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Ardalan E Ahmad,1 Aza Mohammed,2 Bimal Bhindi,1,3 Patrick O Richard,4 Kamel Fadaak,5 Ricardo Leão,6 Antonio Finelli,1 Neil E Fleshner,1 Girish S Kulkarni1 1Division of Urology, Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; 2Department of Urology, Luton and Dunstable University Hospital, Luton, UK; 3Southern Alberta Institute of Urology, Calgary, Alberta, Canada; 4Division of Urology, Department of Surgery, Centre Hospitalier Universitaire de Sherbrooke, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 5Department of Urology, King Fahd Hospital of the University, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 6CUF Department of Urology, Hospital De Braga, Faculty of Medicine, University of Coimbra, PortugalCorrespondence: Girish S KulkarniDivision of Urology, Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, 610 University Ave, 3-130, Toronto, ON M5G 2M9, CanadaTel +1 416 946 2246Fax +1 416 946 6590Email girish.kulkarni@uhn.caPurpose: Elevated adipokines in patients with obesity and metabolic syndrome have been linked to increased risk of prostate cancer (PCa). The association between select serum adipokines and the outcome of prostate biopsies alone and in combination with clinical parameters at different early stages of PCa was investigated.Patients and methods: Clinical data and serum adipokines were retrieved from three retrospective cohorts representing men at different points in PCa detection: 1. Subjects with no prior biopsies (n=1061), 2. subjects with a prior negative biopsy (REDUCE trial, control arm) (n=1209), 3. subjects with low-risk PCa on active surveillance (AS) (n=154). Adipokines were chosen based on an unpublished pilot study and included: Resistin, Tumor Necrosis Factor-α, Interleukin-6, Monocyte Chemoattractant Protein-1, Hepatocyte Growth Factor, and Nerve Growth Factor. The primary outcome was the absence of PCa on biopsy and the secondary outcome was diagnosis of low-risk PCa fitting the criteria for continuing AS. Logistic regression analysis was used to assess the association of adipokines and negative and/or low-risk PCa at prostate biopsy.Results: In men with no prior prostate biopsy or with prior negative biopsy, adipokines were not predictors of prostate biopsy outcomes on multivariable regression analysis controlling for known clinical variables. In the AS cohort, MCP-1 and Resistin were significant predictors of biopsy outcome on multivariable analysis (OR 0.20, 95% CI: 0.05–0.85, p= 0.03 & OR 0.30, 95% CI: 0.10 −0.86, p= 0.03).Conclusion: Our findings do not support a strong role for adipokines for predicting the outcome of prostate biopsies at any early stage in PCa diagnosis.Keywords: adipokines, biopsy outcomes, prostate biopsy, early prostate cancer

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.

The computerization of public administration tasks is a reality. In contrast, the intelligence of public administration is shrouded in myths. For many decades, administrative science has contributed to the clarification of this distinction. Digital constitutionalism and technology-oriented administrative law doctrine have recently been added to this research. The basic regulations, proposed and adopted within individual states, in the European Union and in international organizations, whether it concerns the protection of personal data, cyber security, or artificial intelligence, do establish new tasks for public administration, but they affect methods rather than forms of administrative activity. Emerging technology raises concerns about the ability to understand artificial reasoning and its methods of classification, personalization, and prediction. It is questionable to assume that all actions can be quantified and thus everything becomes objective. Technology compounds the situation and has its own imperative.

