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Abstract Background To determine the feasibility, acceptability, and preliminary efficacy of a 6-month tailored non-linear progressive physical activity intervention (PAI) for lymphoma patients undergoing chemotherapy. Methods Patients newly diagnosed with lymphoma (non-Hodgkin (NHL) or Hodgkin (HL)) were randomized into the PAI or healthy living intervention (HLI) control (2:1). Feasibility was assessed by examining accrual, adherence, and retention rates. Participants completed assessments of exercise capacity (VO2 peak and 6-min walk distance (6MWD)), objective and self-reported levels of physical activity, MRI-derived cardiovascular functioning (Left Ventricular Ejection Fraction [LVEF], stroke volume, and cardiac output), and self-reported health-related and disease-specific quality of life and self-efficacy for exercise at baseline, 3, and 6 months. Results One hundred and forty-five individuals were screened with 23 of 84 eligible patients agreeing to participate (27%). Three participants withdrew before baseline testing. Out of the 20 participants randomized to the PAI (n = 13) and HLI groups (n = 7), 18 completed the intervention resulting in an overall retention rate of 78%. The adherence rates to the PAI and HLI were 85% and 87%, respectively. One non-serious adverse event was registered. VO2 peak ranged from 15.5–28.0 ml/kg/min at baseline and participants in both groups improved by 6 months. Physical activity levels and cardiovascular function were reduced prior to treatment but did not deteriorate further. Conclusions Implementing a tailored PAI in adults with lymphoma during active treatment is feasible, was well received by participants and shows preliminary efficacy for limiting a decline in function during treatment. Potential Implications for Cancer Survivors: Physical activity may be beneficial for improving exercise capacity and health-related quality of life in patients undergoing chemotherapy. Trial registration #NCT01719562 ClinicalTrials.gov. Registered July 2, 2019—retrospectively registered.

Abstract The orbitofrontal cortex (OFC) is a large cortical structure, expansive across anterior-posterior axes. It is essential for flexibly updating learned behaviors, and paradoxically, also implicated in inflexible and compulsive-like behaviors. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice also demonstrate insensitivity to Pavlovian-to-instrumental transfer, as well as compulsive-like grooming behavior that is ameliorated by fluoxetine and inhibitory, but not excitatory, chemogenetic modulation of excitatory OFC neurons. Thus, these mice offer the opportunity to identify neurobiological factors associated with inflexible and compulsive-like behavior. Experimentally bred mice suffer excitatory dendritic spine attrition, as well as changes in inhibitory synapse-associated proteins, GAD67/GAD1 and SLITRK3, largely in the anterior and not posterior OFC (or medial frontal cortex). They also display higher levels of the excitatory synaptic marker striatin in the nucleus accumbens and lower levels of the excitatory synaptic marker SAPAP3 in the dorsal striatum, striatal nuclei that receive input from the anterior OFC. Together, our findings point to the anterior OFC as a potential locus controlling action flexibility and compulsive-like behavior alike.

Abstract Tropical forests may be nearing critical temperatures, yet tree species may respond differently. Using high-resolution thermal, hyperspectral, and LiDAR imagery, we mapped 652 crowns of four Hawaiian tree species to study the effects of crown traits and abiotic conditions on species’ temperatures at two scales (whole crown vs. sunlit leaves). We show scale-dependent, species-specific relationships with environmental fluctuations. Net radiation was consistently the dominant determinant of crown temperature deviations from air temperature (Tdiff), while vapor pressure deficit, wind speed, and crown traits (e.g., roughness) varied in importance by species and scale. Species explained 17% and 44% of Tdiff variation at the crown and leaf scales, respectively, after controlling for climatic factors. Findings suggest that leaf temperatures overestimate larger-scale temperature differences, while canopy-scale observations underestimate leaf heat stress. Because leaf and crown traits can have opposing effects on Tdiff, disentangling these can advance our understanding of species’ thermoregulation under climate change.

Abstract Background Goal setting for persons within health and social care environments can be a challenging task; although health and social care settings aim to address a person’s care needs, the literature tends to focus on health. Person-centred care should encompass the goals/needs/wants of the person, whether these goals focus on career, relationship, and/or health domains. To understand how a person-centred participatory goal setting process is carried out in a care environment, we used an integrated knowledge translation approach. Methods We conducted 11 semi-structured interviews with community-care staff to understand a person-centred planning process, including key components and impacts. Results The interviews provide a thorough understanding of an implemented approach to person-centred plans, including its creation, implementation, and benefits (for the person-supported, family, friends, and staff). Person-centred plans provide a map with which to plan activities based on a persons’ goals, interests, and capacities, and have positive impacts for the person-supported, family, friends, and staff. Conclusions Our study highlights how a community-care organization can facilitate person-centred services through person-centred plans and has implications for wider uptake of person-centred plans in community-care organizations.

Abstract Mediator, a co-regulator complex required for RNA Polymerase II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We observe reduced Mediator subunit MED15 expression in endocrine hormone-producing pancreatic islets isolated from people living with type 2 diabetes and sought to understand how MED15 and Mediator control gene expression programs important for the function of insulin-producing β-cells. Here we show that Med15 is expressed during mouse β-cell development and maturation. Knockout of Med15 in mouse β-cells causes defects in β-cell maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses found that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. In support of a conserved role during human development, human embryonic stem cell-derived β-like cells, genetically engineered to express high levels of MED15, express increased levels of maturation markers. We provide evidence of a conserved role for Mediator in β-cell maturation and demonstrate an additional layer of control that tunes β-cell transcription factor function.

Abstract Background Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. Methods In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in $$\frac{d}{d\phi }fMRI$$ d d ϕ f M R I and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. Results Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (−0.015 vs. −0.069, p

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Background Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple strategies improve persistence by increasing stem-like properties or sustaining CAR T cell activity with combination therapies. Here, we describe the intrinsic ability of CAR T cells to differentiate into memory T cells, the effect of cytokine armoring, and neoadjuvant CD4 depletion therapy on CAR and tumor-specific endogenous memory T cells.Methods TRP1-specific or NKG2D CAR T cells alone or with Super2+IL-33 (S233) armoring and/or CD4 depletion were evaluated in immunocompetent B16F10 melanoma or MC38 colon cell carcinoma models without preconditioning. We characterized CAR and endogenous tumor-specific memory T cell precursors, establishment of circulating (TCIRC) and resident (TRM) memory T cell subsets, and ability to protect against secondary tumors.Results TRP1-specific or NKG2D CAR T cells had no effect on primary tumor growth in immunocompetent mice unless they were combined with S233 armoring or CD4 depletion. Unarmored CAR T cells expressed a stem-like phenotype in the tumor-draining lymph node and differentiated into CAR TCIRC memory cells in lymphoid organs and CAR TRM cells in the skin. In contrast, S233-armored CAR T cells exhibited an activated effector phenotype and differentiated inefficiently into CAR effector and central memory T cells. Combining CD4 therapy with unarmored CAR T cells increased CAR TCIRC and TRM memory T cells. Either CD4 depletion therapy or S233-armored CAR T cells induced activation of tumor-specific endogenous T cells that differentiated into both TCIRC and TRM memory T cells. CD4 depletion and S233-armored CAR T cell combination therapy synergized to increase endogenous memory T cells.Conclusions Unarmored TRP-1-specific or NKG2D CAR T cells have intrinsic stem-like properties and differentiate into memory T cell subsets but are non-protective against primary or secondary tumors. S233 cytokine armoring alone or with CD4 depletion improved effector responses but limited CAR memory T cell generation. S233-armored CAR T cells or CD4 depletion therapy induced endogenous tumor-specific TCIRC and TRM T cells, but the combination potentiated endogenous memory T cell generation and resulted in improved protection against B16F10 rechallenge.

