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Hydrogels are often employed as temporary platforms for cell proliferation and tissue organization in vitro. Researchers have incorporated photodegradable moieties into synthetic polymeric hydrogels as a means of achieving spatiotemporal control over material properties. In this study protein-based photodegradable hydrogels composed of methacrylated gelatin (GelMA) and a crosslinker containing o-nitrobenzyl ester groups have been developed. The hydrogels are able to degrade rapidly and specifically in response to UV light and can be photopatterned to a variety of shapes and dimensions in a one-step process. Micropatterned photodegradable hydrogels are shown to improve cell distribution, alignment and beating regularity of cultured neonatal rat cardiomyocytes. Overall this work introduces a new class of photodegradable hydrogel based on natural and biofunctional polymers as cell culture substrates for improving cellular organization and function.

Hydrogels are often employed as temporary platforms for cell proliferation and tissue organization in vitro. Researchers have incorporated photodegradable moieties into synthetic polymeric hydrogels as a means of achieving spatiotemporal control over material properties. In this study protein-based photodegradable hydrogels composed of methacrylated gelatin (GelMA) and a crosslinker containing o-nitrobenzyl ester groups have been developed. The hydrogels are able to degrade rapidly and specifically in response to UV light and can be photopatterned to a variety of shapes and dimensions in a one-step process. Micropatterned photodegradable hydrogels are shown to improve cell distribution, alignment and beating regularity of cultured neonatal rat cardiomyocytes. Overall this work introduces a new class of photodegradable hydrogel based on natural and biofunctional polymers as cell culture substrates for improving cellular organization and function.

Abstract Background A dramatic decline in mental health of people worldwide in the early COVID-19 pandemic years has not recovered. In rural and remote Australia, access to appropriate and timely mental health services has been identified as a major barrier to people seeking help for mental ill-health. From 2020 to 2021 a care navigation model, Navicare, was co-designed with rural and remote communities in the Greater Whitsunday Region of Central Queensland in Australia. The Exploration, Preparation, Implementation and Sustainment (EPIS) framework was used to design and guide multiple aspects of a multisite study, The Bridging Study, to evaluate the implementation of Navicare in Australia. Methods A community-engaged hybrid effectiveness-implementation study design will focus on the tailored implementation of Navicare at three new sites as well as monitoring implementation at an existing site established since 2021. Study outcomes assessed will include sustained access as the co-primary outcome (measured using access to Navicare mental health referral services) and Proctor’s Implementation Outcomes of feasibility, acceptability, appropriateness, adoption, fidelity, implementation cost, and sustainability. Data collection for the implementation evaluation will include service usage data, community consultations, interviews, and workshops; analysed using mixed methods and guided by EPIS and other implementation frameworks. Pre-post effectiveness and cost-consequence study components are embedded in the implementation and sustainment phases, with comparison to pre-implementation data and value assessed for each EPIS phase using hospital, service, and resource allocation data. A scaling up strategy will be co-developed using a national roundtable forum in the final year of the study. Qualitative exploration of other aspects of the study (e.g., mechanisms of action and stakeholder engagement) will be conducted. Discussion Our study will use tailoring to local sites and a community-engaged approach to drive implementation of a mental health care navigation service in rural and remote Australia, with expected benefits to mental healthcare access. This approach is consistent with policy recommendations nationally and internationally as building blocks for rural health including the World Health Organization Framework for Action on Strengthening Health Systems to Improve Health Outcomes. Trial registration Prospectively registered on April 2, 2024, on the Australian New Zealand Clinical Trials Registry, no. ACTRN12624000382572. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386665&isReview=true .

Global health prioritizes improving health and achieving equity in health for all people worldwide. It encompasses a wide range of efforts, including disease prevention and treatment, health promotion, healthcare delivery, and addressing health disparities across borders. Short-term medical and surgical missions often contribute to the global health landscape, especially in low and lower-middle income countries. These programs aim to provide healthcare services to underserved populations and-often face challenges related to governance, ethical boundaries, and legal dimensions. Without adequate oversight and accountability, short-term medical and surgical missions may inadvertently perpetuate harmful practices, negatively impact the native healthcare system, and/or fail to address the long-term health needs of the communities they serve. The impact of short-term surgical trips has raised concerns regarding the need for capacity building initiatives, as well as the ethical and legal aspects of short-term medical and surgical missions. Short term surgical aid has a long history and has likely positively impacted the lives of children and adults with no other option for surgical, especially complex surgical care. These same short-term interventions have also been appropriately criticized for a lack of continuity of care, limited focus on training and education of local providers and capacity building within the local health systems, and perpetuation of power imbalances and neocolonialism. In response, there is an increasing call for a more comprehensive approach that incorporates capacity building and establish robust frameworks that ensure quality improvement, outcomes analysis, ethical conduct, sustainability, and equitable impact of short-term medical and surgical missions within global health. Child health is a critical concern, especially in less developed countries where almost half the population is under 20 years old. Pediatric surgical conditions have a significant impact on child health, and integrating surgical care with global health initiatives can effectively address important child health goals. Global surgery and global pediatric surgery aim to improve health outcomes and achieve equity in surgical care for underserved populations. Pediatric surgical conditions encompass various diseases, with a substantial portion requiring time-sensitive interventions. Establishing sustainable pediatric surgical capabilities within local health systems, including governance, alignment with health priorities, and effective leadership, is crucial. Selecting and supporting individuals for training and ensuring timely access to quality specialist advice are essential for achieving positive clinical outcomes. This review examines existing recommendations for ensuring the sustainable benefit of short-term medical missions, with a specific focus on surgical outreach trips. It highlights the need for standardization and emphasizes the importance of considering the legal and ethical dimensions in guiding these missions. Key aspects include the promotion of local leadership, cultural contextualization, and field-testing of guidelines. By incorporating these elements, medical missions can strive to achieve quality improvement, adhere to ethical principles, and operate within legal frameworks, thereby maximizing their impact and contributing to global health endeavors.

