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This article explores the importance of calibration in prediction models when applied to new populations. It compares different calibration approaches and introduces Elkan's general updating approach (GUA), which accounts for differences in base rates between populations without re-estimation. The article explains how calibrated probability can be expressed as a function of base rates, which are estimated using proportions of subjects with a certain outcome in training and calibration data. The text discusses two approaches for estimating base probability in a training data set: Elkan's GUA calculates the average of the target variable, while Baker's GUA suggests using the average of the conditional probability. Both approaches assume that the only difference between populations is the change in base rate and require a calibration data set. A simulation study comparing different calibration methods for machine learning models found that beta calibration performed the best, while isotonic calibration and IVAP calibration were similar. Elkan calibration and Baker calibration also showed similar performance. The article provides detailed information on the simulation scenarios and the performance of each calibration method. [Extracted from the article]

Periodontitis is a common chronic inflammatory disease, affecting approximately 19% of the global adult population. A relationship between periodontal disease and Alzheimer disease has long been recognized, and recent evidence has been uncovered to link these 2 diseases mechanistically. Periodontitis is caused by dysbiosis in the subgingival plaque microbiome, with a pronounced shift in the oral microbiota from one consisting primarily of Gram-positive aerobic bacteria to one predominated by Gram-negative anaerobes, such as Porphyromonas gingivalis. A common phenomenon shared by all bacteria is the release of membrane vesicles to facilitate biomolecule delivery across long distances. In particular, the vesicles released by P gingivalis and other oral pathogens have been found to transport bacterial components across the blood-brain barrier, initiating the physiologic changes involved in Alzheimer disease. In this review, we summarize recent data that support the relationship between vesicles secreted by periodontal pathogens to Alzheimer disease pathology. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory disease driven by dysbiosis in subgingival microbial communities leading to increased abundance of a limited number of pathobionts, including Porphyromonas gingivalis and Treponema denticola. Oral health, particularly periodontitis, is a modifiable risk factor for Alzheimer disease (AD) pathogenesis, with components of both these bacteria identified in postmortem brains of persons with AD. Repeated oral inoculation of mice with P. gingivalis results in brain infiltration of bacterial products, increased inflammation, and induction of AD-like biomarkers. P. gingivalis displays synergistic virulence with T. denticola during periodontitis. The aim of the current study was to determine the ability of P. gingivalis and T. denticola , grown in physiologically relevant conditions, individually and in combination, to induce AD-like pathology following chronic oral inoculation of female mice over 12 weeks. P. gingivalis alone significantly increased all 7 brain pathologies examined: neuronal damage, activation of astrocytes and microglia, expression of inflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 and production of amyloid-β plaques and hyperphosphorylated tau, in the hippocampus, cortex and midbrain, compared to control mice. T. denticola alone significantly increased neuronal damage, activation of astrocytes and microglia, and expression of IL-1β, in the hippocampus, cortex and midbrain, compared to control mice. Coinoculation of P. gingivalis with T. denticola significantly increased activation of astrocytes and microglia in the hippocampus, cortex and midbrain, and increased production of hyperphosphorylated tau and IL-1β in the hippocampus only. The host brain response elicited by oral coinoculation was less than that elicited by each bacterium, suggesting coinoculation was less pathogenic. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is an inherited disorder often leading to severe heart failure. Linkage studies in affected families have revealed hundreds of different mutations that can cause DCM, with most occurring in genes associated with the cardiac sarcomere. We have developed an investigational pipeline for discovering mechanistic genotype-phenotype relationships in DCM and here apply it to the DCM-linked tropomyosin mutation TPM1 M8R. Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin. Applying these molecular effects to a Markov model of the cardiac thin filament reproduced the shifts in Ca2+sensitivity, maximum force, and a qualitative drop in cooperativity that were observed in an in vitro system containing TPM1 M8R. The model was then used to simulate the impact of M8R expression on twitch contractions of intact cardiac muscle, predicting that M8R would reduce peak force and duration of contraction in a dose-dependent manner. To evaluate this prediction, TPM1 M8R was expressed via adenovirus in human engineered heart tissues and isometric twitch force was observed. The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions. Additional exploratory simulations suggest that M8R-mediated alterations in tropomyosin-actin interactions contribute more potently than tropomyosin chain stiffness to cardiac twitch dysfunction, and presumably to the ultimate manifestation of DCM. This study is an example of the growing potential for successful in silico prediction of mutation pathogenicity for inherited cardiac muscle disorders. [ABSTRACT FROM AUTHOR]

Recovery is the process of restoring performance capabilities between training sessions. Recovery strategies must be implemented to meet contextual demands, yet this process is not well-understood from an athlete perspective. Drawing on previous descriptions of self-regulation in learning, this study aimed to describe the process of implementing recovery from the perspective of endurance athletes. Twelve elite Canadian endurance athletes (6 women, 6 men; 25–31 years-old; each had competed in multiple Olympics or World Championships) participated in two semi-structured interviews, separated by 1 week of recording their thoughts, feelings, and activities of recovery in an activity journal. Through reflexive thematic analysis, we found that recovery was athlete-led; they used self-regulatory processes pertaining to self-knowledge and planning (the theme of "Knowing my body"), self-awareness and interpretation ("Listening to my body"), and self-control and adjustment ("Respecting my body"). The athletes' described their recovery as integrated with their environment; various people and places supplemented, facilitated, and provided aspects for their recovery. Our results suggest that recovery can be effectively understood as a series of athlete-led skills, supported and enhanced through specific environmental interactions, which we summarize in a novel heuristic called the Athlete Recovery Regulation Cycle. These findings advance a new perspective on recovery as a product of skills that athletes can develop to hone the effectiveness of their recovery from training. Keywords: self-regulated learning; sport performance; sport practice; mental performance. Lay summary: We asked elite endurance athletes to describe their process of implementing recovery around training. This process was primarily athlete-led, involving a set of self-regulatory skills, integrated with the support of people and places in their environment. Recovery should be considered in terms of skills that athletes can develop and for which they can take ownership. IMPLICATIONS FOR PRACTICE: Elite endurance athletes describe taking responsibility for and shaping their approaches to recovery using self-regulatory skills that they develop with practice and experience. They rely on people and places in their environment to supplement, facilitate, and/or supply provisions for their efforts to self-regulate their recovery. Recovery should be examined for skills similar to the mental and perceptual-cognitive skills that define superior training and performance in athletes. [ABSTRACT FROM AUTHOR]

Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aβ-induced paralysis. Methods: Using C. elegans expressing human amyloid-β (Aβ)1–42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD. [ABSTRACT FROM AUTHOR]

Worldwide, estuaries are increasingly constrained by human interventions, such as wetland reclamations. Intertidal area has an important influence on the extent of estuarine salt intrusion. Previous research has shown conflicting effects of intertidal area on the salt intrusion. Therefore, this study explores this interaction for three estuary classes: (a) salt wedge, (b) partially mixed, and (c) well‐mixed. Our findings show that the effect of intertidal area on the salt intrusion depends on the estuary class: enlarging the intertidal area reduces the salt intrusion for salt wedge and partially mixed estuaries, but vice versa for well‐mixed estuaries. These opposing responses are explained by the balance between salt fluxes driven by the estuarine circulation versus by the tidal oscillation. In general, enlarging intertidal area results in the suppression of the estuarine circulation. Such system understanding is especially relevant in an era of increasing coastal urbanization. Plain Language Summary: Worldwide, estuaries are increasingly modified due to human activities, like reclaiming wetlands (i.e., areas that are submerged at high tide but exposed at low tide). Changes in these intertidal zones of estuaries can affect how far the salty water reaches inland, so‐called salt intrusion. Past studies have given conflicting answers as to how the intertidal area influences salt intrusion. This study focuses on three classes of estuaries: (a) salt wedge (poorly‐mixed), (b) partially mixed, and (c) well‐mixed. We have found that the impact of the intertidal area on salt levels depends on the estuary class. Increasing the intertidal area reduces salt intrusion for salt wedge and partially mixed estuaries, while an opposite effect occurs in well‐mixed estuaries. These different outcomes are connected to the balance between salt transport by density‐driven currents and that driven by the tides. Our contribution to the understanding of these complex natural dynamics is of growing relevance in an age of magnified pressures on estuaries. Key Points: Enlargement of the intertidal area can both increase and reduce estuarine salt intrusionThe effect of the intertidal area on the estuarine salt intrusion depends on estuary classEnlargement of the intertidal area suppresses the estuarine circulation [ABSTRACT FROM AUTHOR]

The paper introduces a new model of compressive membrane action (CMA) for a conical fan failure mechanism around a patch load in a reinforced concrete plate with in-plane restraint. The new model is based on a concept of 3-dimensional wedging and it is fundamentally different from conventional arching models of CMA. The new model accounts for the effects of CMA on the bending resistance at yield lines and the complementary wedging effect of compressive membrane forces at the yield lines, considering the interaction between the radial and tangential forces acting on the wedgelike segments in a restrained fan. The model was developed in the context of an investigation of the strength of fiber reinforced shotcrete (FRS) tunnel linings, but it is readily adaptable for conventional reinforced concrete plates and slabs. The paper compares the wedging model results (predicted load-deflection curves) with field test results for FRS tunnel linings. It is shown that the wedging model provides a good approximation to the available test results. [ABSTRACT FROM AUTHOR]

At a global scale, deltas are vital economic hubs, in part due to the combination of their access to inland regions via river systems with their proximity to sea. However, with the sea in close vicinity also comes the threat of freshwater contamination by saline seawater, especially during droughts. This study explores the potential of a mitigation measure to estuarine salt intrusion, namely the construction of a (temporary) earthen sill—a measure implemented in the Lower Mississippi River near New Orleans (LA, USA). This study suggests design guidelines on how a sill can be used to mitigate estuarine salt intrusion: the design should focus on the longitudinal placement and the height of the sill, and the mitigating efficiency of the sill reduces with increasing tidal range. Overall, a (temporary) sill has great potential to reduce salt intrusion in salt wedge estuaries if there is sufficient water depth available. [ABSTRACT FROM AUTHOR]

Purpose: The 2022 World Health Organization classification of renal neoplasia expanded the spectrum of oncocytic neoplasms to encompass newly established and emerging entities; one of the latter is the low-grade oncocytic tumor (LOT). This study reports the radiologic appearance and clinical behavior of LOT. Methods: In this IRB-approved, HIPPA-compliant retrospective study, our institution's pathology database was searched for low-grade oncocytic tumors or neoplasms. Patient age, gender, and comorbidities were obtained from a review of electronic medical records, and imaging characteristics of the tumors were assessed through an imaging platform. Results: The pathology database search yielded 14 tumors in 14 patients. Four patients were excluded, as radiologic images were not available in three, and one did not fulfill diagnostic criteria after pathology re-review. The resulting cohort consisted of 10 tumors (median diameter 2.3 cm, range 0.7–5.1) in 10 patients (median age 68 years, range 53–91, six women). All tumors presented as a solitary, well-circumscribed, mass with solid components. All enhanced as much or almost as much as adjacent renal parenchyma; all but one enhanced heterogeneously. None had lymphadenopathy, venous invasion, or metastatic disease at presentation or at clinical follow-up (median, 22.2 months, range 3.4–71.6). Among five tumors undergoing active surveillance, mean increase in size was 0.4 cm/year at imaging follow-up (median 16.7 months, range 8.9–25.4). Conclusion: LOT, a recently described pathologic entity in the kidney, can be considered in the differential diagnosis of an avidly and typically heterogeneously enhancing solid renal mass in an adult patient. [ABSTRACT FROM AUTHOR]

