. The non-seismic design, following British detailing provisions, has a thicker fin plate located higher on the beam web and it positions the beam web closer to the column face compared to the seismic design detail based on New Zealand provisions. Finite elements in ABAQUS are used to model the subassembly, which is subjected to the ISO 834 fire with and without a cooling phase. The analyses indicate the same failure mode in both subassemblies, with yielding at the beam web top bolt hole in bearing and fracture of the top bolt in shear. However, under the same fire regime, peak compressive and moment demands of the seismic detail were approximately 25% less than those for the non-seismic detail. When subjected to heating only, time to runaway failure was similar for the seismic and non-seismic detail, occurring at 15.0 and 14.8 min into the analyses respectively. When a cooling phase was included, beginning 10 min after initial fire exposure, both subassemblies recovered without failure. A parametric study showed a larger gap between the beam end and column face decreased compression in the beam but did not significantly affect the failure characteristics of the joint. Use of thicker fin plates was also found to increase the time to failure. The results show that the seismic detailing provides limited improvement over the non-seismic detail for the analysed fin plates. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal mental health problems are associated with morbidity for the pregnant person, and their infants are at long-term risk for poor health outcomes. We aim to explore how the SARS-CoV-2 pandemic affected the mental health of pregnant people in the United Kingdom (UK), and to further identify resilience factors which may have contributed to varying mental health outcomes. We also aim to examine the quality of antenatal care provided during the pandemic in the UK and to identify potential inadequacies to enhance preparedness for future events. Methods: During June-November 2020, we recruited 3666 individuals in the UK for the EPPOCH pregnancy cohort (Maternal mental health during the COVID-19 pandemic: Effect of the Pandemic on Pregnancy Outcomes and Childhood Health). Participants were assessed for depression, anxiety, anger and pregnancy-related anxiety using validated scales. Additionally, physical activity, social support, individualized support and personal coping ability of the respondents were assessed as potential resilience factors. Results: Participants reported high levels of depression (57.05%), anxiety (58.04%) and anger (58.05%). Higher levels of social and individualized support and personal coping ability were associated with lower mental health challenges. Additionally, pregnant individuals in the UK experienced higher depression during the pandemic than that reported in Canada. Finally, qualitative analysis revealed that restrictions for partners and support persons during medical appointments as well as poor public health communication led to increased mental health adversities and hindered ability to make medical decisions. Discussion: This study revealed increased mental health challenges among pregnant individuals in the UK during the SARS-CoV-2 pandemic. These results highlight the need for reassessing the mental health support measures available to pregnant people in the UK, both during times of crisis and in general. [ABSTRACT FROM AUTHOR]

Background and purpose: The number of older people in prisons is increasing across the globe. Many have poor physical and mental health, higher prevalence of head injury, cognitive impairment and dementia than found in community populations. Meeting the complex needs of this vulnerable group has become an increasing concern for prison and prison healthcare services. The aim of this multi method qualitative study was to investigate how men with diagnosed or suspected dementia were identified, assessed, and cared for in Scottish prisons. It also explored the lived experience of individuals being assessed for or diagnosed with dementia within four prisons. The data from twenty nine interviews was thematically analysed and used to collaboratively propose principles for dementia care in prison and present the resultant co-designed care pathway. Results: At the time of data collection almost all the men known to have a dementia diagnosis or suspected dementia had complex health and social care needs, and some were living with advanced dementia. Prison healthcare staff reported taking a 'case by case' approach to their pre- and post-diagnostic care. Meeting these prisoner's needs was complicated by the absence of organisational leads for care of older adults or people with dementia and there was no pathway or model in place to guide staff. Prison healthcare teams often had difficulty accessing specialist community services to support diagnosis. There was a lack of dementia education and knowledge about how to provide pre and post diagnostic dementia care in this setting amongst staff. The findings arising from this research have informed the co-production of two important evidence informed innovations namely a Model of Care and a pre- and post-diagnostic Care Pathway. Conclusion: This research adds insights critical to understanding the adequacy of current approaches to meeting dementia related needs within the prison setting. To our knowledge this paper offers the first co-produced evidence informed pre- and post- diagnostic dementia care pathway and model of care for use in prisons. These could serve as tools for change that could enable prison healthcare staff to deliver the right care, at the right time, by the right people, and provide an opportunity to assess risk and plan care for the future. [ABSTRACT FROM AUTHOR]