A promising alternative approach to conventional vector and rodent control practices is the use of a bait containing a rodenticide and acaricide in controlling vectors and pathogen reservoirs concurrently. In the United States, Lyme disease continues to be the most prevalent vector-borne disease with approximately 500,000 Lyme disease cases estimated each year. Previous research has demonstrated the usefulness of a low dose fipronil bait in controlling Ixodes scapularis larvae feeding on white-footed mice. However, considering white-footed mice can be an unwanted species because of their association with tick-borne disease and hantaviruses, a combination rodent and tick bait (RTB) might provide a useful alternative to encourage additional community participation in integrated tick management (ITM) efforts. The purpose of this research was to evaluate the use of RTB (0.025 % warfarin, 0.005 % fipronil) in controlling white-footed mice and I. scapularis larvae. Studies were designed in part based on Environmental Protection Agency (EPA) guidelines. A laboratory choice test was conducted to evaluate the use of RTB in controlling white-footed mice over 15-day exposure when they were exposed to an alternative diet. Mice were observed every day for mortality and signs of warfarin toxicity. A simulated field test was conducted to evaluate the use of RTB, presented in the presence of an alternative diet, in controlling I. scapularis parasitizing white-footed mice over 4-day exposure. Mice were fitted with capsules and manually infested with I. scapularis larvae. The inside of each capsule was observed to evaluate tick attachment. Replete larvae detaching from each mouse were collected. Blood was collected from all treatment group mice via cardiac puncture to determine the fipronil sulfone concentration in plasma for each animal. Results indicated that RTB would be adequately consumed in the presence of an alternative diet under laboratory and simulated field conditions. Treatment with RTB resulted in 100 % mortality of white-footed mice during 15-day exposure and prevented 100 % larvae from feeding to repletion during 4-day exposure. All mice succumbing to RTB showed signs of warfarin toxicity. All mice parasitized with ticks that were exposed to RTB had fipronil sulfone detectable in plasma, with even the lowest concentration detected (8.1 parts per billion) controlling 100 % parasitizing I. scapularis larvae. The results suggest that RTB could be a useful means of rodent and tick control for use in ITM programs.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Abstract Background Current automated planning solutions are calibrated using trial and error or machine learning on historical datasets. Neither method allows for the intuitive exploration of differing trade-off options during calibration, which may aid in ensuring automated solutions align with clinical preference. Pareto navigation provides this functionality and offers a potential calibration alternative. The purpose of this study was to validate an automated radiotherapy planning solution with a novel multi-dimensional Pareto navigation calibration interface across two external institutions for prostate cancer. Methods The implemented ‘Pareto Guided Automated Planning’ (PGAP) methodology was developed in RayStation using scripting and consisted of a Pareto navigation calibration interface built upon a ‘Protocol Based Automatic Iterative Optimisation’ planning framework. 30 previous patients were randomly selected by each institution (IA and IB), 10 for calibration and 20 for validation. Utilising the Pareto navigation interface automated protocols were calibrated to the institutions’ clinical preferences. A single automated plan (VMATAuto) was generated for each validation patient with plan quality compared against the previously treated clinical plan (VMATClinical) both quantitatively, using a range of DVH metrics, and qualitatively through blind review at the external institution. Results PGAP led to marked improvements across the majority of rectal dose metrics, with Dmean reduced by 3.7 Gy and 1.8 Gy for IA and IB respectively (p

Mesial temporal lobe epilepsy (mTLE) is the most prevalent type of epilepsy in adults. First and subsequent generations of anti-epileptic therapy regimens fail to decrease seizures in a large number of patients suffering from mTLE, leaving surgical ablation of part of the hippocampus as the only therapeutic option to potentially reach seizure freedom. GluK2 has recently been identified as a promising target for the treatment of mTLE using gene therapy. Here, we engineered an adeno-associated virus serotype 9 vector expressing a cluster of two synthetic microRNAs (miRNAs), expressed from the human synapsin promoter, that target GRIK2 mRNA. Intra-hippocampal delivery of this vector in a mouse model of mTLE significantly reduced GRIK2 expression and daily seizure frequency. This treatment also improved the animals' health, reduced their anxiety, and restored working memory. Focal administration of the vector to the hippocampus of cynomolgus monkeys in GLP toxicology studies led to the selective transduction of hippocampal neurons with little exposure elsewhere in the brain and no transduction outside the central nervous system. Expression of miRNAs in hippocampal neurons resulted in substantially decreased GRIK2 mRNA expression. These data suggest that the intra-hippocampal delivery of a GMP-grade AAV9 encoding a synthetic miRNAs targeting GRIK2 is a promising treatment strategy for mTLE.