Abstract Introduction: Translational science rarely addresses the needs of rural communities, perpetuating health inequities. Furthermore, policy and resource allocation reflect this dynamic. Through a partnership between a rural community and a community engagement program, the Rural Health Initiative (RHI) was developed with the goal of building capacity for community-driven translational research in rural settings. Methods: We describe the process of forming the RHI and selection of a community health priority to motivate the translational research agenda in this particular rural setting. We used a mixed methods approach utilizing literature review, community survey data, and qualitative evaluation of community meeting discussions. Consensus on a final health priority was built through voting and comparison of voting responses across the three RHI counties through Fisher’s Exact test. Results: Four priority topics were identified through literature search, community needs assessment, state/national trend data, and community experts. Priority ranking from a community forum and survey selected the final health priority topic. Healthcare access was selected by all three counties in the RHI community as the most critical health priority to address. Conclusions: This program highlights the importance of and methods for community involvement in directing the research conducted in their community. Additionally, through this project, guidance was developed to define the role of community engagement programs supporting work led by communities.

Ground beef is a common source of US Salmonella illnesses and outbreaks. However, the demographic and socioeconomic factors that are related to risk in ground beef-associated outbreaks of Salmonella infections are poorly understood. We describe the individual-level demographic characteristics and county-level indicators of social vulnerability for people infected with Salmonella linked to outbreaks associated with ground beef in the United States during 2012–2018. Non-Hispanic (NH) White and NH American Indian/Alaska Native persons, and people living in nonmetropolitan areas, were overrepresented among people in salmonellosis outbreaks linked to ground beef. Case patients disproportionately resided in counties with high social vulnerability, suggesting that one or more community social risk factors may contribute to or be associated with some food safety risks. Collecting and analyzing socioeconomic and demographic characteristics of people in outbreaks can help identify disparities in foodborne disease, which can be further characterized and inform equity-focused interventions.

This paper links the ideas of surveillance capitalism and what Jeff Pooley has described as surveillance publishing with that of the citation economy. A few companies with dominance over academic publishing have been able to capture and use surplus value created through the publishing lifecycle. This extraction—of academic labour, of data, of information—is reinvested into their proprietary data analytics products. This is both literally, as the data collected by the publishing side can be incorporated into data analytics algorithms, and financially, as the profit margins of these academic publishing arms are astonishingly high. Crucially, these profits have been used to expand these companies’ portfolios of extractive data services across industries as academic publishers transition from information vendors to technology-driven data brokers. By providing their labour directly (as editors, reviewers, etc.) or indirectly (as authors) to these companies, scholars are complicit in data collection and analysis used for everything from advertising to law enforcement. This data is sold back to universities who use it to evaluate and surveil the publishing practices of their employees, using proprietary metrics and methods that do not align with principles of academic freedom. This paper provides an overview of this landscape, concluding with implications and recommendations for the scholars and librarians ensnared in it. It also includes a mini-zine we plan to distribute to help contextualize academics’ roles in the citation economy and the ethical implications for their work.

Abstract We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.

Abstract Introduction This study aimed to gain insight from patients with refractory Mycobacterium avium complex lung disease (MAC-LD) into strategies used to manage adverse events (AEs) associated with amikacin liposome inhalation suspension (ALIS). Methods We conducted semi-structured interviews with US patients with refractory MAC-LD prescribed ALIS in a real-world setting. Interview transcripts were analyzed and coded to identify patterns in participants’ descriptions of their ALIS treatment experiences, including AEs and their disruptiveness, and AE mitigation strategies, including participants’ ratings of strategies’ effectiveness. Concept saturation was also assessed. Results Twenty participants (mean age 48.7 years; 80% women; mean ALIS duration 5.45 months) were interviewed. At the time of the interview, 15 participants (75%) had received ALIS for > 1 month and 13 (65%) were currently receiving ALIS. Participants described 44 unique AE mitigation strategies, which can be categorized into three groups: prepare for treatment; prevent increased emergence of AEs; and persist on treatment by mitigating AEs. Common strategies (reported by ≥ 50% of participants) included use of educational materials from the patient support program, localized management of throat irritation, and symptom management to reduce fatigue. Evidence of concept saturation was observed: no new strategies were identified in the last five interviews, which suggests the sample was robust enough to identify all mitigation strategies likely to be used by the broader patient population. Conclusions This real-world study identified a diverse set of potential AE mitigation strategies intended to help individual patients prepare for ALIS treatment, prevent the increased emergence of certain AEs, and mitigate the impact of AEs on treatment persistence. Developing a comprehensive accounting of the types of mitigation strategies in use among patients in real-world settings can inform future investigation of the effectiveness of such strategies, and support evidence-based recommendations for treatment management.