Background:. Obesity is widely recognized as a significant risk factor for postoperative complications of breast reconstruction. Despite extensive research, there remains a lack of consensus regarding the specific complications and outcomes experienced by patients with obesity who undergo deep inferior epigastric perforator (DIEP) flap reconstruction. To provide a clearer understanding of the challenges faced by patients with obesity, we present a single-center outcome analysis of individuals who underwent DIEP flap reconstruction. Methods:. A cohort of 194 patients who underwent at least 1 DIEP flap was retrospectively analyzed at the University of Nebraska Medical Center utilizing electronic medical records. Patients who underwent DIEP flap breast reconstruction were organized into 5 categories using World Health Organization weight status by body mass index (BMI) obtained from the day of surgery. Surgical complications within 120 days and postsurgical complication-related procedural interventions were also evaluated and compared. Comparisons of variables of interest between weight groups were assessed using Mantel–Haenszel chi-square tests or Spearman correlations. Results:. Increases in patient weight category were associated with increased length of operation (P = 0.003), increased rates of breast fat necrosis (P = 0.04), breast wound dehiscence (P = 0.01), abdominal wound dehiscence (P = 0.02), numbers of abdominal complications (P = 0.001), and rates of requiring an intervention (P = 0.03). Conclusions:. The findings imply that higher BMI values may lead to a higher likelihood of postoperative complications and the need for intervention. It is crucial for patients with obesity to be aware of the elevated risk associated with rising BMI values.

Understanding and predicting individual responses to common stressors is essential for optimising performance in high-stress environments. This article outlines a protocol for a study to identify biomarkers that predict performance under heat, musculoskeletal, psychosocial and sleep stress, for future integration into a wearable sensor system. In Phase I, healthy adults aged between 18 and 45 years (n=104) will be recruited for an intervention trial that involves exposure to one of the four stressors: heat, musculoskeletal, psychosocial or sleep deprivation. Biomarkers will be identified from molecular markers in biological samples (eg, blood, saliva, sweat and stool), physiological measures and psychological assessments to predict cognitive and physical performance under stress. A within-subjects design will determine changes in molecular and non-molecular markers before and after stress exposure. In Phase II, we will use the biomarkers identified in Phase I to develop a wearable sensor to predict and monitor human performance under stress.

Interprofessional teamwork is vital to effective patient care, and targeting healthcare learners earlier in their education can lead to greater improvement in confidence and competence in teamwork skills. Despite this, institutions have continued struggling to integrate competency-based interprofessional teamwork curriculum in undergraduate health care professions’ education. The current article provides guidance related to design, implementation, and assessment for institutions seeking to implement competency-based teamwork education and training strategies for healthcare students. Guiding principles and strategies for curricular design focus on conducting thorough interprofessional needs analyses and building transportable, evidence-based competencies that apply across professions. For implementation, key principles center on strategies to ensure adequate professional representation and faculty development. Assessment considerations focus on building infrastructure for evaluation that spans professional schools. These strategies aim to create a robust, effective, and sustainable IPE curriculum that enhances collaboration and teamwork among future healthcare professionals. By addressing the key areas of design, implementation, and assessment, this article offers comprehensive guidelines for advancing interprofessional education. We believe incorporating the key guiding principles and strategies from this paper will enable institutions to integrate teamwork education and training more effectively into undergraduate healthcare training, which will facilitate institutions’ ability to ensure learners are “team ready” as they transition into the workforce after graduation.

Abstract In situ soil respiration is driven by annual patterns of temperature and soil moisture, but what about extracellular enzyme activities responsible for depolymerizing soil organic matter? We conducted biweekly measurements of potential soil β‐glucosidase activities during a 4‐month period from March soil thawing through July in annually cropped field plots in eastern South Dakota. Our objective was to determine the best sampling time to resolve the effects of crop rotational diversity on soil microbial activities. Potential β‐glucosidase activities were elevated immediately following soil thaw, peaked in May, and declined to their lowest value in mid‐summer. Temperature and precipitation had no value in predicting enzyme activities; however, enzyme activities were affected by crop rotational diversity and responded to current crop and previous crop. These findings are pertinent to the use of soil extracellular enzymes in soil health assessments and as indicators of microbial substrate preference with implications for soil carbon stabilization.

Background: Children living in both kinship and foster care placements often face considerable adversity. It is possible that these placements can have differential impacts on children’s socioemotional, psychological, and educational outcomes and well-being. Objective: This study examined the similarities and differences between children and youth who reside in kinship placements and those who reside in foster placements. Specifically, similarities and differences in children's mental health care and service requirements, as well as their family's strengths and resources were explored to better understand the needs of children placed in out-of-home care. Participants: The final sample included assessments from 5356 treatment-seeking children, ages three to 18 years old, from across 66 select mental health agencies in Ontario. Methods: Children were assessed using the interRAI ChYMH, the ChYMH-S, or the ChYMH-DD. These assessments include a variety of embedded evidence-informed scales and algorithms to examine the mental health needs, preferences and strengths of these vulnerable children. Results: Compared to children in kinship placements, children in foster care were more likely to: (a) exhibit greater externalizing symptoms, (b) display concerns regarding sexual behaviour, (c) encounter trauma, and (d) experience more polyvictimization. No differences were found in terms of spirituality and cultural connectedness. Additionally, kinship caregivers tended to experience greater distress, compared to foster caregivers. Conclusions: Findings from this study highlight important areas where children residing in out-of-home care, particularly those in foster care, require increased access to mental health resources and support. Furthermore, trauma-informed care should always be at the forefront when working with foster and kinship care children and their families.