INTRODUCTION Cigarette package inserts that describe quitting benefits and tips may promote cessation; however, research is needed to understand better their effects, including potentially enhancing the effects of pictorial health warning labels (PHWLs). METHODS A randomized trial with a 2x2 factorial design was conducted with adult smokers (n=356) assigned to either small text-only health warning labels (HWLs; control); inserts with cessation messages, and the small text-only HWLs (inserts-only); large PHWLs (PHWLs-only); both inserts and PHWLs (inserts + PHWLs). Participants received a 14-day supply of their preferred cigarettes with packs labeled to reflect their group. Upon finishing the trial, participants reported their past 14-day frequency of noticing, reading, thinking about smoking harms and cessation benefits, talking about labels, and forgoing cigarettes because of the labels. Ordered logistic models regressed these outcomes on labeling groups, and mediation analyses assessed whether attention (i.e. noticing, reading) to labels mediated effects of labeling exposure on other outcomes (i.e. thinking about harms/benefits, talking, forgoing). RESULTS The inserts + PHWLs group reported higher frequencies than the control group for all outcomes. Compared to the control group, both the inserts-only and PHWLs-only groups reported higher frequency of noticing (AOR=3.53 and 2.46, respectively) and reading labels (AOR=2.89 and 1.71), thinking about smoking risks because of the labels (AOR=1.93 and 1.82), and talking about labels (AOR=2.30 and 2.70). Participants in the inserts-only group also reported more frequent thinking about quitting benefits (AOR=1.98). Attention mediated all labeling effects except for the contrast between PHWLs only and control. CONCLUSIONS Compared to text-only HWLS, cigarette labeling that involves inserts, PHWLs, or both appears more effective at drawing attention to warnings, which mediated the effects on cessation-related psychosocial and behavioral outcomes. [ABSTRACT FROM AUTHOR]

Background: In the UK, tens of millions of working days are lost due to work‐related ill health every year, costing billions of pounds. The role of Occupational Health (OH) services is vital in helping workers to maintain employment when they encounter injury or illness. OH providers traditionally rely on a clinical workforce to deliver these services, particularly doctors and nurses with OH qualifications. However, the increasing demand for OH services is unlikely to be met in the future using this traditional model, due to the declining number of OH‐trained doctors and nurses in the UK. Multi‐disciplinary models of OH delivery, including a more varied range of healthcare and non‐healthcare professionals, could provide a way to meet this new demand for OH services. There is a need to identify collaborative models of OH service delivery and review their effectiveness on return‐to work outcomes. There is an existing pool of systematic review evidence evaluating workplace based, multi‐disciplinary OH interventions, but it is difficult to identify which aspects of the content and/or delivery of these interventions may be associated with improved work‐related outcomes. Objectives: The aim of this evidence and gap map (EGM) was to provide an overview of the systematic review evidence that evaluates the effectiveness and cost‐effectiveness of multi‐disciplinary OH interventions intending to improve work‐related outcomes. Search Methods: In June 2021 we searched a selection of bibliographic databases and other academic literature resources covering a range of relevant disciplines, including health care and business studies, to identify systematic review evidence from a variety of sectors of employment. We also searched Google Search and a selection of topically relevant websites and consulted with stakeholders to identify reports already known to them. Searches were updated in February 2023. Selection Criteria: Systematic reviews needed to be about adults (16 years or over) in employment, who have had absence from work for any medical reason. Interventions needed to be multi‐disciplinary (including professionals from different backgrounds in clinical and non‐clinical professions) and designed to support employees and employers to manage health conditions in the workplace and/or to help employees with health conditions retain and/or return to work following medical absence. Effectiveness needed to be measured in terms of return to work, work retention or measures of absence, or economic evaluation outcomes. These criteria were applied to the title and abstract and full text of each systematic review independently by two reviewers, with disagreements resolved through discussion. We awarded each systematic review a rating of 'High', 'Medium' or 'Low' relevance to indicate the extent to which the populations, interventions and their contexts synthesised within the review were consistent with our research question. We also recorded the number of primary studies included within each of the 'High' and 'Medium' reviews that were relevant to research question using the same screening process applied at review level. Data Collection and Analysis: Summary data for each eligible review was extracted. The quality of the systematic reviews, rated as 'High' or 'Medium' relevance following full text screening, was appraised using the AMSTAR‐2 quality appraisal tool. All data were extracted by one reviewer and checked by a second, with disagreements being settled through discussion. Summary data for all eligible systematic reviews were tabulated and described narratively. The data extracted from reviews of 'High' and 'Medium' relevance was imported into EPPI‐Mapper software to create an EGM. Stakeholder Involvement: We worked alongside commissioners and policy makers from the Department of Health and Social Care (DHSC) and Department of Work and Pensions (DWP), OH personnel, and people with lived experience of accessing OH services themselves and/or supporting employees to access OH services. Individuals contributed to decision making at all stages of the project. This ensured our EGM reflects the needs of individuals who will use it. Main Results: We identified 98 systematic reviews that contained relevant interventions, which involved a variety of professionals and workplaces, and which measured effectiveness in terms of return to work (RTW). Of these, we focused on the 30 reviews where the population and intervention characteristics within the systematic reviews were considered to be of high or medium relevance to our research questions. The 30 reviews were of varying quality, split evenly between High/Moderate quality and Low/Critically‐Low quality ratings. We did not identify any relevant systematic review evidence on any other work‐related outcome of interest. Interventions were heterogenous, both within and across included systematic reviews. The EGM is structured according to the health condition experienced by participants, and the effectiveness of the interventions being evaluated, as reported within the included systematic reviews. It is possible to view (i) the quality and quantity of systematic review evidence for a given health condition, (ii) how review authors assessed the effectiveness or cost‐effectiveness of the interventions evaluated. The EGM also details the primary studies relevant to our research aim included within each review. Authors' Conclusions: This EGM map highlights the array of systematic review evidence that exists in relation to the effectiveness or cost‐effectiveness of multi‐disciplinary, workplace‐based OH interventions in supporting RTW. This evidence will allow policy makers and commissioners of services to determine which OH interventions may be most useful for supporting different population groups in different contexts. OH professionals may find the content of the EGM useful in identifying systematic review evidence to support their practice. The EGM also identifies where systematic review evidence in this area is lacking, or where existing evidence is of poor quality. These may represent areas where it may be particularly useful to conduct further systematic reviews. [ABSTRACT FROM AUTHOR]

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear. [ABSTRACT FROM AUTHOR]

Clinical ethics consultants (CECs) work in complex environments ripe with multiple types of expectations. Significantly, some are due to the perspectives of professional colleagues and the patients and families with whom CECs consult and concern how CECs can, do, or should function, thus adding to the moral complexity faced by CECs in those particular circumstances. We outline six such common expectations: Ethics Police, Ethics Equalizer, Ethics Superhero, Ethics Expediter, Ethics Healer or Ameliorator, and, finally, Ethics Expert. Framed by examples of requests for ethics consultation that illustrate each kind, along with brief descriptions, we argue that while these expectations ought to be resisted for clear and practical reasons, they also create opportunities for CECs to articulate, educate, and ultimately be responsible to the professional demands of clinical ethics work. Recognizing, acknowledging, and at times resisting those expectations thus become key activities and responsibilities in the performance of ethics consultation. [ABSTRACT FROM AUTHOR]