Introduction In Canada, care for individuals with hereditary cancer is fragmented across the provinces and territories, with carriers of pathogenic variants in cancer-susceptibility genes seeing multiple doctors and often advocating for their own management plans. The need for a national registry of carriers has been well established. While other cancer consortia exist, barriers in clinical and genomic data sharing limit the utility of the information gathered.Methods and analysis Within the province of Ontario, the Ontario Hereditary Cancer Research Network (OHCRN), funded by and located at the Ontario Institute for Cancer Research, is being developed to fill this gap. The registry will hold clinical, genomic and self-reported data from consented carriers and will make this data available to qualified researchers in anonymised and aggregated form. Individuals must agree to certain components to participate in OHCRN; there are also optional consents participants can agree to without impacting their involvement in OHCRN. We plan to open the registry for participant enrolment in mid-2025.Ethics and dissemination Ethics approval for registry creation was obtained from the Ontario Cancer Research Ethics Board, a centralised body that streamlines reviews for cancer research studies in Ontario. Registry data will be disseminated to participants and researchers as aggregate data through the OHCRN website and presented at scientific conferences, made available to Ontario Health (Cancer Care Ontario) to inform policy and evidence-based practice, as well as be available to the scientific community for further analysis and answering relevant questions.

Objective To highlight progress in facilitating and supporting pan-Canadian data analysis research that is supported by a central coordinating center. This process will be illustrated with the use of a recently completed project that has been supported using data from Alberta, British Columbia, and Ontario. Approach The project represents a significant endeavor within the central coordinating center, as it necessitates coordination for data access, data importation and analytical support across three provinces. The focus will be on the administrative processes refined to support collaborative research endeavors. While specific project details will remain undisclosed, procedural enhancements within the central coordinating center framework will be highlighted. Key discussion points include standardized protocols for data access, collaborative efforts to streamline data importation, and facilitation of analytical support across jurisdictions. The type of cross-jurisdictional analytic support will as well be highlighted; data variables harmonization and sharing of data algorithms cohorts across the participating provincial data centers in support of the meta-analysis. Results The successful completion of the final data analysis underscores the effectiveness of a unified data access coordination center for researchers seeking multi-regional health data in Canada. By highlighting advancements enabled by the central coordinating center and provincial data centers, this submission aims to inform researchers about the current landscape of pan-Canadian research and foster opportunities for future collaboration. Implications Sharing insights and lessons from this project emphasizes the advancements facilitated by the central coordinating center and provincial data centers, informing researchers about the potential of pan-Canadian research, and encouraging future collaborative endeavors.

Post-stroke gait asymmetry leads to inefficient gait and a higher fall risk, often causing limited home and community ambulation. Two types of treadmills are typically used for training focused on symmetry: split-belt and single belt treadmills, but there is no consensus on which treadmill is superior to improve gait symmetry in individuals with stroke. To comprehensively determine which intervention is superior, we considered multiple spatial and temporal gait parameters (step length, stride time, swing time, and stance time) and their symmetries. Ten individuals with stroke underwent a single session of split-belt treadmill training and single belt treadmill training on separate days. The changes in step length, stride time, swing time, stance time and their respective symmetries were compared to investigate which training improves both spatiotemporal gait parameters and symmetries immediately after the intervention and after 5 min of rest. Both types of treadmill training immediately increased gait velocity (0.08 m/s faster) and shorter step length (4.15 cm longer). However, split-belt treadmill training was more effective at improving step length symmetry (improved by 27.3%) without sacrificing gait velocity or step length. However, this step length symmetry effect diminished after a 5-min rest period. Split-belt treadmill training may have some advantages over single belt treadmill training, when targeting step length symmetry. Future research should focus on comparing the long-term effects of these two types of training and examining the duration of the observed effects to provide clinically applicable information.