Recent research has demonstrated that mindfulness-based meditation facilitates basic aspects of cognition, including memory and attention. Further developing this line of inquiry, here we considered the possibility that similar effects may extend to another core psychological process—instrumental learning. To explore this matter, in combination with a probabilistic selection task, computational modelling (i.e., reinforcement drift diffusion model analysis) was adopted to establish whether and how brief mindfulness-based meditation influences learning under conditions of uncertainty (i.e., choices based on the perceived likelihood of positive and negative outcomes). Three effects were observed. Compared with performance in the control condition (i.e., no meditation), mindfulness-based meditation (1) accelerated the rate of learning following positive prediction errors; (2) elicited a preference for the exploration (vs. exploitation) of choice selections; and (3) increased response caution. Collectively, these findings elucidate the pathways through which brief meditative experiences impact learning and decision-making, with implications for interventions designed to debias aspects of social-cognitive functioning using mindfulness-based meditation. [ABSTRACT FROM AUTHOR]

Respiratory–swallowing coordination (RSC) is well established as an essential airway‐protective mechanism. Previous studies have used nasal airflow and/or kinematic rib cage and abdominal measures to assess respiration surrounding swallowing, meaning that the direct influence of oral respiration on RSC remains unknown. This study used a partitioned oronasal facemask to compare respiratory phase patterns measured using isolated nasal airflow with those measured using combined oronasal airflow during non‐ingestive and ingestive swallowing tasks. Twenty‐four healthy individuals with no respiratory or swallowing disorders were assessed at rest and during cued dry, 10 mL water, continuous drinking and cracker swallowing tasks. Respiratory phase patterns were determined for discrete swallows using the nasal and combined oronasal channels separately. There was variable agreement between respiratory phase patterns according to the nasal and oronasal channels across swallowing conditions. The frequency of exhale–swallow–exhale, inhale–swallow–exhale and exhale–swallow–inhale patterns increased by 2%–3% each with the addition of oral flow data to nasal data, whereas the prevalence of inhale–swallow–inhale and ambiguous patterns decreased. This suggests that estimates of respiratory phase patterns are altered minimally by inclusion of oral respiratory estimates in a healthy sample. There were several additional findings of note, including lower within‐participant, within‐session trial consistency (test–retest reliability) than expected, suggesting high variability in respiratory phase patterns across trials. Additionally, data showed evidence of swallowing non‐respiratory flow at the beginning and end of the respiratory–swallowing pause, moving in both inward and outward directions, potentially expanding current understanding of swallowing non‐respiratory flow. Further in‐depth physiological investigations are required to improve understanding of these findings. What is the central question of this study?What is the impact of mouth breathing on the frequency of respiratory phase patterns for respiratory–swallowing coordination?What is the main finding and its importance?Added oral flow appeared to alter respiratory phase patterns minimally in healthy individuals. This was probably attributed to increased clarity of the respiratory flow signal, aiding interpretation of respiratory data. This suggests that mouth breathing might impact measurement of respiratory phase patterns. These findings might have implications for the methods used to assess respiratory phase patterns and broader respiratory–swallowing coordination, particularly in patient populations prone to mouth breathing. [ABSTRACT FROM AUTHOR]