ObjectiveThis study aimed to create and validate a novel measure of gender-related minority stress in transgender and non-binary adolescents (TNBA). TNBA face higher risks of varied behavioral health concerns compared to their cisgender peers, a disparity often attributed to the presence of minority stress due to discrimination. To date, no comprehensive measures of gender-related minority stress exist for use with TNBA.MethodThe present study recruited a U.S. national sample (N = 444, aged 12–17; 65.5% White, 9.5% Black, 9.5% Latine, 15.5% other ethnicity; 34.7% transmasculine, 17.3% transfeminine, 38.3% non-binary, 9.5% agender) of TNBA. An initial item pool was developed from life history calendars, a modified Delphi process, and cognitive interviews with TNBA. Analytic methods including principal components analysis, item response theory, measurement invariance testing, and reliability analyses were conducted to establish the final scale. Concurrent validity was established across behavioral outcomes (mental health, suicidal thoughts and behavior, substance use), and convergent and divergent validity compared the Transgender Adolescent Stress Survey–Minority Stress (TASS-MS) to existing measures of gender-related minority stress.ResultsThe TASS-MS and its subscales (disaffirmation, visibility and internalized transnegativity, family) were significantly associated with anxiety and depressive symptoms, PTSD symptoms, suicidal behaviors, non-suicidal self-injury, marijuana, and prescription drug use. The TASS-MS was moderately and weakly correlated with convergent and divergent measures, respectively, indicating specificity to minority stress.ConclusionThe TASS-MS is a reliable and valid measure for future research with TNBA. It is inclusive and usable by all gender minority adolescents, uses a standard simple scoring system, and assesses adolescent-specific stressors.

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.

Surveillance data from wildlife and poultry was used to describe the spread of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in British Columbia (B.C.) and the Yukon, Canada from September 2022 – June 2023 compared to the first “wave” of the outbreak in this region, which occurred April – August 2022, after the initial viral introduction. Although the number of HPAI-positive poultry farms and wildlife samples was greater in “Wave 2”, cases were more tightly clustered in southwestern B.C. and the most commonly affected species differed, likely due to an influx of overwintering waterfowl in the area. Eight HPAI genetic clusters, representing seven genotypes and two inter-continental viral incursions, were detected, with significant variation in the relative abundance of each cluster between the waves. Phylogenetic data suggests multiple spillover events from wild birds to poultry and mammals but could not rule out transmission among farms and among mammals.

Background Nearly half of the global population has some form of oral health-related disease primarily associated with caries or tooth decay, periodontal disease, tooth loss or oral cancer. Oral and face pains are a primary motivator for healthcare consultation. While not specifically included in global estimates, orofacial pain associated with oral diseases and orofacial pain disorders pose significant global public health and financial burdens. Thus, it is paramount to act on opportunities to improve the practice of medicine in dentistry.Examined Literature and Conceptual Advancement This article centers on areas for improvement in the fields of oral health and dentistry in defining, evaluating, and treating musculoskeletal orofacial pains, a category of pain disorders within orofacial pain leading to physical pain and both mental and physical disability. We discuss how features of dentistry, current modes of specialist training, and cultural norms have inadvertently created barriers to improvements in care quality and may even promote harms to patient groups with musculoskeletal pain. We provide critical insights and solutions in patient safety and quality improvement efforts from other areas of medicine, such as in emergency or acute care settings.Practical Implications Because musculoskeletal orofacial pains are a wide-spread, common, and costly constellation of oral health disorders, they represent a keystone treatment area for the fields of dentistry and oral health to bridge with existing patient safety and quality improvement efforts. We conclude by providing several recommendations from lessons learned in patient safety and quality improvement applied to musculoskeletal pain care. Collectively, these lessons stand to: (1) promote sharing of information, (2) encourage collaboration and transdisciplinary problem solving as a medical community, and (3) improve diagnostic accuracy and optimal delivery of the highest quality treatment as safely as possible for both patients and providers.

Abstract People with Parkinson’s disease (PWP) face critical challenges, including lack of access to neurological care, inadequate measurement and communication of motor symptoms, and suboptimal medication management and compliance. We have developed QDG-Care: a comprehensive connected care platform for Parkinson’s disease (PD) that delivers validated, quantitative metrics of all motor signs in PD in real time, monitors the effects of adjusting therapy and medication adherence and is accessible in the electronic health record. In this article, we describe the design and engineering of all components of QDG-Care, including the development and utility of the QDG Mobility and Tremor Severity Scores. We present the preliminary results and insights from an at-home trial using QDG-Care. QDG technology has enormous potential to improve access to, equity of, and quality of care for PWP, and improve compliance with complex time-critical medication regimens. It will enable rapid “Go-NoGo” decisions for new therapeutics by providing high-resolution data that require fewer participants at lower cost and allow more diverse recruitment.

Abstract Background Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF‐15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF‐15‐mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab‐mediated inactivation of circulating GDF‐15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF‐15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. Methods Approximately 168 adults with non‐small‐cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF‐15 concentrations will be randomized in a double‐blind, placebo‐controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12‐week treatment period. This is followed by optional open‐label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient‐reported appetite‐related symptoms assessed by Functional Assessment of Anorexia‐Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer‐Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. Perspective Cancer‐related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF‐15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. Trial registration ClinicalTrials.gov ID: NCT05546476.

Abstract Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach is the long differentiation timeline that generates a heterogeneous population of pancreatic endocrine cells. To address this limitation, an inducible lentiviral overexpression system of mature β-cell markers was introduced into human induced-pluripotent stem cells (hiPSCs). Following the selection of the successfully transduced hiPSCs, the cells were treated with doxycycline in the pancreatic progenitor induction medium to support their transition toward the pancreatic lineage. Cells cultured with doxycycline presented the markers of interest, NGN3, PDX1, and MAFA, after five days of culture, and glucose-stimulated insulin secretion assays demonstrated that the cells were glucose-responsive in a monolayer culture. When cultured as a spheroid, the markers of interest and insulin secretion in a static glucose-stimulated insulin secretion assay were maintained; however, insulin secretion upon consecutive glucose challenges was limited. Comparison to human fetal and adult donor tissues identified that although the hiPSC-derived spheroids present similar markers to adult insulin-producing cells, they are functionally representative of fetal development. Together, these results suggest that with optimization of the temporal expression of these markers, forward programming of hiPSCs towards insulin-producing cells could be a possible alternative for islet transplantation.