Introduction: Elevating Voices, Addressing Depression, Toxic Stress and Equity (EleVATE) is a group prenatal care (GC) model designed to improve pregnancy outcomes and promote health equity for Black birthing people. This article outlines the foundational community-engaged process to develop EleVATE GC and pilot study results. Methods: We used community-based participatory research principles and the Ferguson Commission Report to guide creation of EleVATE GC. The intervention, designed by and for Black birthing people, centers trauma-informed care, antiracism, and integrates behavioral health strategies into group prenatal care to address unmet mental health needs. Using a convenience sample of patients seeking care at one of three safety-net health care sites, we compared preterm birth, small for gestational age, depression scores, and other pregnancy outcomes between patients in individual care (IC), CenteringPregnancy? (CP), and EleVATE GC. Results: Forty-eight patients enrolled in the study (n=11 IC; n=14 CP; n=23 EleVATE GC) and 86% self-identified as Black. Patients participating in group prenatal care (EleVATE GC or CP) were significantly less likely to experience a preterm birth

Abstract Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac stroma, specifically mural cells, and their response to ischemic injury. Here, we combine single-cell and positional transcriptomics to assess the behavior of mural cells within the healing heart. In response to myocardial infarction, mural cells adopt an altered state closely associated with the infarct and retain a distinct lineage from fibroblasts. This response is concurrent with vascular rarefaction and reduced vascular coverage by mural cells. Positional transcriptomics reveals that the infarcted heart is governed by regional-dependent and temporally regulated programs. While the remote zone acts as an important source of pro-angiogenic signals, the infarct zone is accentuated by chronic activation of anti-angiogenic, pro-fibrotic, and inflammatory cues. Together, our work unveils the spatiotemporal programs underlying cardiac repair and establishes an association between vascular deterioration and mural cell dysfunction.

Abstract Background Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine’s antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator. Methods This protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under “real world” conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness. Discussion There is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression. Trial registration EudraCT 2019-003109-92. Registered 2 October 2019. ClinicalTrials.gov NCT04939649. Registered 25 June 2021.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three interventions: tAIH + WALKtSTIM; Placebo + WALKtSTIM; and tAIH + WALKtSHAM. Participants receive daily tAIH (fifteen 90-sec episodes at 10% O2 with 60-sec intervals at 21% O2) or daily placebo (fifteen 90-sec episodes at 21% O2 with 60-sec intervals at 21% O2) before a 45-min session of WALKtSTIM or WALKtSHAM. Our primary outcome measures assess walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up and Go Test). For safety, we also measure pain levels, spasticity, sleep behavior, cognition, and rates of systemic hypertension and autonomic dysreflexia. Assessments occur before, during, and after sessions, as well as at 1, 4, and 8 weeks post-intervention. Results from this study extend our understanding of the functional benefits of tAIH priming by investigating its capacity to boost the neuromodulatory effects of transcutaneous spinal stimulation on restoring walking after SCI. Given that there is no known cure for SCI and no single treatment is sufficient to overcome walking deficits, there is a critical need for combinatorial treatments that accelerate and anchor walking gains in persons with lifelong SCI. Trial Registration: ClinicalTrials.gov, NCT05563103.

The education of a physician is a life-long process that starts in medical school and extends throughout their career. Healthcare is a dynamic field characterized by continuous advancements in medicine, evolving treatment options, changing regulations, care models, and technology. Physicians must keep up-to-date with new practices, procedures, medications, and diseases and fulfill the educational requirements to maintain their medical licensure. Continuing education for physicians serves the essential purpose of nurturing lifelong learning, ensuring that medical practices align with the latest standards, and ultimately enhancing the quality of patient care and outcomes. In a broader context, physician education encompasses all activities designed to enhance skills, professional performance, and relationships that physicians employ to provide services to patients and the public and to improve collaborations within the field. This paper outlines a step-by-step plan for designing high-quality educational conferences for practicing physicians in any field. It aims to assist in developing ongoing education, aligning physician practices with the latest medical care standards, and optimizing their clinical performance to improve patient and community health.

In January 2020, increased mortality was reported in a small broiler breeder flock in County Fermanagh, Northern Ireland. Gross pathological findings included coelomitis, oophoritis, salpingitis, visceral gout, splenomegaly, and renomegaly. Clinical presentation included inappetence, pronounced diarrhoea, and increased egg deformation. These signs, in combination with increased mortality, triggered a notifiable avian disease investigation. High pathogenicity avian influenza virus (HPAIV) was not suspected, as mortality levels and clinical signs were not consistent with HPAIV. Laboratory investigation demonstrated the causative agent to be a low-pathogenicity avian influenza virus (LPAIV), subtype H6N1, resulting in an outbreak that affected 15 premises in Northern Ireland. The H6N1 virus was also associated with infection on 13 premises in the Republic of Ireland and six in Great Britain. The close genetic relationship between the viruses in Ireland and Northern Ireland suggested a direct causal link whereas those in Great Britain were associated with exposure to a common ancestral virus. Overall, this rapidly spreading outbreak required the culling of over 2 million birds across the United Kingdom and the Republic of Ireland to stamp out the incursion. This report demonstrates the importance of investigating LPAIV outbreaks promptly, given their substantial economic impacts.

In this study we combined non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) with 40 h of constraint induced movement therapy (CIMT) in infants. All infants completed the full intervention with no adverse events. Therapists were able to maintain high treatment fidelity and reported high ratings for ease of use and child tolerance. Preliminary results show promising gains on motor outcomes: Mean QUEST increase 19.17 (minimal clinically important difference, MCID 4.89); Mean GMFM increase 13.33 (MCID 1%–3%). Infants also exceeded expectations on Goal Attainment Scores (+1). Early data is promising that taVNS paired with intensive motor CIMT is feasible, reliable, and safe in young infants with hemiplegia, and may help harness activity-dependent plasticity to enhance functional movement.