Maine is a largely rural state where nearly half of the population uses drinking water from private wells. Arsenic (As) is present in some Maine groundwater, has been linked to cancer, and a lack of testing and treatment may expose people with private wells to elevated As levels. Disinfection byproducts (DBPs) include known and suspected carcinogens that form when chlorine or chloramines are added to water. People served by public water systems may be exposed to elevated levels of regulated DBPs such as trihalomethanes and haloacetic acids associated with chlorine and/or unregulated nitrogenous DBPs, or N-DBPs, such as nitrite and N-nitrosodimethylamine associated with chloramines. Contrary to initial expectations, there were no significant associations between median town As in well water and bladder, lung, kidney, or skin cancer incidence. Furthermore, bladder, melanoma, and other skin cancer incidence rates were negatively correlated with the percent of the town population using private wells. Analysis of cancer incidence associated with chlorine and chloramine disinfection showed elevated melanoma, and other skin cancer with chloramine use and elevated bladder and non-melanoma skin cancer with chlorine use compared to the no disinfectant case. We recommend more research on the links between disinfectant use and cancer. [ABSTRACT FROM AUTHOR]

Recognising sex differences in disease prevalence can lead to clues as to its pathogenesis, for example the role of hormonal factors and related influences such as body composition, as well as forming the basis for new treatments. However, if different methods are used to define the disorder it can be difficult to explore differences in prevalence, making it necessary to draw on multiple sources of evidence. This narrative review addresses sex differences in the prevalence of knee and hip osteoarthritis, which are the most common forms of large joint osteoarthritis. Females appear to have a higher prevalence of knee osteoarthritis across a wide range of disease definitions, while findings for the hip vary depending on how the disease is defined. Clinically or symptomatically defined hip osteoarthritis is more common in females, whereas radiographically defined hip osteoarthritis is more common in males. Therefore, understanding sex differences in large joint arthritis requires consideration that osteoarthritis, as defined structurally, more commonly affects females at the knee, whereas the opposite is true at the hip. Furthermore, despite structural changes in hip osteoarthritis being more common in males, symptomatic hip osteoarthritis is more common in females. The basis for these disparities is currently unclear, but may reflect a combination of hormonal, biomechanical and behavioural factors. [ABSTRACT FROM AUTHOR]

Introduction: Congenital hypopituitarism (CH) is characterized by the deficiency of pituitary hormones. Among CH patients, 85% lack a molecular diagnosis. Whole Exome Sequencing (WES) identified a homozygous variant (c.865G>A, p.Val289Ile) in the CDH2 gene, responsible for N-Cadherin production, crucial for cell-cell adhesion. Predicted to be likely pathogenic, the variant was found in a patient deficient in GH, TSH, ACTH, and LH/FSH. Its impact on cell adhesion was confirmed in L1 fibroblast cell lines. Objective: Create a cdh2 knockdown in zebrafish for investigating its role in pituitary development through growth hormone and transcription factors expression. Methods: Utilized pET28B-RfxCas13d-His plasmid for Cas13 mRNA production via in vitro transcription, guiding Cas13 to cdh2 with three RNAs. Injected the complex into single-cell embryos for analysis up to 96 hpf. Assessed gene expression of cdh2, prop1, pit1, and gh1 using RT-qPCR. Evaluated cdh2 protein expression through the western blot technique. Results: Knockdown animals displayed developmental delay. The cdh2 expression decreased by 75% within 24 hours, rebounded by 48 hours, and reached wild-type levels by 96 hpf. gh1 expression decreased at 48h but increased by 96 hpf, aligning with WT. No significant differences in prop1 and pit1 expression were observed. Conclusion: Our findings underscore cdh2's role in pituitary development and hormonal regulation, offering insights for developmental biology research. [ABSTRACT FROM AUTHOR]