Background: Inequities in the incidence and outcomes of first episode psychosis (FEP) for Indigenous peoples are impacted by multiple institutional systems. This study examines Indigenous experiences of these systems to gain an understanding of how to improve institutional responses to FEP inequity. Methods: Critical race theory informed the methods used. Twenty-three participants participated in four focus group interviews, and thirteen individual interviews, including nine Māori youth and young adults with FEP, ten family members, and four Māori health professionals. Participants were asked about lifetime experiences of institutions (health, social, and criminal-justice). An adapted WHO framework for addressing mental health inequities was used to organize and analyse the first round of structural coding, followed by descriptive and pattern coding. Results: Two themes were identified. The first theme signposted opportunities for institutional intervention. Participants critique being processed quickly through institutions that are driven by socio-political agendas, namely perceived risk, threat or crisis. Subsequently, opportunities for meaningful intervention were missed. The second theme identified scope for family orientated responses across sectors. Participants described short-term social interventions and institutional structures that focused on individuals rather than families, emphasizing the need to broaden cross-sector scope to structural interventions for families. Discussion: The findings highlight institutional responses are focused on organisational drivers and downstream issues, that fail to address the fabric of the family social-environmental conditions that maintain Indigenous exposure to psychosis risk and poor outcomes. A pathway to equity would require a shared framework of social responsibility across sectors, that targets structural factors responsive to Indigenous family needs.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.

Introduction Although short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral ketamine, high relapse rates following ketamine dosing and the uncertain role of psychotherapy. This randomised controlled trial (RCT) seeks to establish the feasibility of evaluating repeated oral doses of ketamine and behavioural activation therapy (BAT), compared with ketamine treatment alone, for TR-MDD. We also aim to compare relapse rates between treatment arms to determine the effect size of adding BAT to oral ketamine.Methods and analysis This is a prospectively registered, two-centre, single-blind RCT. We aim to recruit 60 participants with TR-MDD aged between 18 and 65 years. Participants will be randomised to 8 weeks of oral ketamine and BAT, or 8 weeks of oral ketamine alone. Feasibility will be assessed by tracking attendance for ketamine and BAT, acceptability of treatment measures and retention to the study follow-up protocol. The primary efficacy outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS) measured weekly during treatment and fortnightly during 12 weeks of follow-up. Other outcome measures will assess the tolerability of ketamine and BAT, cognition and activity (using actigraphy). Participants will be categorised as non-responders, responders, remitters and relapsed during follow-up. MADRS scores will be analysed using a linear mixed model. For a definitive follow-up RCT study to be recommended, the recruitment expectations will be met and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT and ketamine arm will be achieved.Ethics and dissemination Ethics approval was granted by the New Zealand Central Health and Disability Ethics Committee (reference: 2023 FULL18176). Study findings will be reported to participants, stakeholder groups, conferences and peer-reviewed publications.Trial registration number UTN: U1111-1294-9310, ACTRN12623000817640p.

Goal: Machine learning (ML) technologies that leverage large-scale patient data are promising tools predicting disease evolution in individual patients. However, the limited generalizability of ML models developed on single-center datasets, and their unproven performance in real-world settings, remain significant constraints to their widespread adoption in clinical practice. One approach to tackle this issue is to base learning on large multi-center datasets. However, such heterogeneous datasets can introduce further biases driven by data origin, as data structures and patient cohorts may differ between hospitals. Methods: In this paper, we demonstrate how mechanistic virtual patient (VP) modeling can be used to capture specific features of patients’ states and dynamics, while reducing biases introduced by heterogeneous datasets. We show how VP modeling can be used for data augmentation through identification of individualized model parameters approximating disease states of patients with suspected acute respiratory distress syndrome (ARDS) from observational data of mixed origin. We compare the results of an unsupervised learning method (clustering) in two cases: where the learning is based on original patient data and on data derived in the matching procedure of the VP model to real patient data. Results: More robust cluster configurations were observed in clustering using the model-derived data. VP model-based clustering also reduced biases introduced by the inclusion of data from different hospitals and was able to discover an additional cluster with significant ARDS enrichment. Conclusions: Our results indicate that mechanistic VP modeling can be used to significantly reduce biases introduced by learning from heterogeneous datasets and to allow improved discovery of patient cohorts driven exclusively by medical conditions.