Purpose: Pes cavus can be a debilitating and painful condition requiring surgical intervention. There are many contributing factors to take into account when addressing the deformity. This study documents 21 cases of cavus foot reconstruction using the Cole osteotomy as the primary procedure for feet with an apex of deformity in the midfoot, demonstrating its powerful corrective capabilities. Case study: 16 Patients (21 Feet) (13 female, 3 male) (Ages 16–55, average age 36.8 years) underwent Cole osteotomy for midfoot driven pes cavus. Secondary procedures include: Hammertoe Arthrodesis (7/21), 1st Metatarsal DFWO (6/21), Plantar Fasciotomy (5/21), Tarsal Tunnel Release (3/21), Posterior Calcaneal Spur Resection (3/21), Ankle Ligament Repair (1/21). All patients had preand post-operative measurements of calcaneal inclination and Meary's angle. Results: Mean pre-op calcaneal inclination angle 17°, mean post-op calcaneal inclination angle 7.75°, for an average of 9.25° of correction. Mean pre-op Meary's angle 23.25°, mean post-op Meary's angle 5.5°, for an average of 17.75° of correction. Analysis and discussion: The Cole midfoot osteotomy is an underutilized procedure, and when done correctly can vastly improve deformity and function. All patients in the series had significant pain relief, and all patients with bilateral deformities returned for the contralateral foot. The procedure demonstrates substantial sagittal plane correction that is difficult to obtain by other means. The full write up includes critical detailed steps articulating vital insights to the success of the procedure.

Transcutaneous spinal cord stimulation (tSCS) is becoming a promising neuromodulation technique to promote motor recovery in various neurological conditions, including stroke. As this intervention moves forward into clinical practice, it is important to understand how the elicited neurophysiological measures are related to the functional and neuromuscular deficits of the population of interest in order to personalize tSCS interventions and assess its effectiveness. Specifically, neurophysiological measurements of spinal cord excitability can be achieved by recording with EMG spinal motor evoked responses (sMERs) in muscles after applying single pulses of tSCS to the spinal cord. The objective of this study was to investigate potential correlations between baseline spinal cord excitability, as measured by resting motor threshold (RMT) and peak-to-peak (P2P) amplitude of the sMERs, and various factors including demographic characteristics, severity of spasticity, muscle strength, and gait speed in individuals post-stroke. Additionally, the study sought to explore disparities in excitability between the paretic and non-paretic sides. Fifteen participants with chronic stroke underwent sMER assessments. We observed a strong positive correlation between RMT and body weight, indicating weight as a potential confounding variable when comparing RMTs from sMERs between individuals. Furthermore, paretic muscles exhibited lower RMTs and higher P2P amplitudes compared to non-paretic muscles. The results demonstrate that sMERs hold promise in uncovering disparities in spinal excitability in stroke participants. Furthermore, careful interpretation and analysis of sMERs is advised, particularly as higher RMTs were associated with higher body weight and could impact the clinical feasibility of tSCS for some participants. These results should be considered in future tSCS protocols that aim to develop more personalized interventions across different neurological populations and optimize sMERs' utility as an outcome measure.

This article explores questions of disability access justice within the academy through the lens of an online digital/multimedia storytelling (DS) research workshop conducted during the COVID-19 pandemic. Our investigation uncovers how the shift from in-person to online DS methodologies created newfound opportunities for participation, particularly for individuals with episodic disabilities (EDs). Through an analysis of three co-author participants’ multimedia/digital stories and their reflective insights, we investigate the interplay between research methodologies and the broader context of disability access within the academy. Participants’ stories of inventive adaptations unfold against a backdrop of experiences in traditional academic settings that privilege normative ways of working and seldom accommodate diverse rhythms and access needs, including of students, faculty and staff. In light of these narratives, we advocate for an ongoing commitment to access-centered practices in research and work beyond crisis situations. The article concludes that academic research enterprises can accommodate a wider spectrum of participants—particularly those with episodic disabilities—and enhance research outcomes by recognizing and anticipating diverse bodyminds within the design of research methodologies and techniques.