Recognising sex differences in disease prevalence can lead to clues as to its pathogenesis, for example the role of hormonal factors and related influences such as body composition, as well as forming the basis for new treatments. However, if different methods are used to define the disorder it can be difficult to explore differences in prevalence, making it necessary to draw on multiple sources of evidence. This narrative review addresses sex differences in the prevalence of knee and hip osteoarthritis, which are the most common forms of large joint osteoarthritis. Females appear to have a higher prevalence of knee osteoarthritis across a wide range of disease definitions, while findings for the hip vary depending on how the disease is defined. Clinically or symptomatically defined hip osteoarthritis is more common in females, whereas radiographically defined hip osteoarthritis is more common in males. Therefore, understanding sex differences in large joint arthritis requires consideration that osteoarthritis, as defined structurally, more commonly affects females at the knee, whereas the opposite is true at the hip. Furthermore, despite structural changes in hip osteoarthritis being more common in males, symptomatic hip osteoarthritis is more common in females. The basis for these disparities is currently unclear, but may reflect a combination of hormonal, biomechanical and behavioural factors. [ABSTRACT FROM AUTHOR]

In recirculating aquaculture systems (RASs), ammonia excreted by fish must be converted to the less toxic nitrate before recirculation. Nitrifying microorganisms in biofilters used for this transformation can be sensitive to changes in salinity, which can present issues for systems that raise anadromous fish such as Atlantic salmon. Freshwater biofilters maintained at a low level of salinity (such as biofilters operated in coastal areas) may be better equipped to handle more drastic salinity shifts; therefore, experiments were performed on freshwater and low-salinity (3 ppt) biofilters to assess their ability to recover nitrification activity after an abrupt change in salinity (3, 20, and 33 ppt). Two-week tests showed full nitrification recovery in freshwater biofilters after a shift to 3 ppt but no ammonia oxidation in 20 or 33 ppt. Low-salinity-adapted filters (transitioned from 0 to 3 ppt) showed a small recovery (about 11%) after a shift to 20 ppt, and no activity when shifted to 33 ppt. Illumina sequencing revealed that, while nitrification was slowed or stopped with shifting salinities, the nitrifiers survived the salinity increases; conversely, the heterotrophic communities were more greatly affected and were reduced in proportion with increasing salinity. This work indicates that biofilters operated at low salinity may recover more quickly after large salinity changes, though this slight benefit may not outweigh the cost of low-level salinity maintenance. Further research into halotolerant heterotrophs in biofilms may increase the effectiveness of nitrifying biofilters under variable salinities. [ABSTRACT FROM AUTHOR]

Background/Objectives: The importance of family carer dementia education is highlighted in research, practice guidance, and policy. Less attention is paid to how facilitators learn and prepare for their role. This research aimed to explore and describe facilitator learning experiences within a bespoke Scottish Carers' Academy designed around a theory-guided approach called Care Empathia. A healthcare and university partnership ensured integration with services and the fusion of dementia higher education know-how with clinical practice expertise. Methods: Nineteen facilitator questionnaires were completed from two Carer Academy hubs; thirteen participated in online focus groups. Results: The questionnaire findings highlighted the learning gained from being a facilitator, observing expert facilitators in action, and listening to the testimonies of family carers. The framework analysis of the focus group data identified six themes, including safe learning approaches, the art of facilitation, emotional work, team learning, and leadership. These findings highlight the importance of facilitator preparation and the advantages of co-delivery models that combine clinical and practice education expertise. Conclusion: Facilitators need to understand how to walk the talk of theory-guided educational models, be open to reciprocity in learning, and be prepared for the emotional work of delivering trauma-informed practical dementia care education to family carers. [ABSTRACT FROM AUTHOR]