Background: Immune tolerance induction (ITI) is the gold standard for inhibitor eradication to restore the clinical efficacy of factor replacement therapy in haemophilia. However, as ITI often requires frequent administration over extended periods, it can be considered burdensome for patients and healthcare resources. Therefore, there is a need to optimise ITI treatment, particularly in patients who failed previous ITI attempts. Objectives: The ReITIrate study aimed to prospectively evaluate rescue ITI with efmoroctocog alfa, an extended half-life recombinant FVIII Fc fusion protein (herein rFVIIIFc), within a limited 60-week timeframe in patients with severe haemophilia A and inhibitors who failed previous ITI attempts. Design: ReITIrate was a phase IV, open-label, single-arm, interventional, multicentre study. Methods: Primary endpoint was ITI success (negative titre, 66%; elimination half-life ⩾7 hours) within 60 weeks. Exploratory immunophenotype analyses were performed to characterise anti-drug antibodies (ADA) and cellular immune responses. Results: Nine of 16 enrolled subjects completed the ITI period during ReITIrate, of which one subject attained all 3 ITI success criteria after 46 weeks with no relapse. Two subjects achieved partial success (one subject met 2/3 success criteria; one met all criteria, but not simultaneously, with inhibitor recurrence). One additional subject (ITI failure) achieved negative inhibitor titre. Across these four subjects, median (range) time to negative titre was 19 (11–60) weeks. No new safety concerns were identified. IgG4 was the major contributor to the ADA IgG response. Subjects with partial/complete ITI success had fewer IgG subclasses involved than those who failed/withdrew. Immunophenotyping indicated an increase in regulatory T-cells (CD4 + CD25 + CD127 low ), supporting the ability to perform sensitive blood sampling to identify immune tolerance markers. Conclusion: This study demonstrates that ITI with rFVIIIFc given within a limited timeframe has potential benefit in a difficult-to-treat inhibitor haemophilia population who failed previous ITI attempts. Trial registration: NCT03103542.

IntroductionChildren and adolescents treated in specialty mental health services are more likely to have sleep disturbances than those without mental health problems. Few studies have investigated the relationship between sleep and psychopathology in broad clinical samples of children. We examined the relationship between sleep disturbance and age on internalizing and externalizing psychopathology in a sample who sought treatment at children's mental health centers.MethodsSecondary data analyses were completed on a sample of children (N = 13,472; aged 4 to 18; 55% male) from 39 children's mental health agencies in Ontario, Canada, who completed a semi-structured assessment, the interRAI Children and Youth Mental Health (ChYMH). A split-half sample approach was utilized (S1 n = 6,773, S2 n = 6,699). Hierarchical regressions examined the effects of sleep disturbances (i.e., difficulty falling asleep, staying asleep, night waking, bedtime resistance, falling asleep during the day) on internalizing and externalizing symptoms, above and beyond established child- (i.e., age, sex, sensory sensitivity, pain) and family-level variables (family functioning, caregiver distress, parenting strengths). Age was tested as a moderator for sleep disturbances on both outcome variables.ResultsOverall, 6.7% of children had clinically significant sleep disturbance scores (≥10 out of 16) on the interRAI ChYMH. In both samples, sleep disturbances predicted internalizing (S1 ΔR2 = 10%, S2 ΔR2 = 10%) and externalizing symptoms (S1 ΔR2 = 2%, S2 ΔR2 = 1%), above and beyond child and family variables. Age moderated the relationship between sleep disturbances and internalizing symptoms (S1 ß = 0.07; S2 ß = 0.07; ΔR2 = 0.004 in both samples), but not externalizing symptoms; sleep disturbance was more strongly related to internalizing symptoms amongst adolescents (ß = 0.98) than children (ß = 0.62).DiscussionThe relationship between sleep and internalizing symptoms appears to change as children move through development. Further, sleep was a stronger predictor of internalizing problems in adolescents than children, suggesting an additional focus of clinician efforts in this age group. These findings strengthen the importance of routine assessment of sleep, as is done with the interRAI ChYMH.

Abstract Lyme disease, the most prevalent tick‐borne disease in North America, is caused by the bacterium Borrelia burgdorferi, and in the eastern and central United States, it is spread to humans by the black‐legged tick (Ixodes scapularis). Due to the complex, multiyear and multihost life cycle of this species, a matrix modeling approach is needed to effectively estimate subseasonal, multistage survival and transition dynamics in order to better understand and predict when population growth is high. Of the three questing tick life stages (larvae, nymphs, and adults), nymphs are most often associated with transmitting the bacteria to humans, and previous work suggests a mix of abiotic and biotic drivers are associated with nymph abundance. However, understanding tick population growth requires understanding mortality and transition probabilities for each stage and each stage may be individually and uniquely impacted by climate and host availability. A larval tick, for example, may experience warming temperatures differently than nymph or adults, because they are present on the landscape at different times. Here, we describe and validate a model that accounts for field sampling design and evaluates abiotic (temperature, relative humidity, precipitation) and biotic (host abundance) drivers of variation in tick population growth. To account for the drivers of subseasonal and interannual variability in demography, phenology, and population density, we built stage‐structured population models that account for variability in meteorology and host population abundance throughout the full tick lifecycle. Our model is fit and validated with 11 years of tick and host data from the northeastern United States. In this context, we found that a four‐stage model that includes unique transitions to and from a dormant, overwintering nymph state outperforms a model that only includes the three questing stages, and that incorporating the abundance of the predominant host species, Peromyscus leucopus, and weather variables improved predictions and model fit. Additionally, the model accurately predicted all three questing stages at sites different than where they were calibrated, showing that this model structure is generally transferable. Overall, this model lays a foundation for the real‐time iterative forecasting of tick populations needed to effectively protect public health.

Summary: Neurovascular coupling (NVC) and neurometabolic coupling (NMC) provide the basis for functional magnetic resonance imaging and positron emission tomography to map brain neurophysiology. While increases in neuronal activity are often accompanied by increases in blood oxygen delivery and oxidative metabolism, these observations are not the rule. This decoupling is important when interpreting brain network organization (e.g., resting-state functional connectivity [RSFC]) because it is unclear whether changes in NMC/NVC affect RSFC measures. We leverage wide-field optical imaging in Thy1-jRGECO1a mice to map cortical calcium activity in pyramidal neurons, flavoprotein autofluorescence (representing oxidative metabolism), and hemodynamic activity during wake and ketamine/xylazine anesthesia. Spontaneous dynamics of all contrasts exhibit patterns consistent with RSFC. NMC/NVC relative to excitatory activity varies over the cortex. Ketamine/xylazine profoundly alters NVC but not NMC. Compared to awake RSFC, ketamine/xylazine affects metabolic-based connectomes moreso than hemodynamic-based measures of RSFC. Anesthesia-related differences in NMC/NVC timing do not appreciably alter RSFC structure.