Objective: To investigate trends and rates of severe perineal trauma (SPT), also known as obstetric anal sphincter injury (OASI), between midwife-led and obstetrician-led care in the Netherlands, and factors associated with SPT. Methods: This nationwide cohort study included registry data from 2000 to 2019 (n = 2,169,950) of spontaneous vaginal births of term, live, cephalic, single infants, without a (previous) caesarean section or assisted vaginal birth.First, trends of SPT and episiotomy were shown. Second, differences in SPT rates between midwife- and obstetrician-led care were assessed. Third, associations of care factors with SPT were examined. Multivariable logistic regression analyses were used to determine which factors were important in the associations. All outcomes were stratified for parity. Results: Over time, the SPT incidence increased mainly in midwife-led care and episiotomy rates decreased. Compared to midwife-led care, SPT rates were lower in obstetrician-led care among primiparous women (aOR 0.78; 99 % CI 0.74–0.81) and comparable among multiparous women (aOR 1.04; 99 % CI 0.99–1.10). Among women without epidural analgesia, these differences were smaller for primiparous women (aOR 0.88; 99 % CI 0.84–0.92), but the SPT rate was higher in obstetrician-led care among multiparous women (aOR 1.09; 99 % CI 1.03–1.15). Among women without shoulder dystocia, induction, augmentation, and pain medication, SPT rates were comparable among primiparous women, but higher among multiparous women in obstetrician-led care. In midwife-led care, SPT occurred more often among hospital versus home births. In obstetrician-led care, lower SPT incidences were found among births with epidural analgesia and for multiparous women with induction or augmentation. Conclusions: Iinduction, augmentation, and epidural analgesia in obstetrician-led care may be an explanatory factor for the higher incidence of SPT among primiparous women in midwife-led care. More research is needed to explain differences in SPT rates and to understand how SPT can be prevented, while maintaining a high intact perineum rate.

The education of a physician is a life-long process. Healthcare is a dynamic field characterized by continuous advancements in medicine, evolving treatment options, changing regulations, care models, and technology. Physicians must keep up-to-date with new practices, procedures, medications, and diseases and fulfill the educational requirements to maintain their medical licensure. Continuing education for physicians serves the essential purpose of nurturing lifelong learning, ensuring that medical practices align with the latest standards, and ultimately enhancing the quality of patient care and outcomes. In a broader context, physician education encompasses all activities designed to enhance skills, professional performance, and relationships that physicians employ to provide services to patients and the public and to improve collaborations within the field. This paper outlines a step-by-step plan for designing high-quality education programs for physicians. It aims to assist in ongoing education, aligning their practices with the latest medical care standards, and optimizing their clinical performance to improve patient and community health.

IntroductionPeople living in rural and remote areas face substantial barriers to accessing timely and appropriate mental health services. In the Bowen Basin region of Queensland, Australia, barriers include: limited local providers, long waiting lists, unreliable telecommunication, and reluctance to trial telehealth. Isaac Navicare is a new, community co-designed care navigation service which addresses these barriers by coupling care navigation with supported telehealth, and referrals to mental health providers and other supports. We aimed to understand the reach and effectiveness of Isaac Navicare in improving access to mental health services and address an evidence gap on strategies for improving telehealth acceptability.MethodsThis mixed-methods implementation science evaluation used the RE-AIM Framework. It involved a client database review, survey and semi-structured interviews with service users during the 12-month pilot from November 2021.Results197 clients (128 adults, 69 minors) were referred to Navicare during the pilot. Half of adult clients were unemployed, meaning referral options were limited to low-cost or bulk-billed services. Participants described Navicare as supportive and effective in helping to access timely and appropriate mental health supports. Most clients who expressed a treatment modality preference selected face-to-face (n = 111, 85.4%), however most referrals were for telehealth (n = 103, 66.0%) due to a lack of suitable alternatives. The rapport and trust developed with the care navigator was critical for increasing willingness to trial telehealth. Barriers to telehealth included privacy issues, technical difficulties, unreliable internet/phone, and perceived difficulties developing therapeutic rapport. The supported telehealth site was under-utilised. The majority (88.3%, n = 182) of referrals to Navicare were from local health or community service providers or schools.DiscussionCoupling supportive, individualised care navigation with tele-mental health provider options resulted in increased uptake and acceptance of telehealth. Many barriers could be addressed through better preparation of clients and improving promotion and uptake of the supported telehealth site.ConclusionAttitudes towards telehealth have changed during the COVID-19 pandemic, however although the need exists, barriers remain to uptake. Telehealth alone is not enough. Coupling telehealth with other supports such as care navigation improves acceptance and uptake.

ABSTRACTIn higher education, syllabi have traditionally served as written contracts between instructors and their students, providing first-hand information about the course and expectations. Reading the syllabus may provide students with first impressions or mental images of the instructor, thereby initiating a student-instructor relationship even before any interaction has occurred. Instructors can use syllabi to directly communicate values and practices of equity and inclusion, but students can perceive indirect messages through tone and language that may support or contradict stated values. Here, we share empirically derived recommendations for improving the tone of syllabi with inviting language and stylistic features that promote relationship-building with students.

A teaching statement offers a written summary of one’s beliefs, approaches, and successes in teaching. In this article, I use the teaching statement that I wrote in library school as an autoethnographic artifact to consider my own development as a teacher, and to reflect on the teaching statement as a genre. How do we declare ourselves as teachers, and how does that identity develop and shift over time? I conclude with considerations of how a teaching statement can serve academic librarians.