Individuals diagnosed with Parkinson's disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal mental health problems are associated with morbidity for the pregnant person, and their infants are at long-term risk for poor health outcomes. We aim to explore how the SARS-CoV-2 pandemic affected the mental health of pregnant people in the United Kingdom (UK), and to further identify resilience factors which may have contributed to varying mental health outcomes. We also aim to examine the quality of antenatal care provided during the pandemic in the UK and to identify potential inadequacies to enhance preparedness for future events. Methods: During June-November 2020, we recruited 3666 individuals in the UK for the EPPOCH pregnancy cohort (Maternal mental health during the COVID-19 pandemic: Effect of the Pandemic on Pregnancy Outcomes and Childhood Health). Participants were assessed for depression, anxiety, anger and pregnancy-related anxiety using validated scales. Additionally, physical activity, social support, individualized support and personal coping ability of the respondents were assessed as potential resilience factors. Results: Participants reported high levels of depression (57.05%), anxiety (58.04%) and anger (58.05%). Higher levels of social and individualized support and personal coping ability were associated with lower mental health challenges. Additionally, pregnant individuals in the UK experienced higher depression during the pandemic than that reported in Canada. Finally, qualitative analysis revealed that restrictions for partners and support persons during medical appointments as well as poor public health communication led to increased mental health adversities and hindered ability to make medical decisions. Discussion: This study revealed increased mental health challenges among pregnant individuals in the UK during the SARS-CoV-2 pandemic. These results highlight the need for reassessing the mental health support measures available to pregnant people in the UK, both during times of crisis and in general. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal mental health problems are associated with morbidity for the pregnant person, and their infants are at long-term risk for poor health outcomes. We aim to explore how the SARS-CoV-2 pandemic affected the mental health of pregnant people in the United Kingdom (UK), and to further identify resilience factors which may have contributed to varying mental health outcomes. We also aim to examine the quality of antenatal care provided during the pandemic in the UK and to identify potential inadequacies to enhance preparedness for future events. Methods: During June-November 2020, we recruited 3666 individuals in the UK for the EPPOCH pregnancy cohort (Maternal mental health during the COVID-19 pandemic: Effect of the Pandemic on Pregnancy Outcomes and Childhood Health). Participants were assessed for depression, anxiety, anger and pregnancy-related anxiety using validated scales. Additionally, physical activity, social support, individualized support and personal coping ability of the respondents were assessed as potential resilience factors. Results: Participants reported high levels of depression (57.05%), anxiety (58.04%) and anger (58.05%). Higher levels of social and individualized support and personal coping ability were associated with lower mental health challenges. Additionally, pregnant individuals in the UK experienced higher depression during the pandemic than that reported in Canada. Finally, qualitative analysis revealed that restrictions for partners and support persons during medical appointments as well as poor public health communication led to increased mental health adversities and hindered ability to make medical decisions. Discussion: This study revealed increased mental health challenges among pregnant individuals in the UK during the SARS-CoV-2 pandemic. These results highlight the need for reassessing the mental health support measures available to pregnant people in the UK, both during times of crisis and in general. [ABSTRACT FROM AUTHOR]

Background Internationally, person-centred care (PCC) is embedded in the language of regulations and mandated to be practised in residential aged care (RAC). Despite this, PCC has not been fully adopted in RAC in Australia and internationally, and concerns about the quality of care persist. Over the past 2 decades, Montessori for dementia and ageing has been introduced in RAC to support and inform a cultural change towards PCC. This study aimed to examine the intersection between the goals and approaches of Montessori and PCC in RAC. Methods This qualitative descriptive study reports on a secondary analysis of qualitative data from focus groups (FGs) and interviews with residents, family-members, staff, and volunteers from eight RAC homes in Victoria, Australia. Sixteen FGs and 36 interviews were conducted. A qualitative deductive approach using researcher-developed Montessori for dementia and ageing framework for data analysis was applied. Results Findings provide support for the intersection between PCC and Montessori with participants' descriptions of PCC aligning with many of the goals and approaches of Montessori. Participants most commonly described Montessori approaches of engagement in daily tasks with purposeful roles and promoting cognitive abilities through multi-sensory stimulation. Least frequently-described approaches included focusing on residents' strengths/abilities, maintaining function, using familiar objects, and guided repetition. Conclusions Findings have important implications for practice to use Montessori as a vehicle that supports and upskills the workforce to deliver care that is person-centred. Future research must examine the resources required to support the implementation and sustainability of Montessori as a vehicle for PCC. [ABSTRACT FROM AUTHOR]

