Surrogate endpoint meta-regression: Useful statistics for regulators and trialists.

OBJECTIVES: The main purpose of using a surrogate endpoint is to estimate the treatment effect on the true endpoint sooner than with a true endpoint. Based on a meta-regression of historical randomized trials with surrogate and true endpoints, we discuss statistics for applying and evaluating surrogate endpoints. METHODS: We computed statistics from two types of linear meta-regressions for trial-level data: simple random effects and novel random effects with correlations among estimated treatment effects in trials with more than 2 arms. A key statistic is the estimated intercept of the meta-regression line. An intercept that is small or not statistically significant increases confidence when extrapolating to a new treatment because of consistency with a single causal pathway and invariance to labeling of treatments as controls. For a regulator applying the meta-regression to a new treatment, a useful statistic is the 95% prediction interval. For a clinical trialist planning a trial of a new treatment, useful statistics are the surrogate threshold effect proportion, the sample size multiplier adjusted for dropouts, and the novel true endpoint advantage. RESULTS: We illustrate these statistics with surrogate endpoint meta-regressions involving anti-hypertension treatment, breast cancer screening, and colorectal cancer treatment. CONCLUSION: Regulators and trialists should consider using these statistics when applying and evaluating surrogate endpoints.

Design principles for molecular animation.

Molecular visualization is a powerful way to represent the complex structure of molecules and their higher order assemblies, as well as the dynamics of their interactions. Although conventions for depicting static molecular structures and complexes are now well established and guide the viewer's attention to specific aspects of structure and function, little attention and design classification has been devoted to how molecular motion is depicted. As we continue to probe and discover how molecules move - including their internal flexibility, conformational changes and dynamic associations with binding partners and environments - we are faced with difficult design challenges that are relevant to molecular visualizations both for the scientific community and students of cell and molecular biology. To facilitate these design decisions, we have identified twelve molecular animation design principles that are important to consider when creating molecular animations. Many of these principles pertain to misconceptions that students have primarily regarding the agency of molecules, while others are derived from visual treatments frequently observed in molecular animations that may promote misconceptions. For each principle, we have created a pair of molecular animations that exemplify the principle by depicting the same content in the presence and absence of that design approach. Although not intended to be prescriptive, we hope this set of design principles can be used by the scientific, education, and scientific visualization communities to facilitate and improve the pedagogical effectiveness of molecular animation.

Inherited human RelB deficiency impairs innate and adaptive immunity to infection.

We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB). The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1ß via the canonical NF-κB pathway remains intact. P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells. Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro. Finally, the patients produce neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens. Thus, inherited human RelB deficiency disrupts the alternative NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections.

Family-centred care interventions for children with chronic conditions: A scoping review.

INTRODUCTION: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions. METHODS: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care. RESULTS: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). CONCLUSION: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population. PATIENT OR PUBLIC CONTRIBUTION: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination.

Continuous-wave driving elucidates the desynchronization dynamics of ultrashort dissipative Raman solitons generated in dispersive Kerr resonators.

Phase-coherent pulsed driving of passive optical fiber resonators enables the generation of ultrashort dissipative Raman solitons with durations well below 100 fs. The existence and characteristics of such solitons critically depend on the desynchronization between the pulsed driving source and the resonator round trip time, yet the full mechanism through which these dependencies arise remains unclear. Here, we numerically demonstrate that Raman solitons can exist even under conditions of continuous-wave (CW) driving, and by numerically examining the existence and characteristics of Raman solitons under such conditions, we elucidate the role of desynchronization in pulse-driven systems. In addition to providing new insights into the existence and characteristics of ultrashort Raman solitons, our analysis yields a qualitative explanation for the range of desynchronizations over which the solitons can exist.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-ß Toxicity in C. elegans via Distinct Mechanisms.

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 Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)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-ß 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.

A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

α-Bungarotoxin labelling of AMPA receptor-associated TARPs in living neurons.

In mammalian central neurons AMPARs are clustered at glutamatergic synapses where they mediate fast excitatory transmission. In addition to four pore-forming subunits (GluA1-4), AMPARs contain auxiliary transmembrane AMPAR regulatory proteins (γ2, γ3, γ4, γ5, γ7 or γ8) whose incorporation can vary between neuron types, brain regions, and stages of development. As well as modulating the functional properties of AMPARs, these auxiliary subunits play a central role in AMPAR trafficking. Directly visualizing TARPs could therefore provide a valuable insight into mechanisms underlying these processes. Although antibodies are routinely used for the detection of surface proteins, our experience suggests anti-TARP antibodies are too bulky to access their target, possibly due to close interactions between the extracellular domains of TARP and AMPAR subunits. We therefore assessed the utility of a small monovalent probe - fluorescent α-bungarotoxin (α-Btx) - for TARP labelling in living neurons. We inserted the bungarotoxin binding site (BBS) within the extracellular domain of TARPs to enable their detection in cells exposed to fluorescent α-Btx. Focusing on the prototypical TARP γ2, we demonstrate that the small size of fluorescent α-Btx allows it to bind to the BBS-tagged TARP when associated with AMPARs. Importantly, labelled γ2 enhances AMPAR function in the same way as unmodified γ2. In living neurons, fluorescent α-Btx-labelled γ2 associates with AMPAR clusters at synapses. As a proof-of-principle, we employed our method to compare the surface trafficking of γ2 and γ7 in cerebellar stellate neurons. Our approach provides a simple way to visualize TARPs within AMPARs in living cells.