There is growing interest in multicancer detection tests, which identify molecular signals in the blood that indicate a potential preclinical cancer. A key stage in evaluating these tests is a prediagnostic performance study, in which investigators store specimens from asymptomatic individuals and later test stored specimens from patients with cancer and a random sample of controls to determine predictive performance. Performance metrics include rates of cancer-specific true-positive and false-positive findings and a cancer-specific positive predictive value, with the latter compared with a decision-analytic threshold. The sample size trade-off method, which trades imprecise targeting of the true-positive rate for precise targeting of a zero-false-positive rate can substantially reduce sample size while increasing the lower bound of the positive predictive value. For a 1-year follow-up, with ovarian cancer as the rarest cancer considered, the sample size trade-off method yields a sample size of 163 000 compared with a sample size of 720 000, based on standard calculations. These design and analysis recommendations should be considered in planning a specimen repository and in the prediagnostic evaluation of multicancer detection tests. [ABSTRACT FROM AUTHOR]

Background: Interventional Radiology (IR) is a highly rewarding specialty, both for its salutary effects for patients, as will as the satisfaction it provides for the operating radiologists. Nonetheless, arduous work and long hours have led to numerous reports of burnout amongst interventional radiologists (IRs). Materials and Methods: Six long-term academic radiologists in leadership positions briefly chronicle their becoming IRs, their type of transitioning from IR, and the pros and cons of those respective transitions. Results: The specific transitions include reduced time in IR, switching to diagnostic radiology, becoming involved in medical school education, ceasing IR leadership, and retirement. Pros and cons of the various transition strategies are highlighted. Conclusion: As the taxing work and long hours are so ubiquitous for IRs, and as burnout is so common, transitioning from IR is highly likely eventually for IRs. The varied transition experiences highlighted in this report hopefully will be helpful for current and aspiring IRs. [ABSTRACT FROM AUTHOR]

Purpose: To assess VIRADS performance and inter-reader agreement for detecting muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumor (TURBT). Methods: An IRB-approved, HIPAA-compliant, retrospective study from 2016 to 2020 included patients with bladder urothelial carcinoma who underwent MRI after TURBT, and cystectomy within 3 months without post-MRI treatments. Three radiologists blinded to pathology results independently reviewed MR images and assigned a VI-RADS score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of VI-RADS were assessed for diagnosing MIBC using VI-RADS scores ≥ 3 and ≥ 4. Inter-reader agreement was assessed using Gwet's agreement coefficient (AC) and percent agreement. Results: The cohort consisted of 70 patients (mean age, 68 years ± 11 [SD]; range 39–85; 58 men) and included 32/70 (46%) with MIBC at cystectomy. ROC analysis revealed an AUC ranging from 0.67 to 0.77 and no pairwise statistical difference between readers (p-values, 0.06, 0.08, 0.97). Percent sensitivity, specificity, PPV, NPV and accuracy for diagnosing MIBC for the three readers ranged from 81.3–93.8, 36.8–55.3, 55.6–60.5, 77.3–87.5, and 62.9–67.1 respectively for VI-RADS score ≥ 3, and 78.1–81.3, 47.4–68.4, 55.6–67.6, 72.0–78.8 and 61.4–72.9 respectively for VI-RADS score ≥ 4. Gwet's AC was 0.63 [95% confidence interval (CI): 0.49,0.78] for VI-RADS score ≥ 3 with 79% agreement [95% CI 72,87] and 0.54 [95%CI 0.38,0.70] for VI-RADS score ≥ 4 with 76% agreement [95% CI 69,84]. VIRADS performance was not statistically different among 31/70 (44%) patients who received treatments prior to MRI (p ≥ 0.16). Conclusion: VI-RADS had moderate sensitivity and accuracy but low specificity for detection of MIBC following TURBT, with moderate inter-reader agreement. [ABSTRACT FROM AUTHOR]

Microtubule-associated protein Tau (MAPT) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the MAPT gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that MAPT mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of MAPT were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in MAPT mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in MAPT mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology. [ABSTRACT FROM AUTHOR]

Low-lying, tropical coral reef-lined coastlines are becoming increasingly vulnerable to wave-driven flooding due to population growth, coral reef degradation, and sea-level rise. Early-warning systems (EWS) are needed to enable coastal authorities to issue timely alerts and coordinate preparedness and evacuation measures for their coastal communities. At longer time scales, risk management and adaptation planning require of robust assessments of future flooding hazard considering uncertainties. However, due to diversity in reef morphologies and complex reef hydrodynamics compared to sandy shorelines, there have been no robust, analytical solutions for wave runup to allow the development of large-scale coastal wave-driven flooding EWS and risk assessment frameworks for reef-lined coasts. To address the need for a fast, robust prediction of runup along reef-lined coasts, we constructed the BEWARE-2 (Broad-range Estimator of Wave Attack in Reef Environments) meta-process modeling system. We developed this meta-process model using a training dataset of hydrodynamics and wave runup computed by the XBeach Non-Hydrostatic+ process-based hydrodynamic model for 440 combinations of water level, wave height, and wave period on 195 morphologically diverse representative reef profiles. In validation, the BEWARE-2 modeling system produced runup results that had a root-mean square error of 0.63 m and bias of 0.26 m, relative to runup of 0.17–20.9 m simulated by XBeach Non-Hydrostatic+ for a large range of oceanographic forcing conditions and for a diverse reef morphologies. Incorporating parametric modifications in the modeling system to account for variations in reef roughness and beach slope allows systematic errors (relative bias) in BEWARE-2 predictions to be reduced by a factor of 1.5–6.5 for relatively coarse or smooth reefs, and mild or steep beach slopes. This relatively accurate solution is provided by the BEWARE-2 modeling system 4–5 orders of magnitude faster than the full, process-based hydrodynamic model and could therefore be integrated in large-scale EWS for tropical, reef-lined coasts, as well as used for large-scale flood risk assessments. [ABSTRACT FROM AUTHOR]