ObjectiveTransgender and nonbinary adolescents (TNBA) may experience gender dysphoria arising from incongruities between their body and their gender. Prior dysphoria measures have largely focused on clinical diagnosis with little regard to comparability of forms for people assigned male or female at birth, overall psychometric performance, or applicability to nonbinary populations. This study develops and validates the Transgender Adolescent Stress Survey-Dysphoria (TASS-D), intended to address these gaps.MethodsThe current study recruited a U.S. national sample of TNBA (N = 444, aged 12–17; 65.5% White, 9.5% Black, 9.5% Latine, 15.5% other ethnicity; 34.7% transmasculine, 17.3% transfeminine, 38.3% nonbinary, 9.5% agender). The item pool was developed from life history calendars, a modified Delphi process, and cognitive interviews with TNBA. Scale development included factor analysis, item response theory modeling, measurement invariance testing, and reliability analyses. Associations were examined between the TASS-D and existing measures of gender dysphoria (convergent validity), gender minority stress (divergent validity), and behavioral health outcomes (criterion validity).ResultsTASS-D and its subscales (body distress and gender expression burden) were significantly and strongly associated with gender dysphoria; significantly but weakly associated with gender minority stress; and significantly associated with most indicators of psychological distress including depressive, anxiety, and posttraumatic stress symptoms, suicidal behaviors and nonsuicidal self-injury.ConclusionsThe TASS-D is a reliable and valid measure of gender dysphoria for TNBA, offering notable benefits over existing measures: It is psychometrically sound, inclusive of all gender identities, and does not assume that respondents identify binarily or desire medical transition as a terminal goal.

Clostridioides difficile is a spore-forming pathogen and the most common cause of healthcare-associated diarrhea and colitis in the United States. Besides producing the main virulence factors, toxin A (TcdA) and toxin B (TcdB), many of the common clinical strains encode the C. difficile transferase (CDT) binary toxin. The role of CDT in the context of C. difficile infection (CDI) is poorly understood. Inflammation is a hallmark of CDI and multiple mechanisms of inflammasome activation have been reported for TcdA, TcdB, and the organism. Some studies have suggested that CDT contributes to this inflammation through a TLR2-dependent priming mechanism that leads to the suppression of protective eosinophils. Here, we show that CDT does not prime but instead activates the inflammasome in bone marrow-derived dendritic cells (BMDCs). In bone marrow-derived macrophages (BMDMs), the cell binding and pore-forming component of the toxin, CDTb, alone activates the inflammasome and is dependent on K+ efflux. The activation is not observed in the presence of CDTa and is not observed in BMDMs derived from Nlrp3-/- mice suggesting the involvement of the NLRP3 inflammasome. However, we did not observe evidence of CDT-dependent inflammasome priming or activation in vivo. Mice were infected with R20291 and an isogenic CRISPR/Cas9-generated R20291 ΔcdtB strain of C. difficile. While CDT contributes to increased weight loss and cecal edema at 2 days post infection, the relative levels of inflammasome-associated cytokines, IL-1β and IL-18, in the cecum and distal colon are unchanged. We also saw CDT-dependent weightloss in Nlrp3-/- mice, suggesting that the increased weightloss associated with the presence of CDT is not a result of NLRP3-dependent inflammasome activation. This study highlights the importance of studying gene deletions in the context of otherwise fully isogenic strains and the challenge of translating toxin-specific cellular responses into a physiological context, especially when multiple toxins are acting at the same time.

Abstract Background Soil microbial communities are difficult to measure and critical to soil processes. The bulk soil microbiome is highly diverse and spatially heterogeneous, which can make it difficult to detect and monitor the responses of microbial communities to differences or changes in management, such as different crop rotations in agricultural research. Sampling a subset of actively growing microbes should promote monitoring how soil microbial communities respond to management by reducing the variation contributed by high microbial spatial and temporal heterogeneity and less active microbes. We tested an in-growth bag method using sterilized soil in root-excluding mesh, “sterile sentinels,” for the capacity to differentiate between crop rotations. We assessed the utility of different incubation times and compared colonized sentinels to concurrently sampled bulk soils for the statistical power to differentiate microbial community composition in low and high diversity crop rotations. We paired this method with Oxford Nanopore MinION sequencing to assess sterile sentinels as a standardized, fast turn-around monitoring method. Results Compared to bulk soil, sentinels provided greater statistical power to distinguish between crop rotations for bacterial communities and equivalent power for fungal communities. The incubation time did not affect the statistical power to detect treatment differences in community composition, although longer incubation time increased total biomass. Bulk and sentinel soil samples contained shared and unique microbial taxa that were differentially abundant between crop rotations. Conclusions Overall, compared to bulk soils, the sentinels captured taxa with copiotrophic or ruderal traits, and plant-associated taxa. The sentinels show promise as a sensitive, scalable method to monitor soil microbial communities and provide information complementary to traditional soil sampling.

Abstract Background Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood–brain barrier (BBB). Methods We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. Results Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor. Conclusion Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.

Abstract Background We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. Methods Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. Results The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 95% CI 0.09–0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). Conclusions The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000

Summary: Many addictive drugs increase stress hormone levels. They also alter the propensity of organisms to prospectively select actions based on long-term consequences. We hypothesized that cocaine causes inflexible action by increasing circulating stress hormone levels, activating the glucocorticoid receptor (GR). We trained mice to generate two nose pokes for food and then required them to update action-consequence associations when one response was no longer reinforced. Cocaine delivered in adolescence or adulthood impaired the capacity of mice to update action strategies, and inhibiting CORT synthesis rescued action flexibility. Next, we reduced Nr3c1, encoding GR, in the orbitofrontal cortex (OFC), a region of the brain responsible for interlacing new information into established routines. Nr3c1 silencing preserved action flexibility and dendritic spine abundance on excitatory neurons, despite cocaine. Spines are often considered substrates for learning and memory, leading to the discovery that cocaine degrades the representation of new action memories, obstructing action flexibility.

Introduction: Extended-release buprenorphine (XR-Bup) is associated with reduced opioid use and opioid negative urine drug screens. Little is known about its use in outpatient addiction care provided within health systems. Methods: Individuals prescribed XR-Bup were identified from electronic health records; chart abstraction was conducted. Primary outcome was all-cause emergency department (ED) use. Secondary outcomes included ED use or inpatient stays for mental health or substance use, ED use for any other cause, discontinuation reasons, and drug substitution. Statistical comparisons used nonparametric tests from related samples (McNemar’s test and Wilcoxon matched pair tests) to test outcomes six months prior and 6 months following XR-Bup initiation. Results: 152 individuals had an XR-Bup order, 126 received >1 injection. Among those consistently insured 6 months prior to and following XR-Bup initiation (n=99), the mean number of injections following initiation was 3.95; one-third received 6 doses in the 6 months. The proportion of individuals using ED services for all causes declined (41% prior vs. 28% following XR-Bup initiation, p

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

Abstract This study created an image-to-image translation model that synthesizes diffusion tensor images (DTI) from conventional diffusion weighted images, and validated the similarities between the original and synthetic DTI. Thirty-two healthy volunteers were prospectively recruited. DTI and DWI were obtained with six and three directions of the motion probing gradient (MPG), respectively. The identical imaging plane was paired for the image-to-image translation model that synthesized one direction of the MPG from DWI. This process was repeated six times in the respective MPG directions. Regions of interest (ROIs) in the lentiform nucleus, thalamus, posterior limb of the internal capsule, posterior thalamic radiation, and splenium of the corpus callosum were created and applied to maps derived from the original and synthetic DTI. The mean values and signal-to-noise ratio (SNR) of the original and synthetic maps for each ROI were compared. The Bland–Altman plot between the original and synthetic data was evaluated. Although the test dataset showed a larger standard deviation of all values and lower SNR in the synthetic data than in the original data, the Bland–Altman plots showed each plot localizing in a similar distribution. Synthetic DTI could be generated from conventional DWI with an image-to-image translation model.