AbstractBackground: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case’s onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Students enrolled in online courses tend to be less successful as measured by the rate of A’s, B’s, and C’s than students enrolled in face-to-face courses. Yet little work has been done addressing whether these gaps vary depending on students’ broader relationship with the university, including whether they are degree-seeking students and whether they take any face-to-face courses. We use institutional data on Economics enrollments between 2012 and 2018 at a mid-sized land-grant university to deconstruct online/face-to-face success gaps into a student’s term modality (or modalities) and institutional affiliation components. We identify these components by using a fixed effects regression methodology and comparing outcomes across four student groups: affiliated students who are enrolled in exclusively online courses, exclusively face-to-face courses, or in a mix of courses each term, as well as unaffiliated (external) students exclusively taking online courses. Although students in online courses are less successful on average, part of this gap is explained by the student’s institutional affiliation and whether they exclusively take online courses. External students are the least successful in online courses while students who are affiliated with the institution fare much better. We examine potential reasons for these patterns using survey data from several online courses. These findings suggest that institutions should take steps to ensure that institutional support services and activities exist and extend to students in online courses.

Abstract Background Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. Methods We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer’s Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3–45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3–45 participant ID for those who continued to an in-person screening visit after study enrollment. Results Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3–611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. Conclusion Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.

Abstract Background The Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome (PRO) measure scored by body system composites to assess signs/symptoms of coronavirus disease 2019 (COVID-19). In addition to cross-sectional and longitudinal psychometric evaluations, qualitative exit interviews were conducted to support the content validity of the SIC. Methods In a cross-sectional study, adults diagnosed with COVID-19 in the United States completed the web-based SIC and additional PRO measures. A subset was invited to participate in phone-based exit interviews. Longitudinal psychometric properties were assessed in ENSEMBLE2, a multinational, randomized, double-blind, placebo-controlled, phase 3 trial of the Ad26.COV2.S COVID-19 vaccine. Psychometric properties evaluated included structure, scoring, reliability, construct validity, discriminating ability, responsiveness, and meaningful change thresholds of SIC items and composite scores. Results In the cross-sectional study, 152 participants completed the SIC (mean age, 51.0 ± 18.6 years) and 20 completed follow-up interviews. Fatigue (77.6%), feeling unwell (65.8%), and cough (60.5%) were symptoms most frequently reported. SIC inter-item correlations were all positive and mostly moderate (r ≥ 0.3) and statistically significant. SIC items and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) scores correlated as hypothesized (all r ≥ 0.32). Internal consistency reliabilities of all SIC composite scores were satisfactory (Cronbach’s alpha, 0.69–0.91). SIC composite scores correlated moderately (r = 0.30–0.49) to strongly (r ≥ 0.50) with PROMIS-29 scores and Patient Global Impression of Severity (PGIS) ratings (all P

Abstract Background Distribution of naloxone and training on its proper use are evidence-based strategies for preventing opioid overdose deaths. In-person naloxone training was conducted in major metropolitan areas and urban centers across Texas as part of a state-wide targeted opioid response program. The training program transitioned to a live, virtual format during the COVID-19 public health emergency declaration. This manuscript describes the impact of this transition through analyses of the characteristics of communities reached using the new virtual training format. Case presentation Training participant addresses were compared to county rates of opioid overdose deaths and broadband internet access, and census block comparison to health services shortages, rural designation, and race/ethnicity community characteristics. Conclusions The virtual training format reached more learners than the in-person events. Training reached nearly half of the counties in Texas, including all with recent opioid overdose deaths. Most participants lived in communities with a shortage of health service providers, and training reached rural areas, those with limited broadband internet availability, and majority Hispanic communities. In the context of restrictions on in-person gathering, the training program successfully shifted to a live, online format. This transition increased participation above rates observed pre-pandemic and reached communities with the need for equipping those most likely to witness an opioid overdose with the proper use of naloxone.

Abstract Artificial Intelligence is revolutionizing many aspects of the pharmaceutical industry. Deep learning models are now routinely applied to guide drug discovery projects leading to faster and improved findings, but there are still many tasks with enormous unrealized potential. One such task is the reaction yield prediction. Every year more than one fifth of all synthesis attempts result in product yields which are either zero or too low. This equates to chemical and human resources being spent on activities which ultimately do not progress the programs, leading to a triple loss when accounting for the cost of opportunity in time wasted. In this work we pre-train a BERT model on more than 16 million reactions from 4 different data sources, and fine tune it to achieve an uncertainty calibrated global yield prediction model. This model is an improvement upon state of the art not just from the increase in pre-train data but also by introducing a new embedding layer which solves a few limitations of SMILES and enables integration of additional information such as equivalents and molecule role into the reaction encoding, the model is called BERT Enriched Embedding (BEE). The model is benchmarked on an open-source dataset against a state-of-the-art synthesis focused BERT showing a near 20-point improvement in r2 score. The model is fine-tuned and tested on an internal company data benchmark, and a prospective study shows that the application of the model can reduce the total number of negative reactions (yield under 5%) ran in Janssen by at least 34%. Lastly, we corroborate the previous results through experimental validation, by directly deploying the model in an on-going drug discovery project and showing that it can also be used successfully as a reagent recommender due to its fast inference speed and reliable confidence estimation, a critical feature for industry application.

Abstract Background Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. Results Male and female C57BL/6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1β, IL-1β; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA; and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. Conclusion These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.