Purpose: To assess indications, safety, and effectiveness of percutaneous adrenal mass biopsy in contemporary practice. Methods: This institutional review board-approved, retrospective study included all patients undergoing percutaneous image-guided adrenal mass biopsies at an academic health system from January 6, 2015, to January 6, 2023. Patient demographics, biopsy indications, mass size, laboratory data, pathology results, and complications were recorded. Final diagnoses were based on pathology or ≥ 1 year of imaging follow-up when biopsy specimens did not yield malignant tissue. Test performance calculations excluded repeat biopsies. Continuous variables were compared with Student's t test, dichotomous variables with chi-squared test. Results: A total of 160 patients underwent 186 biopsies. Biopsies were indicated to diagnose metastatic disease (139/186; 74.7%), for oncologic research only (27/186; 14.5%), diagnose metastatic disease and oncologic research (15/186; 8%), and diagnose an incidental adrenal mass (5/186; 2.7%). Biopsy specimens were diagnostic in 154 patients (96.3%) and non-diagnostic in 6 (3.8%). Diagnostic biopsies yielded malignant tissue (n = 136), benign adrenal tissue (n = 12), and benign adrenal neoplasms (n = 6) with sensitivity = 98.6% (136/138), specificity = 100% (16/16), positive predictive value = 100% (136/136), and negative predictive value = 88.9% (16/18). Adverse events followed 11/186 procedures (5.9%) and most minor (7/11, 63.6%). The adverse event rate was similar whether tissue was obtained for clinical or research purposes (10/144; 6.9% vs. 1/42; 2.4%, p = 0.27), despite more specimens obtained for research (5.8 vs. 3.7, p < 0.001). Conclusion: Percutaneous adrenal mass biopsy is safe, accurate, and utilized almost exclusively to diagnose metastatic disease or for oncologic research. The negative predictive value is high when diagnostic tissue samples are obtained. Obtaining specimens for research does not increase adverse event risk. [ABSTRACT FROM AUTHOR]

Underrepresentation of historically marginalized populations in clinical trials continues to threaten the validity of health intervention research. Evidence supports the merits of intercept and other proactive forms of recruitment for achieving more equitable representation. However, researchers also report lower retention and adherence to protocols among these populations, particularly in longitudinal studies. Few studies have compared recruitment methods for longitudinal randomized trials testing health interventions, with even fewer having done so for trials involving ecological momentary assessment (EMA). As intervention research integrates EMA and other data collection approaches requiring substantial participant effort, it is critical to better understand the effectiveness and implications of strategies to improve the representativeness of health research. This secondary data analysis compared outcomes of proactive and reactive recruitment strategies (mobile lab intercepts and internet/flyer advertising, respectively) in study inclusion, task completion, and retention within a 14-day randomized controlled trial that used EMA to evaluate cigarette package health messages. Proactive recruitment resulted in higher proportions of participants with low income and education, limited health literacy, and of diverse racial/ethnic makeup. However, this recruitment method also resulted in lower task completion, especially in the second week of the trial period, and lower retention, although group differences were not explained by participant sociodemographic characteristics targeted by inclusion efforts. We conclude that proactive recruitment via intercepts is an effective strategy for health intervention research that aims to include stakeholders from historically marginalized groups but that researchers and funders must recognize these methods require additional resources, considerations, and capacity to address non-trivial challenges to successful participation. [ABSTRACT FROM AUTHOR]

Smoking is one of the major causes of preventable death and is considered the greatest threat to global public health. While the prevalence of smoking has decreased, population growth has led to an increase in the absolute number of smokers. There are many proven smoking cessation interventions available to support smokers in their quit attempts. Most people who smoke, however, underutilize the treatments available to them. This scoping review aimed to identify the current barriers experienced by all stakeholders (smokers, service providers and policymakers) to existing evidence-based smoking cessation interventions in community healthcare settings. Five electronic databases (CINAHL, Ovid MEDLINE, PsycINFO, Scopus and Web of Science) were searched for relevant literature. A total of 40 eligible articles from different countries published between 2015 and 2022 were included in the review and content analysis carried out to identify the key barriers to smoking cessation interventions. Seven key themes were found to be common to all stakeholders: (i) literacy, (ii) competing demands and priorities, (iii) time, (iv) access to product, (v) access to service, (vi) workforce and (vii) motivation/readiness. These themes were mapped to the Capability, Opportunity, Motivation-Behaviour (COM-B) model. This study presents the effect the barriers within these themes have on current smoking cessation services and highlights priorities for future interventions. [ABSTRACT FROM AUTHOR]

The cause of Alzheimer's disease (AD), and the pathophysiological mechanisms involved, remain major unanswered questions in medical science. Oral bacteria, especially those species associated with chronic periodontitis and particularly Porphyromonas gingivalis, are being linked causally to AD pathophysiology in a subpopulation of susceptible individuals. P. gingivalis produces large amounts of proteolytic enzymes, haem and iron capture proteins, adhesins and internalins that are secreted and attached to the cell surface and concentrated onto outer membrane vesicles (OMVs). These enzymes and adhesive proteins have been shown to cause host tissue damage and stimulate inflammatory responses. The ecological and pathophysiological roles of P. gingivalis OMVs, their ability to disperse widely throughout the host and deliver functional proteins lead to the proposal that they may be the link between a P. gingivalis focal infection in the subgingivae during periodontitis and neurodegeneration in AD. P. gingivalis OMVs can cross the blood brain barrier and may accelerate AD-specific neuropathology by increasing neuroinflammation, plaque/tangle formation and dysregulation of iron homeostasis, thereby inducing ferroptosis leading to neuronal death and neurodegeneration. [ABSTRACT FROM AUTHOR]

B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders. [ABSTRACT FROM AUTHOR]

Summary: The essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)‐secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high‐affinity Ag‐specific Abs of different classes, enabling effective pathogen neutralization and long‐lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non‐redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B‐cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses. [ABSTRACT FROM AUTHOR]