Female soccer players report that the menstrual cycle (MC) can negatively impact sporting performance, with barriers identified in communicating their MC experiences to coaches and support staff. Whilst research is growing, there are few studies exploring the coaching staff perspective in soccer, and none from those at the youth level. The aim was to explore soccer coaches' awareness, perceptions and experiences of the MC and the perceived impact on performance. Thirteen coaches (female n = 4; male n = 9, aged 33 ± 9 years) from Scottish elite adult and youth soccer participated in individual semi-structured interviews (average interview time 39 ± 11 min). Interviews were audio recorded and transcribed verbatim, with reflexive thematic analysis (RTA) performed. RTA generated three key themes from 232 meaning units: environment and culture, coach–athlete dynamic, and coach support and education. Coaches perceived a societal culture of the MC being hidden, or taboo, with similar barriers noted within the club environment. Coaches were often embarrassed to discuss the MC with players and believed players were embarrassed. Communication differed depending on the coach–athlete relationship, with trust and familiarity cited as improving comfort in communication. Coach awareness and understanding of the MC both generally and within a sporting context influenced their perceived ability to communicate and support players. Findings highlight the need to support coaches by providing MC education, and practical guidance on how to support players' health and wellbeing. Improved confidence in communication should allow players to feel supported and normalise conversations about the MC. [ABSTRACT FROM AUTHOR]

The 23 human zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases catalyze long-chain S-acylation at cysteine residues across an extensive network of hundreds of proteins important for normal physiology or dysregulated in disease. Here we present a technology to directly map the protein substrates of a specific ZDHHC at the whole-proteome level, in intact cells. Structure-guided engineering of paired ZDHHC 'hole' mutants and 'bumped' chemically tagged fatty acid probes enabled probe transfer to specific protein substrates with excellent selectivity over wild-type ZDHHCs. Chemical–genetic systems were exemplified for five human ZDHHCs (3, 7, 11, 15 and 20) and applied to generate de novo ZDHHC substrate profiles, identifying >300 substrates and S-acylation sites for new functionally diverse proteins across multiple cell lines. We expect that this platform will elucidate S-acylation biology for a wide range of models and organisms. The substrates of specific S-acyltransferases are mapped proteome-wide in live cells. [ABSTRACT FROM AUTHOR]

Climate change presents unique challenges for grape growers across the world. In Ontario, three distinct viticultural regions are experiencing climatic shifts towards warmer growing seasons. According to historical records collected from Environment and Climate Change Canada, Lake Erie North Shore has transitioned from an intermediate-to-warm growing season classification, the Niagara Peninsula from the lower to upper limits of the intermediate zone, and Prince Edward County from cool to intermediate, when analyzing their average growing season temperatures. Terroir is directly related to vine water status, an indicator of grapevine stress. Biophysical responses controlled by air temperature and precipitation include fluctuations in vapour pressure deficits, evapotranspiration, and water-use-efficiency rates, as well as soil water content levels. By conducting an extensive literature review, the development of a conceptual model addresses how variations in climatic controls, under the scope of climate change, may influence grapevine water status, biophysical responses, and associated production outcomes for Ontario vineyards. Cool-to-intermediate air temperatures, when paired with increased precipitation will lead to no or low vine stress, increasing photosynthesis and transpiration rates, and variable plant water-use-efficiency levels, producing higher yields and lower quality grapes, if no management strategies are applied. Oppositely, higher air temperature as a product of climate change, when paired with variable precipitation may produce mild-to-severe stress, reducing yield, and increasing grape quality. With the appropriate management strategies, both traditional and new, growers may be able to accommodate for the influence of climate change on their vineyards. [ABSTRACT FROM AUTHOR]

Introduction Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. Methods Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n  = 98 646) who received continuous androgen deprivation therapy (n  = 29 453), died of prostate cancer (2013-2018, n  = 3864), and received life-prolonging therapy for mCRPC (n  = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. Results Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n  = 447) or started BTA only after first bone radiotherapy (n  = 401). More patients received denosumab (n  = 825, 77%) than zoledronic acid (n  = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P  = .023), de novo metastases (OR = 1.4, P  = .005), medical oncologist involvement (OR = 2.0, P  = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P  = .034), and academic center (OR = 0.061, P  = .007). Conclusion A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy. [ABSTRACT FROM AUTHOR]