Abstract Background GPT-4-based ChatGPT demonstrates significant potential in various industries; however, its potential clinical applications remain largely unexplored. Methods We employed the New England Journal of Medicine (NEJM) quiz “Image Challenge” from October 2021 to March 2023 to assess ChatGPT's clinical capabilities. The quiz, designed for healthcare professionals, tests the ability to analyze clinical scenarios and make appropriate decisions. We evaluated ChatGPT's performance on the NEJM quiz, analyzing its accuracy rate by questioning type and specialty after excluding quizzes which were impossible to answer without images. ChatGPT was first asked to answer without the five multiple-choice options, and then after being given the options. Results ChatGPT achieved an 87% (54/62) accuracy without choices and a 97% (60/62) accuracy with choices, after excluding 16 image-based quizzes. Upon analyzing performance by quiz type, ChatGPT excelled in the Diagnosis category, attaining 89% (49/55) accuracy without choices and 98% (54/55) with choices. Although other categories featured fewer cases, ChatGPT's performance remained consistent. It demonstrated strong performance across the majority of medical specialties; however, Genetics had the lowest accuracy at 67% (2/3). Conclusion ChatGPT demonstrates potential for diagnostic applications, suggesting its usefulness in supporting healthcare professionals in making differential diagnoses and enhancing AI-driven healthcare.

Abstract Background White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer’s disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. Methods We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) at Seoul National University. Results Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values

The United States claims one of the highest rates of pregnancy-related mortality (PRM) and one of the highest rates of infant mortality (IM) among all high-income countries.1,2 Such findings are largely driven by the fact that almost one million U.S. pregnant individuals (i.e., 1 in 4) are affected by one or more chronic comorbid conditions, drastically increasing risk for mother and infant.3?7 Overall, the higher ages of pregnant individuals combined with a rising maternal chronic disease burden (e.g., hypertension, diabetes, mental health conditions, substance use disorders) and the growing impact of social determinants of health inequities have cumulatively increased the medical and social complexities faced by individuals during and after pregnancy.1 Importantly, non-Hispanic Black Americans are also more likely to face a complex pregnancy and/or a new onset complex condition after pregnancy than individuals of any other demographic group, leading to striking racial disparities in maternal and infant health.8?11 One complication that is considerably more common among mothers affected by a complex pregnancy is preterm birth (PTB) or birth of an infant before 37 weeks gestation. The United States has one of the highest PTB rates of all countries, affecting 1 in 10 pregnancies.12 Again, Black Americans bear a disproportionate burden of the complication, being 1.5???more likely to have a PTB and more than 2???more likely to have an early PTB13 PTBs (particularly early PTBs) are strong drivers of IM and racial disparities in IM.14,15 Mothers transitioning out of a pregnancy affected by PTB are also at higher risk for postpartum morbidity and mortality, new-onset chronic conditions, and a subsequent complicated pregnancy, highlighting the importance of maternal care after a complicated pregnancy. Indeed, longitudinal postpregnancy and interpregnancy clinical care can yield significant public health benefits, including a decreased chronic disease burden among the mother and reduced rates of subsequent PTB.16?18 Thus, longitudinal postpartum care is critical for both reducing current and future maternal disease severity and optimizing health for future pregnancies.19 Longitudinal postpartum and interpregnancy care serves as a compelling strategy to prevent recurrent adverse pregnancy outcomes, including PTB.20,21 For example, the American College of Obstetrics and Gynecology (ACOG) consensus guidelines recommend ongoing, multiepisode longitudinal postpartum and interpregnancy care, personalized to meet individual needs.16,22 Per ACOG, optimal interpregnancy care should be delivered by a multidisciplinary team of obstetric, primary care, and subspecialty clinicians, as a continuation of postpartum care to improve short and long-term health outcomes for individuals and their infants.16 Furthermore, primary care organizations, such as the Society of General Internal Medicine and the American Association of Family Physicians, have emphasized the importance of postpartum primary care in equitably addressing the health care needs of pregnant individuals across the life course.23,24 However, accumulating data has shed light on the inability of current U.S. postpartum health care models to deliver optimal postpartum and interpregnancy care, as the health care infrastructures needed to systematically connect individuals to longitudinal, multidisciplinary care after pregnancy are lacking. Moreover, existing care models often fail to address the needs of minoritized individuals who experience a higher burden of adverse social determinants of health, impeding their access to and utilization of postpartum preventive services.3,25?29 As such, few individuals receive any postpartum care and even fewer receive ongoing, longitudinal postpartum and interpregnancy care, even after high-risk pregnancy.30,31 Such data are particularly alarming considering that over half of PRM occurs during the year after childbirth,32 usually outside of the hospital setting.32 Poorly managed chronic conditions during the interpregnancy period also greatly increase risk for complications during subsequent pregnancies, including repeat PTB. Indeed, more than 80% of PRM is considered preventable,33 highlighting the significant gap in U.S. maternity care services that occurs during the months and even years after childbirth.34?36 Individuals transitioning out of a pregnancy affected by PTB have unique needs. The experience of PTB not only increases risk of subsequent PTB but also results in the need for intensive postpartum health care utilization.37 Individuals who experience PTB have a higher risk of postpartum depression, severe maternal morbidity, and all-cause mortality than those who carry pregnancies to term.38?42 Yet, they infrequently access primary care in the 12 months after delivery.43 Systematizing interpregnancy care after PTB not only has the potential to broadly address poor U.S. maternal health outcomes but also the unacceptable maternal health disparities embedded within these outcomes.44 While over 5 decades of research, policy, and practice has informed frameworks and evidence-based practice guidelines for the primary care of the preterm infant during the 1st year and beyond,45?51 interpregnancy and postpartum care of the mother after PTB remains a neglected topic.52?55 In their article, ?Integrating care for mother?infant dyads after preterm birth: A qualitative study of clinician perspectives on feasibility,? Gregory et al. elicit perspectives of multidisciplinary clinicians who provide care to postpartum individuals and infants after PTB to identify potential barriers and facilitators of using pediatric access points for maternal postpartum and interpregnancy care delivery through a dyadic mother?infant care model.56 The frequent (often ?6) pediatric visits in the year after birth has spurred development of focused professional guidelines and reimbursement structures to address maternal health needs for topics such as postpartum depression screening in pediatric settings. However, many unused opportunities remain to leverage infant care access points to address maternal postpartum care gaps.56 Some mother/infant dyadic care approaches exist for delivery by providers who care for both postpartum individuals and children, including family medicine, adolescent medicine, and dual internal medicine/pediatrics physicians.54,57?59 Importantly, Gregory et al. highlight that these models have limited application for mothers of the 80% of U.S. infants who receive primary care from pediatricians.56 Thus, leveraging pediatric care access points for postpartum and interpregnancy care require coordination across multiple settings and provider specialties, spanning pediatrics, neonatology, internal medicine, family medicine, and obstetrics and gynecology.56 Clinicians interviewed in the Gregory et al. qualitative study articulated multiple structural, systemic, and policy barriers to multispecialty, multisetting dyadic care.56 These barriers included inadequate care handoffs between specialties, communication barriers across health care settings, lack of care coordination between specialties, inconsistent access to counterparts in other specialties during clinical urgencies, privacy restrictions limiting communication between maternal and infant care teams, scheduling systems created to accommodate individuals instead of dyads, and lack of comprehensive electronic health record (EHR) access to both mother and infant charts.56 Clinicians in the Gregory et al. study also articulated concerns about pitfalls that could potentially arise from delivering care outside of one's area of licensure and expertise and described that responsibilities for maternal follow-up care across specialties were poorly delineated.56 Gregory et al. also noted that while their study recruited clinicians involved in the care of preterm infants, clinician-reported barriers were not restricted to dyads who experienced PTB.56 Multispecialty mother/infant dyadic care, leveraging pediatric well-child visit access points, may provide compelling opportunities to address postpartum and interpregnancy care gaps, including after PTB. Gregory et al. report many structural, policy, and practice barriers to implementation of this dyadic model for longitudinal interpregnancy care delivery,56 while also proposing some practical steps to facilitate collaborative care models. These include repurposing existing EHR team-based communication for handoffs, establishing clinician directories and call schedules to ease cross-dyad consultations, and clinically colocating dyad relevant medical specialties.56 Beyond these local interventions, these data can inform roadmaps guiding the policy changes and quality initiatives required to promote routine multispecialty interpregnancy dyadic care. First, incorporating longitudinal postpartum care, including primary care transition, into perinatal Medicaid programmatic, policy, and quality transformations may incentivize and resource the health system collaborative infrastructures needed for implementation of multispecialty dyadic programs.60 Prior transformations effected by Centers of Medicare and Medicaid Services (CMS) and select state Medicaid agencies have successfully improved obstetric postpartum visit attendance and quality.60 Broad adoption of postpartum Medicaid extension, with implementation or planned implementation in 46 states, provides national opportunities to apply similar approaches to incentivize optimal care after PTB and other high-risk pregnancies.61 Second, CMS can require that health systems with public-facing hospital designations (e.g., ?Birthing-Friendly? Hospital Designations) transition patients to established multidisciplinary interpregnancy care after PTB or high-risk pregnancy. The ?Birthing-Friendly? Hospital Designation was established in 2022 to help patients identify hospitals that have implemented maternal care best practices.62 CMS currently assigns ?Birthing-Friendly? Hospital Designation to systems that participate in state or national pregnancy quality collaboratives and act on their recommendations.63 There remain many opportunities to iteratively expand designation requirements over time to include transition to multidisciplinary, longitudinal postpartum care. Third, coalitions, such as the Alliance for Innovation in Maternal Health, can set priorities and establish consensus bundles to support state agencies and health systems in implementing the complex cross-sector strategies needed to ensure high-quality, evidence-based postpartum and interpregnancy care, especially after complex pregnancy.64,65 These interventions will help to overcome the barriers and facilitate the solutions proposed by Gregory et al.56 to improve postpartum maternal health outcomes through systematization of dyadic interpregnancy care after complex pregnancy, including PTB.