Introduction: Athletic training can result in electrical and structural changes of the right ventricle that may mimic phenotypical features of arrhythmogenic right ventricular cardiomyopathy (ARVC), such as T-wave inversion and right heart dilatation. An erroneous interpretation may have consequences ranging from false reassurance in an athlete vulnerable to cardiac arrhythmias, to unnecessary sports restriction in a healthy individual. The primary aim of this study was to define normal RV dimension reference ranges for academy adolescent footballers of different ethnicities. Secondary aims include analysis of potential overlap between this adolescent group with ARVC criteria and comparison with normal adult ranges. Results: Electrocardiographic (ECG) and echocardiographic data of 1087 academy male footballers aged between 13 and 18 years old (mean age 16.0 ± 0.5 years), attending mandatory cardiac screening were analysed. Ethnicity was categorised as white (n = 826), black (African/Caribbean; n = 166) and mixed-race (one parent white and one parent black; n = 95). Arrhythmogenic right ventricular cardiomyopathy major criteria for T-wave inversion was seen in 3.3% of the cohort. This was more prevalent in black footballers (12%) when compared to mixed race footballers (6.3%) or white footballers (1%), P < 0.05. Up to 59% of the cohort exceeded adult reference ranges for some of the right ventricular parameters, although values were similar to those seen in adult footballers. There were no differences in right ventricular dimensions between ethnicities. In particular, the right ventricular outflow tract diameter would fulfil major criteria for ARVC dimension in 12% of footballers. Overall, 0.2% of the cohort would fulfil diagnosis for 'definite' arrhythmogenic right ventricular cardiomyopathy and 2.2% would fulfil diagnosis for 'borderline' arrhythmogenic right ventricular cardiomyopathy for RV dimensions and ECG changes. This was seen more frequently in black footballers (9.9%) than mixed race footballers (3.9%) or white footballer (0.6%), P < 0.05. Among athletes meeting definite or borderline arrhythmogenic right ventricular cardiomyopathy criteria, no cardiomyopathy was identified after comprehensive clinical assessment, including with cardiac magnetic resonance imaging, exercise testing, ambulatory electrocardiograms and familial evaluation. Conclusion: Right heart sizes in excess of accepted adult ranges occurred in as many as one in two adolescent footballers. Structural adaptations in conjunction with anterior T-wave inversion may raise concern for ARVC, highlighting the need for evaluation in expert settings. [ABSTRACT FROM AUTHOR]

Background: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. Methods: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. Discussion: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make. Plain English Summary: Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research. [ABSTRACT FROM AUTHOR]

We investigate experimentally and theoretically a system ruled by an intricate interplay between topology, nonlinearity, and spontaneous symmetry breaking. The experiment is based on a two-mode coherently-driven optical resonator where photons interact through the Kerr nonlinearity. In presence of a phase defect, the modal structure acquires a synthetic Möbius topology enabling the realization of spontaneous symmetry breaking in inherently bias-free conditions without fine tuning of parameters. Rigorous statistical tests confirm the robustness of the underlying symmetry protection, which manifests itself by a periodic alternation of the modes reminiscent of period-doubling. This dynamic also confers long term stability to various localized structures including domain walls, solitons, and breathers. Our findings are supported by an effective Hamiltonian model and have relevance to other systems of interacting bosons and to the Floquet engineering of quantum matter. They could also be beneficial to the implementation of coherent Ising machines. Applications of spontaneous symmetry breaking are hindered by unavoidable imperfections. Here, the authors reveal how a phase defect provides topological robustness to this process, enabling a bias free realization without fine tuning of parameters. [ABSTRACT FROM AUTHOR]

Background: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. Methods: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. Discussion: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make. Plain English Summary: Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the feasibility and safety of using a bipolar radiofrequency track cautery device during percutaneous image-guided abdominal biopsy procedures in at-risk patients. Methods: Forty-two patients (26–79 years old; female 44%) with at least one bleeding risk factor who underwent an abdominal image-guided (CT or US) biopsy and intended bipolar radiofrequency track cautery (BRTC) were retrospectively studied. An 18G radiofrequency electrode was inserted through a 17G biopsy introducer needle immediately following coaxial 18G core biopsy, to cauterize the biopsy track using temperature control. Bleeding risk factors, technical success, and adverse events were recorded. Results: BRTC was technically successful in 41/42 (98%) of procedures; in one patient, the introducer needle retracted from the liver due to respiratory motion prior to BRTC. BRTC following percutaneous biopsy was applied during 41 abdominal biopsy procedures (renal mass = 12, renal parenchyma = 10, liver mass = 9, liver parenchyma = 5, splenic mass or parenchyma = 4, gastrohepatic mass = 1). All patients had one or more of the following risk factors: high-risk organ (spleen or renal parenchyma), hypervascular mass, elevated prothrombin time, renal insufficiency, thrombocytopenia, recent anticoagulation or anticoagulation not withheld for recommended interval, cirrhosis, intraprocedural hypertension, brisk back bleeding observed from the introducer needle, or subcapsular tumor location. No severe adverse events (grade 3 or higher) occurred. Two (2/41, 5%) mild (grade 1) bleeding events did not cause symptoms or require intervention. Conclusion: Bipolar radiofrequency track cautery was feasible and safe during percutaneous image-guided abdominal biopsy procedures. IRB approval: MBG 2022P002277 [ABSTRACT FROM AUTHOR]

Background: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. Methods: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. Results: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12–$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. Conclusion: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. Patient or Public Contributions: The patient partner coauthor informed protocol development, identified data items, and interpreted findings. [ABSTRACT FROM AUTHOR]

External driving of passive, nonlinear optical resonators has emerged over the past decade as a novel route for the generation of ultrashort optical pulses and corresponding broadband frequency combs. Although the pulse formation dynamics in such systems dramatically differ from those manifesting themselves in conventional mode-locked lasers, the demarcation between the two traditionally distinct paradigms has recently begun to blur, with demonstrations of hybrid systems incorporating both external driving and active media shown to offer specific advantages. Here we explore a new pathway for ultrashort pulse generation at the interface of externally driven passive resonators and lasers. By leveraging the nonlinear Raman gain inherent in fused silica, we achieve the deterministic generation of low-noise dissipative solitons with durations well below 100 fs via the phase-coherent pulsed driving of resonators made of standard, commercially available optical fibre. We explore and explain the physics of the new dissipative Raman soliton states, identifying scaling laws that govern the pulses' characteristics and that allow output repetition rates to be scaled at will without influencing the soliton duration. The scheme explored in our work enables the shortest-ever pulses generated in resonators (active or passive) made from a single commercially available optical fibre, to the best of our knowledge, and it has the potential to be transferred into a chip-scale format by using existing dispersion-engineered silica microresonators. By exploiting the nonlinear Raman gain inherent in fused silica, short sub-100-fs dissipative Raman soliton pulses can be formed in fused-silica fibre resonators that are driven by electro-optically generated picosecond pulses. [ABSTRACT FROM AUTHOR]