Background Women treated with hemodialysis report lower health-related quality of life (HRQoL) compared with men. Whether this is related to sex-specific (biological) (e.g. under-dialysis due to body composition differences) or gender-specific (sociocultural) factors (e.g. greater domestic/caregiver responsibilities for women) is unknown. We examined the association between sex assigned at birth, gender score and HRQoL in individuals initiating conventional and incremental hemodialysis. Methods In this prospective multi-center cohort study, incident adult hemodialysis patients were recruited between 1 June 2020 and 30 April 2022 in Alberta, Canada. Sex assigned at birth and gender identity were self-reported. Gender-related characteristics were assessed by self-administered questionnaire to derive a composite measure of gender. The primary outcome was change in Kidney Disease Quality of Life 36 physical (PCS) and mental (MCS) component scores after 3 months of hemodialysis. Results Sixty participants were enrolled (conventional hemodialysis: 14 female, 19 male; incremental hemodialysis: 12 female, 15 male). PCS improved from baseline with conventional (P = .01) but not incremental (P = .52) hemodialysis in female participants. No difference in MCS was observed by hemodialysis type in female participants. Gender score was not associated with changes in PCS in female participants, irrespective of hemodialysis type. Higher gender score was associated with increased MCS with incremental (P = .04), but not conventional (P = .14), hemodialysis (P = .03 conventional vs incremental) in female participants. No change in PCS or MCS was seen in male participants, irrespective of hemodialysis type or gender score. Conclusion In this exploratory study, conventional hemodialysis was associated with improved PCS in female participants, while incremental hemodialysis was associated with improved MCS in female participants with more roles and responsibilities traditionally ascribed to women. Large prospective studies are required to further investigate these relationships. [ABSTRACT FROM AUTHOR]

MUTYH‐associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic MUTYH variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. This narrative review is aimed at exploring the phenotypic spectrum of MAP to better characterize the MAP phenotype. Literature search was conducted to identify articles reporting on MAP‐specific phenotypes. Clinical data from 2109 MAP patients identified from the literature showed that 1123 patients (53.2%) had CRC. Some patients with CRC had no associated adenomas, suggesting that adenomas are not an obligatory component of MAP. Carriers of the two missense founder variants, and possibly truncating variants, had an increased cancer risk when compared to those who carry other pathogenic variants. It has been suggested that somatic G:C > T:A transversions are a mutational signature of MAP and could be used as a biomarker in screening and identifying patients with atypical MAP, or in associating certain phenotypes with MAP. The extracolonic and extraintestinal manifestations that have been associated with MAP include duodenal adenomas, duodenal cancer, fundic gland polyps, gastric cancer, ovarian cancer, bladder cancer, and skin cancer. The association of breast cancer and endometrial cancer with MAP remains disputed. Desmoid tumors and congenital hypertrophy of the retinal pigment epithelium (CHRPEs) are rarely reported in MAP but have long been seen in FAP patients and thus could act as a distinguishing feature between the two. This collection of MAP phenotypes will assist in the assessment of pathogenic MUTYH variants using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) Variant Interpretation Guidelines and ultimately improve patient care. [ABSTRACT FROM AUTHOR]

Background: Pathological reactivation of latent Cytomegalovirus (CMV) is triggered by inflammation and immunosuppression; both present in the pathogenesis and treatment of Inflammatory Bowel Disease (IBD). Whether CMV reactivation is associated with escalating medical therapy, further hospital admissions, or worse clinical outcomes remains controversial. This study aimed to follow up IBD patients with an index episode of CMV colitis and analyse the clinical outcomes. Methods: A retrospective study of patients with IBD treated for CMV colitis was completed. The outcome results were collected at 6-month and 12-month time points after the first episode of CMV colitis. A total of 13 patients with Ulcerative Colitis and 1 with Crohn's Disease were included. Results: CMV colitis recurrence occurred in 29% of patients at 12 months. A total of 43% of patients had changed their biologic dose at 6 months and 29% had escalated their biologic dose at 12 months. At 12 months, 36% of patients had been re-hospitalised, including three colectomies. Disease remission was only achieved by 29% of patients at 12 months. Conclusions: IBD patients with CMV colitis have substantial rates of re-hospitalisation, failed medical therapy, and colectomy. These risks may be greater at <6 months from an index episode of CMV colitis. [ABSTRACT FROM AUTHOR]