They are still children: a scoping review of conditions for positive engagement in elite youth sport.

OBJECTIVE: The objective of this study is to characterise the key factors that influence positive engagement and desirable developmental outcomes in sport among elite youth athletes by summarising the methods, groups and pertinent topical areas examined in the extant published research. DESIGN: Scoping review. DATA SOURCES: We searched the databases SPORTDiscus, APA PsycINFO, Web of Science and Sports Medicine & Education Index for peer-reviewed, published in English articles that considered the factors influencing positive developmental outcomes for athletes under 18 years competing at a national and/or international level. RESULTS: The search returned 549 articles, of which 43 met the inclusion criteria. 16 studies used a qualitative approach, 14 collected quantitative data, 2 adopted mixed methods and 11 were reviews. Seven articles involved athletes competing in absolute skill contexts (ie, against the best athletes of any age) while the majority involved athletes competing in relative skill contexts (ie, against the best in a specific age or developmental group). The studies described the characteristics of the athletes, as well as their training, relationships with others, social and physical environments, and/or their overall developmental pathways. CONCLUSION: Existing research on positive engagement in elite youth sport aligned with and mapped onto established models of positive development in youth sport more generally. Our findings further support that, while certain youth athletes may demonstrate extraordinary performance capabilities, they are still children who benefit from positive engagement prompted and reinforced by developmentally appropriate and supportive activities, relationships and environments.

STAT3 gain of function: Too much of a good thing in the skin!

Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome.

Flow Cytometric Identification of Human IgE+ B Lineage Subsets.

The use of flow cytometry for immunophenotyping is contingent on the ability to accurately assign biological relevance to the detected signal. This process has historically been challenging when defining IgE expressing B cells or IgE expressing antibody-secreting cells due to widespread expression of receptors for IgE on various leukocyte subsets, including human B cells. Here we describe our implementation of intracellular staining for human IgE following a blocking step to negate the challenge of surface-bound IgE. We also describe our experience with a human B cell culture system that can be used to robustly validate this approach before application to primary human samples. Orthogonal confirmatory techniques remain essential; these are not described in detail, but several possible strategies are suggested.

Embedding Patient and Health Care Professional Voices in Clinical Trials.

This Viewpoint discusses the need to include patient and health care professional perspectives in the design of clinical trials to improve trial features and implementation.

Comments on "sensitivity of estimands in clinical trials with imperfect compliance" by Chen and Heitjan.

Chen and Heitjan (Sensitivity of estimands in clinical trials with imperfect compliance. Int J Biostat. 2023) used linear extrapolation to estimate the population average causal effect (PACE) from the complier average causal effect (CACE) in multiple randomized trials with all-or-none compliance. For extrapolating from CACE to PACE in this setting and in the paired availability design involving different availabilities of treatment among before-and-after studies, we recommend the sensitivity analysis in Baker and Lindeman (J Causal Inference, 2013) because it is not restricted to a linear model, as it involves various random effect and trend models.

Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis.

BACKGROUND: Dexmedetomidine is increasingly used for surgical patients requiring general anaesthesia. However, its effectiveness on patient-centred outcomes remains uncertain. Our main objective was to evaluate the patient-centred effectiveness of intraoperative dexmedetomidine for adult patients requiring surgery under general anaesthesia. METHODS: We conducted a systematic search of MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to October 2023. Randomised controlled trials (RCTs) comparing intraoperative use of dexmedetomidine with placebo, opioid, or usual care in adult patients requiring surgery under general anaesthesia were included. Study selection, data extraction, and risk of bias assessment were performed by two reviewers independently. We synthesised data using a random-effects Bayesian regression framework to derive effect estimates and the probability of a clinically important effect. For continuous outcomes, we pooled instruments with similar constructs using standardised mean differences (SMDs) and converted SMDs and credible intervals (CrIs) to their original scale when appropriate. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our primary outcome was quality of recovery after surgery. To guide interpretation on the original scale, the Quality of Recovery-15 (QoR-15) instrument was used (range 0-150 points, minimally important difference [MID] of 6 points). RESULTS: We identified 49,069 citations, from which 44 RCTs involving 5904 participants were eligible. Intraoperative dexmedetomidine administration was associated with improvement in postoperative QoR-15 (mean difference 9, 95% CrI 4-14, n=21 RCTs, moderate certainty of evidence). We found 99% probability of any benefit and 88% probability of achieving the MID. There was a reduction in chronic pain incidence (odds ratio [OR] 0.42, 95% CrI 0.19-0.79, n=7 RCTs, low certainty of evidence). There was also increased risk of clinically significant hypotension (OR 1.98, 95% CrI 0.84-3.92, posterior probability of harm 94%, n=8 RCTs) and clinically significant bradycardia (OR 1.74, 95% CrI 0.93-3.34, posterior probability of harm 95%, n=10 RCTs), with very low certainty of evidence for both. There was limited evidence to inform other secondary patient-centred outcomes. CONCLUSIONS: Compared with placebo or standard of care, intraoperative dexmedetomidine likely results in meaningful improvement in the quality of recovery and chronic pain after surgery. However, it might increase clinically important bradycardia and hypotension. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023439896).