Previous studies have shown that language learners’ auditory word recognition behavior provides evidence for independent contributions of perceptual and phonolexical representations, and learners’ patterns of auditory word recognition have been characterized as resulting from “fuzziness” or “imprecision” associated with these representations. More recently, it has been argued that representational “fuzziness” may in fact take various forms (e.g., neutralized, precise, ambiguous). The purpose of the present study is to further build on this line of work by elaborating additional logically possible scenarios by crossing larger sets of logically possible types of perceptual and phonolexical representational precision/imprecision, as an exercise in exploring the empirical and theoretical implications of our characterizations of representational fuzziness in language learners. We collect new empirical data for the purpose of demonstrating how we might evaluate auditory word recognition performance relative to this fuller set of predicted scenarios. We computed the set of hypothesized scenarios by crossing possible perceptual and lexical representations. We crossed four possible perceptual representations (NeutralizedC + NeutralizedV, NeutralizedC + PreciseV, PreciseC + NeutralizedV, or PreciseC + PreciseV) and six possible phonolexical representations (Neutralized, Ambiguous, Not X, Precise, Fuzzy Word, or Word Length), for a total of 24 scenarios, each accompanied by a set of predictions with respect to accuracy on an auditory word–picture matching test. We interpret the group and individual performance relative to these scenarios with the ultimate aim of better understanding the implications of our assumptions about the nature of perceptual and phonolexical representations relative to observed patterns of learner behavior. Our hope is that in computing this factorial typology of logically possible scenarios and demonstrating a starting point for how we might empirically evaluate its predictions, we set the stage for future research to refine the hypothesis space through empirical studies of auditory word processing in language learners.

The expansion of the tiger mosquito, a vector that can transmit diseases such as dengue, chikungunya, and Zika virus, poses a growing threat to global health. This study focuses on the entomological surveillance of Kastellorizo, a remote Greek island affected by its expansion. This research employs a multifaceted approach, combining KAP survey (knowledge, attitude, practices), mosquito collection using adult traps and human landing catches, and morphological and molecular identification methods. Results from questionnaires reveal community awareness and preparedness gaps, emphasizing the need for targeted education. Mosquito collections confirm the presence of the Aedes albopictus, Aedes cretinus, and Culex pipiens mosquitoes, highlighting the importance of surveillance. This study underscores the significance of community engagement in entomological efforts and proposes a citizen science initiative for sustained monitoring. Overall, this research provides essential insights for developing effective mosquito control programs in remote island settings, thereby emphasizing the importance of adopting a One Health approach to mitigate the spread of vector-borne diseases.