Abstract Background The Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome measure to evaluate the presence and severity of COVID-19 signs/symptoms in adults. This study expanded the context of use of the adult SIC among adolescents aged 12–17 years and supported a pediatric adaptation (the Pediatric SIC [PedSIC]) for caregiver assessment of signs/symptoms in children aged

Abstract Dissolved organic phosphorus (DOP) concentration distributions in the global surface ocean inform our understanding of marine biogeochemical processes such as nitrogen fixation and primary production. The spatial distribution of DOP concentrations in the surface ocean reflect production by primary producers and consumption as an organic nutrient by phytoplankton including diazotrophs and other microbes, as well as other loss processes such as photolysis. Compared to dissolved organic carbon and nitrogen, however, relatively few marine DOP concentration measurements have been made, largely due to the lack of automated analysis techniques. Here we present a database of marine DOP concentration measurements (DOPv2021) that includes new (n = 730) and previously published (n = 3140) observations made over the last ~30 years (1990–2021), including 1751 observations in the upper 50 m. This dataset encompasses observations from all major ocean basins including the poorly represented Indian, South Pacific, and Southern Oceans and provides insight into spatial distributions of DOP in the ocean. It is also valuable for researchers who work on marine primary production and nitrogen fixation.

Objective: To analyze the use of services regarding fertility preservation (FP) in cancer patients at a single institution. Design: A retrospective cohort study. Setting: Academic medical center. Patient(s): A total of 208 FP referrals. Intervention(s): None. Main Outcome Measure(s): Method of FP; time from referral to FP intervention. Result(s): A total of 553 patients were referred to a reproductive specialist for FP in the setting of a medical diagnosis from 2011 to 2016. Of these, 208 patients satisfied the inclusion criteria and met with a reproductive specialist. Ninety patients underwent FP services. The average age at referral was 30.9 ± 7.9 years. Breast cancer (n=94, 45%) and leukemia/lymphoma (n=62, 30%) were the most prevalent cancer diagnoses. A 68.9% of patients underwent oocyte cryopreservation (n=62), 26.7% underwent embryo cryopreservation (n=24) and 4.4% underwent ovarian tissue preservation (n=4). The time interval from the referral to the FP intervention ranged from 1 to 810 days, with a median of 17 days. Conclusion(s): In the setting of a cancer diagnosis, most patients undergoing FP intervention underwent oocyte cryopreservation, were

Due to their biocompatibility, ease of surface modification, and heating capabilities, gold nanomaterials are considered excellent candidates for the advancement of photothermal therapy techniques and related applications in cancer treatment. Various morphologies of gold nanomaterials have been shown to heat when exposed to high-powered laser irradiation, especially that which is from the near-infrared (NIR) region. While these lasers work well and are effective, light-emitting diodes (LEDs) may offer a safe and low-powered alternative to these high energy lasers. We investigated the heating capability of NIR-dye conjugated gold nanorods when exposed to an 808 nm LED light source using polyethylene glycol (PEG)-coated gold nanorods as the control. In this way, since the rods exhibited a surface plasmon resonance peak between 795 and 825 nm for both the PEG-coated rods and the dye-conjugated rods, which are fairly close to the frequency of the 530 mW, 850 nm LED light source, we were able to reveal the heating effect of the dye modification. While both morphologies heat when irradiated with the LED light, we demonstrated that the addition of an NIR dye increases the rate of heating and cooling, compared to the PEGylated counterpart. To our knowledge, the complementary effect given by the conjugated NIR-dye has not been previously reported in the literature. The targeting abilities of the NIR-dye combined with the increased heating rate of the modified particles used in this proof-of-concept work suggests that these particles may be exceptional candidates for theranostic applications.

Prostate cancer is generally considered an immunologically “cold” tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-β type II receptor, bolstering its activity in the TGF-β–rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-β–rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line–derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Unionid mussels are among the most imperiled group of organisms in North America, and Pustulosa pustulosa is a freshwater species with a relatively wide latitudinal distribution that extends from southern Ontario, Canada, to Texas, USA. Considerable morphological and geographic variation in the genus Pustulosa (formerly Cyclonaias) has led to uncertainty over species boundaries, and recent studies have suggested revisions to species-level classifications by synonymizing C. aurea, C. houstonensis, C. mortoni, and C. refulgens with C. pustulosa (currently P. pustulosa). Owing to its wide range and shallow phylogenetic differentiation, we analyzed individuals of P. pustulosa using mitochondrial DNA sequence data under a population genetics framework. We included 496 individuals, which were comprised of 166 samples collected during this study and 330 additional sequences retrieved from GenBank. Pairwise ΦST measures based on ND1 data suggested there may be up to five major geographic groups present within P. pustulosa. Genetic differentiation between regions within Texas was higher compared to populations from the Mississippi and Great Lakes populations, which may reflect differences in historical connectivity. Mitochondrial sequence data also revealed varying demographic histories for each major group suggesting each geographic region has also experienced differential population dynamics in the past. Future surveys should consider exploring variation within species after phylogeographic delimitation has been performed. In this study, we begin to address this need for freshwater mussels via the P. pustulosa system.