Self-reported attention and responses to cigarette package labels at the end of a two-week randomized trial of cigarette package labeling configurations.

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 2×2 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.

What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.

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.

Differential responses to cigarette package labeling alternatives among adults who smoke: Results from a randomized trial.

INTRODUCTION: Little experimental research has evaluated whether the effects of cigarette package inserts with efficacy messages and/or pictorial health warning labels (PHWLs) differ across key subgroups of adults who smoke. METHODS: Adults who reported currently smoking (n=367) were randomly assigned to one of four groups: small text-only health warning labels (HWLs) on pack sides (control); inserts with efficacy messages and small HWLs (inserts-only); PHWLs showing harms of smoking (PHWLs-only); both (inserts+PHWLs). Participants received a 14-day supply of cigarettes labeled to reflect their group. Every evening over two weeks, participants reported forgoing and stubbing out cigarettes before they finished smoking over the prior 24 hours, combined into a binary indicator of either behavior (e.g., forgoing/stubbing). Separate mixed-effects logistic models were estimated to evaluate moderation of labeling group contrasts (i.e., PHWLs vs not; inserts vs. not; inserts-only vs. inserts+PHWLs; PHWLs-only vs. inserts+PHWLs) by baseline covariates (self-efficacy to quit, intention to quit, education, health literacy, time discounting), predicting day-level forgoing/stubbing. RESULTS: Education moderated PHWL effects, with PHWLs predicting more forgoing/stubbing only among those with low education (OR=4.68, p<0.001). Time discounting moderated insert effects, with inserts promoting fogoing/stubbing only among those with low time discounting (i.e., lower impulsivity; OR=4.35, p<0.001). CONCLUSIONS: Inserts with efficacy messages appear effective mostly among people with low time discounting, whereas PHWLs appear most effective amongst those with low education, suggesting their potential to address education-related disparities. Labeling strategies appeared equally effective across subgroups defined by self-efficacy to quit, quit intention, and health literacy. Combining inserts with PHWLs did not appear to mitigate moderation effects. IMPLICATIONS: This randomized trial with adults who smoke suggests that cigarette packs with inserts describing cessation benefits and tips can promote cessation-related behaviors (i.e., forgoing or stubbing out cigarettes) among those with low time discounting (i.e., low impulsivity). Alternative interventions may be needed for people with high time discounting, as found in cessation trials. Pictorial health warning labels (PHWLs) appear most effective among those with low education, potentially addressing education-related disparities. No differential effects were found for those with different levels of self-efficacy to quit, quit intentions, or health literacy. Combining inserts and PHWLs may not be more effective than either alone.

Does proactive care in care homes improve survival? A quality improvement project.

BACKGROUND: NHS England's 'Enhanced Health in Care Homes' specification aims to make the healthcare of care home residents more proactive. Primary care networks (PCNs) are contracted to provide this, but approaches vary widely: challenges include frailty identification, multidisciplinary team (MDT) capability/capacity and how the process is structured and delivered. AIM: To determine whether a proactive healthcare model could improve healthcare outcomes for care home residents. DESIGN AND SETTING: Quality improvement project involving 429 residents in 40 care homes in a non-randomised crossover cohort design. The headline outcome was 2-year survival. METHOD: All care home residents had healthcare coordinated by the PCN's Older Peoples' Hub. A daily MDT managed the urgent healthcare needs of residents. Proactive healthcare, comprising information technology-assisted comprehensive geriatric assessment (i-CGA) and advanced care planning (ACP), were completed by residents, with prioritisation based on clinical needs.Time-dependent Cox regression analysis was used with patients divided into two groups:Control group: received routine and urgent (reactive) care only.Intervention group: additional proactive i-CGA and ACP. RESULTS: By 2 years, control group survival was 8.6% (n=108), compared with 48.1% in the intervention group (n=321), p<0.001. This represented a 39.6% absolute risk reduction in mortality, 70.2% relative risk reduction and the number needed to treat of 2.5, with little changes when adjusting for confounding variables. CONCLUSION: A PCN with an MDT-hub offering additional proactive care (with an i-CGA and ACP) in addition to routine and urgent/reactive care may improve the 2-year survival in older people compared with urgent/reactive care alone.