Advances in omics technologies have enabled the in-depth study of microbial communities and their metabolic profiles from all environments. Here metagenomes were sampled from piranha (Serrasalmus rhombeus) and from river water from the Rio São Benedito (Amazon Basin). Shotgun metagenome sequencing was used to explore diversity and to test whether fish microbiomes are a good proxy for river microbiome studies. The results showed that the fish microbiomes were not significantly different from the river water microbiomes at higher taxonomic ranks. However, at the genus level, fish microbiome alpha diversity decreased, and beta diversity increased. This result repeated for functional gene abundances associated with specific metabolic categories (SEED level 3). A clear delineation between water and fish was seen for beta diversity. The piranha microbiome provides a good and representative subset of its river water microbiome. Variations seen in beta biodiversity were expected and can be explained by temporal variations in the fish microbiome in response to stronger selective forces on its biodiversity. Metagenome assembled genomes construction was better from the fish samples. This study has revealed that the microbiome of a piranha tells us a lot about its river water microbiome and function. [ABSTRACT FROM AUTHOR]

Background: Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP. Objective: This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients. Method: This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected. Result: The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn's syndrome and two had nonspecific subclinical results. Conclusion: In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research. [ABSTRACT FROM AUTHOR]

Self-relevance has been demonstrated to impair instrumental learning. Compared to unfamiliar symbols associated with a friend, analogous stimuli linked with the self are learned more slowly. What is not yet understood, however, is whether this effect extends beyond arbitrary stimuli to material with intrinsically meaningful properties. Take, for example, stimulus valence an established moderator of self-bias. Does the desirability of to-be-learned material influence self-learning? Here, in conjunction with computational modelling (i.e. Reinforcement Learning Drift Diffusion Model analysis), a probabilistic selection task was used to establish if and how stimulus valence (i.e. desirable/undesirable posters) impacts the acquisition of knowledge relating to object-ownership (i.e. owned-by-self vs. owned-by-friend). Several interesting results were observed. First, undesirable posters were learned more rapidly for self compared to friend, an effect that was reversed for desirable posters. Second, learning rates were accompanied by associated differences in reward sensitivity toward desirable and undesirable choice selections as a function of ownership. Third, decisional caution was greater for self-relevant (vs. friend relevant) responses. Collectively, these findings inform understanding of self-function and how valence and stimulus relevance mutually influence probabilistic learning. [ABSTRACT FROM AUTHOR]

The personalities of leaders have been shown to impact the culture of their organizations and are also expected to have a more distal impact on the firm's financial performance. However, the authors also expect that leader gender is an important intervening variable such that exhibiting various personality dimensions may result in unique cultural and performance-based outcomes for women and men leaders. Thus, the authors seek to examine first the impact of leader personality on organizational performance, as driven through organizational culture as a mediating mechanism. In doing so, the authors propose the expected impact of specific personality dimensions on certain types of organizational cultures, and those cultures' subsequent impact on the organization's performance. The authors then extend to consider the moderating effects of leader gender on the relationship between leader personality and organization. To support their propositions, the authors draw from upper echelons and implicit leadership theories. The authors encourage researchers to consider the proposition within a sample of the largest publicly traded US companies (i.e., Fortune 500) at an important era in history such that for the first time, 10% of these companies are led by women. In doing so, the authors hope to understand the leadership dynamics at the highest echelons of corporate governance and provide actionable insights for companies aiming to optimize their leadership composition and drive sustainable performance. [ABSTRACT FROM AUTHOR]