Abstract A central assumption in the behavioral sciences is that choice behavior generalizes enough across individuals that measurements from a sampled group can predict the behavior of the population. Following from this assumption, the unit of behavioral sampling or measurement for most neuroimaging studies is the individual; however, cognitive neuroscience is increasingly acknowledging a dissociation between neural activity that predicts individual behavior and that which predicts the average or aggregate behavior of the population suggesting a greater importance of individual differences than is typically acknowledged. For instance, past work has demonstrated that some, but not all, of the neural activity observed during value-based decision-making is able to predict not just individual subjects’ choices but also the success of products on large, online marketplaces—even when those two behavioral outcomes deviate from one another—suggesting that some neural component processes of decision-making generalize to aggregate market responses more readily across individuals than others do. While the bulk of such research has highlighted affect-related neural responses (i.e. in the nucleus accumbens) as a better predictor of group-level behavior than frontal cortical activity associated with the integration of more idiosyncratic choice components, more recent evidence has implicated responses in visual cortical regions as strong predictors of group preference. Taken together, these findings suggest a role of neural responses during early perception in reinforcing choice consistency across individuals and raise fundamental scientific questions about the role sensory systems in value-based decision-making processes. We use a multivariate pattern analysis approach to show that single-trial visually evoked electroencephalographic (EEG) activity can predict individual choice throughout the post-stimulus epoch; however, a nominally sparser set of activity predicts the aggregate behavior of the population. These findings support an account in which a subset of the neural activity underlying individual choice processes can scale to predict behavioral consistency across people, even when the choice behavior of the sample does not match the aggregate behavior of the population.

Introduction: Historic data, often in analog format, is a valuable resource for assessing effects of directional changes in climate and climatic variability. However, historic data can be difficult to locate, interpret, and reformat into a useful state.Methods: Teams of scientists, librarians, archivists, and data managers at four US institutions have undertaken various projects to gather, describe, and in some cases, transform historic data. They have also surveyed researchers who either possess historic data or have used it in their work.Results: Historic data projects involved locating data, writing data descriptions, and connecting with individuals who had knowledge about the data’s collection. The surveys and interviews found that researchers valued historic data and were worried that it was at risk of loss. They noted the lack of best practices.Discussion: Each project attempting to rescue or enhance access to historic data has a unique path but being guided by FAIR principles should be at the core whether or not the end result is machine-readable data. Working with a team incorporating librarians, archivists, and data managers can aid individual researchers’ in producing accessible, and reusable datasets. There is much work to be done in raising awareness about the value of historic data but motivating factors for doing so include its usefulness in environmental research and other disciplines and its risk of loss as researchers retire and are unsure of how to save historic data, both in analog and electronic formats.

Sports participation confers many health benefits yet greatly increases injury risk. Long-term health outcomes in former athletes and transition to life after competitive sports are understudied. Ending a sport may pose physical and psychosocial challenges. The purpose was to determine the lived experiences of former competitive athletes and how their sports participation impacted their long-term health and well-being. Former college varsity athletes participated in semistructured interviews focusing on their experiences, including past and current health, the impact of injuries, activity, exercise, diet and transition to life after competitive sport. Thematic analysis was completed using a collaborative, iterative process. Thirty-one (16 female, 15 male) former college athletes aged 51.3±7.4 years were interviewed. Six themes emerged: (1) lifelong athlete identity; (2) structure, support and challenges of the college athlete experience; (3) a big transition to life beyond competitive sport; (4) impact of competitive sport on long-term health; (5) facilitators and barriers to long-term health after sport and (6) transferable life skills. Continuing sports eased the transition for many but often delayed their postathlete void. Challenges included managing pain and prior injury (eg, If I didn't have my knee injury, I would definitely be more active), reducing energy needs and intake (eg, When I was an athlete, I could eat anything; and unfortunately, that’s carried into my regular life), lack of accountability, changed identity and lost resources and social support. Participants suggested a programme, toolkit, mentoring or exit course to facilitate the transition. While former athletes benefit from transferrable life skills and often continue sports and exercise, they face unique challenges such as managing pain and prior injury, staying active, reducing energy intake and changing identity. Future research should develop and evaluate a toolkit, programme and other resources to facilitate life after ending competitive sports under ‘normal’ conditions (eg, retirement) and after a career-ending injury.

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) ​≥ ​30 ​kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA. Trial registration: ClinicalTrials.gov Identifier: NCT05946044.

Background: Road trauma is a leading cause of death and disability for young Australians (15–24 years). Young adults are overrepresented in crashes due to sleepiness, with two-thirds of their fatal crashes attributed to sleepy driving. This trial aims to examine the effectiveness of a sleep extension and education program for improved road safety in young adults. Methods: Young adults aged 18–24 years (n = 210) will be recruited for a pragmatic randomised controlled trial employing a placebo-controlled, parallel-groups design. The intervention group will undergo sleep extension and receive education on sleep, whereas the placebo control group will be provided with information about diet and nutrition. The primary outcomes of habitual sleep and on-road driving performance will be assessed via actigraphy and in-vehicle accelerometery. A range of secondary outcomes including driving behaviours (driving simulator), sleep (diaries and questionnaire) and socio-emotional measures will be assessed. Discussion: Sleep is a modifiable factor that may reduce the risk of sleepiness-related crashes. Modifying sleep behaviour could potentially help to reduce the risk of young driver sleepiness-related crashes. This randomised control trial will objectively assess the efficacy of implementing sleep behaviour manipulation and education on reducing crash risk in young adult drivers.

Swimming is an important behavior for all penguin species. However, zoo-housed penguins typically do not swim as often as their wild counterparts, which may have consequences for their health and welfare. In an effort to increase the swimming time of the African penguin (Spheniscus demersus) population at Lincoln Park Zoo in Chicago, IL, USA (21 adults: 13 males, 8 females), we introduced a commercially available bubble curtain to the outdoor pool within the penguins’ habitat. The bubble curtain pushes pressurized air out through a hose fitted with small holes to create a stream of bubbles that generate water movement, which could entice penguins to swim. Over the course of 2 months, the penguins were exposed to a series of alternating conditions characterized by the bubble curtain being off or on for 2-week periods. A total of 228 swimming bouts were observed during this study. The bubble curtain did not increase the amount of time the penguins spent swimming, nor the maximum number of penguins in the pool during swim bouts. Rather, the penguins spent more time swimming when the bubble curtain was turned off, and the number of penguins in the pool during swim bouts was consistent across experimental phases. Additionally, we found that penguins swam the most when air temperatures were between 31 and 40 °F (approximately −1 to −4 °C). Unexpectedly, at least three individual penguins swam overnight between the hours of midnight and 6:00, highlighting the value of monitoring animals during entire 24 h periods. Collectively, this study provides detailed information about the swimming behavior of a zoo-housed African penguin population, and indicates that a bubble curtain was ineffective at stimulating swimming.

Summary: Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer’s disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

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