Background: The test tradeoff curve helps investigators decide if collecting data for risk prediction is worthwhile when risk prediction is used for treatment decisions. At a given benefit-cost ratio (the number of false-positive predictions one would trade for a true positive prediction) or risk threshold (the probability of developing disease at indifference between treatment and no treatment), the test tradeoff is the minimum number of data collections per true positive to yield a positive maximum expected utility of risk prediction. For example, a test tradeoff of 3,000 invasive tests per true-positive prediction of cancer may suggest that risk prediction is not worthwhile. A test tradeoff curve plots test tradeoff versus benefit-cost ratio or risk threshold. The test tradeoff curve evaluates risk prediction at the optimal risk score cutpoint for treatment, which is the cutpoint of the risk score (the estimated risk of developing disease) that maximizes the expected utility of risk prediction when the receiver-operating characteristic (ROC) curve is concave. Methods: Previous methods for estimating the test tradeoff required grouping risk scores. Using individual risk scores, the new method estimates a concave ROC curve by constructing a concave envelope of ROC points, taking a slope-based moving average, minimizing a sum of squared errors, and connecting successive ROC points with line segments. Results: The estimated concave ROC curve yields an estimated test tradeoff curve. Analyses of 2 synthetic data sets illustrate the method. Conclusion: Estimating the test tradeoff curve based on individual risk scores is straightforward to implement and more appealing than previous estimation methods that required grouping risk scores. Highlights: The test tradeoff curve helps investigators decide if collecting data for risk prediction is worthwhile when risk prediction is used for treatment decisions. At a given benefit-cost ratio or risk threshold, the test tradeoff is the minimum number of data collections per true positive to yield a positive maximum expected utility of risk prediction. Unlike previous estimation methods that grouped risk scores, the method uses individual risk scores to estimate a concave ROC curve, which yields an estimated test tradeoff curve. [ABSTRACT FROM AUTHOR]

Background: X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition. Case: A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment. Methods: Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR. Results: WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation. Conclusion: This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype–phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR. [ABSTRACT FROM AUTHOR]

Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. Methods: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. Results: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient’s SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. Conclusions: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants. [ABSTRACT FROM AUTHOR]

Background Cigarette pack inserts with messages on cessation benefits and advice are a promising labeling policy that may help promote smoking cessation. Purpose To assess insert effects, with and without accompanying pictorial health warning labels(HWLs), on hypothesized psychosocial and behavioral outcomes. Methods We conducted a 2 × 2 between-subject randomized trial (inserts with efficacy messages vs. no inserts; large pictorial HWLs vs. small text HWLs), with 367 adults who smoked at least 10 cigarettes a day. Participants received a 14-day supply of their preferred cigarettes with packs modified to reflect their experimental condition. Over 2 weeks, we surveyed participants approximately 4–5 times a day during their smoking sessions, querying feelings about smoking, level of worry about harms from smoking, self-efficacy to cut down on cigarettes, self-efficacy to quit, hopefulness about quitting, and motivation to quit. Each evening, participants reported their perceived susceptibility to smoking harms and, for the last 24 hr, their frequency of thinking about smoking harms and cessation benefits, conversations about smoking cessation or harms, and foregoing or stubbing out cigarettes before they finished smoking. Mixed-effects ordinal and logistic models were estimated to evaluate differences between groups. Results Participants whose packs included inserts were more likely than those whose packs did not include inserts to report foregoing or stubbing out of cigarettes (OR = 2.39, 95% CI = 1.36, 4.20). Otherwise, no statistically significant associations were found between labeling conditions and outcomes. Conclusions This study provides some evidence, albeit limited, that pack inserts with efficacy messages can promote behaviors that predict smoking cessation attempts. [ABSTRACT FROM AUTHOR]

Background To control infections, behavioral non-pharmaceutical interventions (NPIs) such as social distancing and hygiene measures (masking, hand hygiene) were implemented widely during the COVID-19 pandemic. At the same time, adherence to NPIs has also been implied in an increase in mental health problems. However, the designs of many existing studies are often poorly suited to disentangle complex relationships between NPI adherence, mental health symptoms, and health-related cognitions (risk perceptions, control beliefs). Purpose To separate between- and temporal within-person associations between mental health, health-related cognitions, and NPI adherence. Methods Six-month ecological momentary assessment (EMA) study with six 4-day assessment bouts in 397 German adults. Daily measurement of adherence, mental health symptoms, and cognitions during bouts. We used dynamic temporal network analysis to estimate between-person, as well as contemporaneous and lagged within-person effects for distancing and hygiene NPIs. Results Distinct network clusters of mental health, health cognitions, and adherence emerged. Participants with higher control beliefs and higher susceptibility were also more adherent (between-person perspective). Within-person, similar findings emerged, additionally, distancing and loneliness were associated. Lagged findings suggest that better adherence to NPIs was associated with better mental health on subsequent days, whereas higher loneliness was associated with better subsequent hygiene adherence. Conclusions Findings suggest no negative impact of NPI adherence on mental health or vice versa, but instead suggest that adherence might improve mental health symptoms. Control beliefs and risk perceptions are important covariates of adherence—both on between-person and within-person level. [ABSTRACT FROM AUTHOR]

While many countries require prominent pictorial health warning labels (PHWLs) on the outside of cigarette packs to communicate the harms of smoking, there is evidence that cigarette pack inserts that contain efficacy messages may enhance the effectiveness of PHWLs. The US Food and Drug Administration (FDA) has regulatory authority to communicate with smokers through inserts. While current labeling regulations do not require inclusion of inserts, the FDA could implement them in the future. This study assesses US smokers' perceptions of cigarette package inserts at the conclusion of a two-week randomized trial on cigarette labeling where half of participants were exposed to insert messages (two response-efficacy messages and two self-efficacy messages) in their packs. Participants (n  = 359) completed a 30- to 60-min interview with both quantitative and qualitative assessments, including measures of recall and perceived message effectiveness (PME) for specific inserts. Correlates of recall and PME were estimated using mixed-effects regression models. Qualitative responses to PME items were analyzed using thematic analysis. Response-efficacy messages had higher PME and recall than self-efficacy messages. People had diverse responses to the inserts, including that they were positive, thought-provoking, and helpful. Reactions to and perceptions of the inserts indicate potential benefits of integrating efficacy messages into labeling policies. [ABSTRACT FROM AUTHOR]

The article introduces an upper respiratory tract OC43 infection model for evaluating airway immune-modifying therapies, conducted on mice using OC43 viral challenges and various treatments. Topics include the experimental methods, viral challenge procedures, and comprehensive analyses encompassing nasal and bronchoalveolar lavage, histology, immunofluorescence, and immune transcriptome expression analysis.

We seek to elucidate the precise nature of mechanical loading that precipitates conduction deficits in a concealed-phase model of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive disorder often resulting from mutations in desmosomal proteins. Exercise has been shown to worsen disease progression and unmask arrhythmia vulnerability, yet the underlying pathomechanisms may depend on the type and intensity of exercise. Because exercise causes myriad changes to multiple interdependent hemodynamic parameters, it is difficult to isolate its effects to specific changes in mechanical load. Here, we use engineered heart tissues (EHTs) with induced pluripotent stem cell (iPSC)-derived cardiomyocytes expressing R451G desmoplakin, an ACM-linked mutation, which results in a functionally null model of desmoplakin (DSP). We also use a novel bioreactor to independently perturb tissue strain at different time points during the cardiac cycle. We culture EHTs under three strain regimes: normal physiological shortening; increased diastolic stretch, simulating high preload; and isometric culture, simulating high afterload. DSPR451G EHTs that have been cultured isometrically undergo adaptation, with no change in action potential parameters, conduction velocity, or contractile function, a phenotype confirmed by global proteomic analysis. However, when DSPR451G EHTs are subjected to increased diastolic stretch, they exhibit concomitant reductions in conduction velocity and the expression of connexin-43 (Cx43). These effects are rescued by inhibition of both lysosome activity and ERK signaling. Our results indicate that the response of DSPR451G EHTs to mechanical stimuli depends on the strain and the timing of the applied stimulus, with increased diastolic stretch unmasking conduction deficits in a concealed-phase model of ACM. [ABSTRACT FROM AUTHOR]

Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing. How and to what extent oligodendrocytes (OLs) contribute to learning and cognition is not well understood. Here, the authors show that the performance of mice in working memory-dependent cognitive tasks depends on OL genesis and is proportional to the number of OL precursors and OLs generated during training. [ABSTRACT FROM AUTHOR]

Background: Patient engagement in research refers to collaboration between researchers and patients (i.e., individuals with lived experience including informal caregivers) in developing or conducting research. Offering non-financial (e.g., co-authorship, gift) or financial (e.g., honoraria, salary) compensation to patient partners can demonstrate appreciation for patient partner time and effort. However, little is known about how patient partners are currently compensated for their engagement in research. We sought to assess the prevalence of reporting patient partner compensation, specific compensation practices (non-financial and financial) reported, and identify benefits, challenges, barriers and enablers to offering financial compensation. Methods: We conducted a systematic review of studies citing the Guidance for Reporting the Involvement of Patients and the Public (GRIPP I and II) reporting checklists (October 2021) within Web of Science and Scopus. Studies that engaged patients as research partners were eligible. Two independent reviewers screened full texts and extracted data from included studies using a standardized data abstraction form. Data pertaining to compensation methods (financial and non-financial) and reported barriers and enablers to financially compensating patient partners were extracted. No formal quality assessment was conducted since the aim of the review is to describe the scope of patient partner compensation. Quantitative data were presented descriptively, and qualitative data were thematically analysed. Results: The search identified 843 studies of which 316 studies were eligible. Of the 316 studies, 91% (n = 288) reported offering a type of compensation to patient partners. The most common method of non-financial compensation reported was informal acknowledgement on research outputs (65%, n = 206) and co-authorship (49%, n = 156). Seventy-nine studies (25%) reported offering financial compensation (i.e., honoraria, salary), 32 (10%) reported offering no financial compensation, and 205 (65%) studies did not report on financial compensation. Two key barriers were lack of funding to support compensation and absence of institutional policy or guidance. Two frequently reported enablers were considering financial compensation when developing the project budget and adequate project funding. Conclusions: In a cohort of published studies reporting patient engagement in research, most offered non-financial methods of compensation to patient partners. Researchers may need guidance and support to overcome barriers to offering financial compensation. Plain English summary: The term patient engagement in research is used to describe research that is conducted "with" patients, rather than "on" patients. It is important that researchers recognize patient partners for their time and expertise. In order to gain a better understanding of approaches to recognition for patient partners we reviewed published studies to: (1) assess how often financial compensation is reported, (2) identify how patient partners are reported as being compensated, and (3) understand what benefits, challenges, barriers and enablers might exist to offering financial compensation. We conducted a systematic review of articles citing the Guidance for Reporting the Involvement of Patients and the Public (GRIPP) guidelines. We included all study designs if patients were engaged as partners. Studies in which patients were participants only were excluded. Data collected included information about details of patient partner compensation (financial and non-financial practices) as well as challenges relating to financial compensation. Numerical data were analysed descriptively. Textual data were coded by two reviewers and collated into overarching themes. Our search identified 316 papers. Of these, 91% reported offering compensation to patient partners. Most common methods were acknowledgement (65%) and co-authorship (49%). Only 79 studies (25%) reported offering financial compensation to patient partners. Limited funding and lack of institutional guidance were identified as two key barriers that may be preventing researchers from offering financial compensation. Our review found that non-financial methods of compensation are reported more often than financial compensation. Researchers may require more support when offering financial compensation to patient partners. [ABSTRACT FROM AUTHOR]