This meta-empirical study delves into the conflicts between Sweden and its forestry industry in response to the EU-commission's demands for sustainable forest management. Combining theoretical foundations with empirical analysis of existing research, this study grounds itself in a clear definition of forests as intricate, adaptive, and ever-evolving systems. The central research question revolves around the efficacy of Sweden's guiding principle, ''freedom under responsibility,'' in shaping forest policy and fostering long-term sustainability.To dissect the core of this conflict, two fundamental hypotheses are explored. The first centers on the clash of interests between the Swedish government and forest industry stakeholders, while the second delves into the tension between monetarily valued ecosystem services and those without a market value, a natural market being absent. These questions are scrutinized using a novel method tailored for conflict analysis. A model article and two specific analysis articles are developed, each focusing on distinct facets of forest management, and are subsequently compared to reveal insightful contrasts.This contrasting approach unveils a comprehensive socio-economic framework underlying these conflicts—a framework that often remains concealed due to deeply ingrained patterns of thought and behavior within homogeneous groups. The method's greatest strength lies in its ability to render the invisible visible and the ''silent'' audible. It clarifies what might be obscured in the model article, bringing the contours of the conflict into sharp relief.The study findings affirm the value and democratic nature of the ''freedom under responsibility'' principle. However, for it to yield the intended outcomes, substantial and continuous educational efforts directed at relevant forest management stakeholders are imperative. This meta-empirical study highlights the necessity of a robust educational campaign to ensure the principle's success.Moreover, this study contributes theoretical insights that could serve as a foundation for conflict resolution: • Forests are complex, adaptive, and dynamic systems. • Human intervention prompts responses and adaptations within this system. • The choice of management strategies plays a pivotal role in achieving specific outcomes, whether biomass production or the preservation of natural forest characteristics. • The production of forest ecosystem services necessitates active management and does not occur automatically.

Local authorities are central to the implementation of English Integrated Care Systems' health inequalities agendas, embedding public health into population health management planning. They work with partners to deliver a range of 'health determinant' services and facilities for people in a defined geographic area. This work is substantially premised on the use of cross-sectoral data that is linked at the individual level, readily available, longitudinal and contemporaneous. However, multiple challenges exist to such data availability. This paper elaborates upon these challenges to local authority public health systems and their potential solutions.

Abstract Background There is a dearth of research to support the treatment of people with postural tachycardia syndrome (PoTS). Despite expert consensus suggesting exercise is recommended for this patient group, there are no randomised control trials examining this rigorously. The aim was to co-create a feasibility trial protocol and a rehabilitation intervention for people living with PoTS. Methods The intervention and feasibility trial design were co-created as part of the PostUraL tachycardia Syndrome Exercise (PULSE) study. We used the ‘three co’s framework’ of co-define, co-design and co-refine. Recruitment included key national charities and National Health Service Trusts treating people living with PoTS in the UK. Eighteen patient and public involvement members attended the co-define session, and 16 co-creators with a mix of expertise attended the subsequent co-design and co-refine sessions. Seven intervention practitioners were trained in the rehabilitation intervention, providing feedback for further co-refinement. Results The final co-created intervention comprises online physical activity, and lifestyle and behaviour change support sessions. It is based on functional movement activities using a patient-centred approach tailored to individual needs. Physical activity intensity is guided by individuals’ perception of effort rather than by objective measures. Recumbent bikes are provided for home use. Patients deemed randomisation to be acceptable because research in this area was considered important. Conclusions An innovative approach was used to co-create the PULSE intervention and feasibility trial protocol to meet the evidence-based and logistical needs of people living with PoTS, clinicians, service deliverers, third-sector organisations, academics and funders. This can be used as a successful example and template for future research internationally. People living with PoTS were recognised as experts and involved in every aspect of conceptualisation, design and refinement. This complex rehabilitation intervention is currently being tested in a randomised feasibility trial comparing the PULSE intervention with best-practice usual care for people living with PoTS. Trial registration ISRCTN45323485 was registered on April 7, 2020.

Abstract Aims Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular–vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. Methods and results Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near‐normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = −0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e′) on echocardiography (r = −0.307, P = 0.014). Conclusions This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at‐risk intermediate phenotypes (e.g. pre‐HFpEF) before overt HFpEF occurs.

Much research has raised concerns about how a warming planet will interact with natural cyclical climatic variations, and the implications for the resilience and vulnerability of coastal communities. As the anticipated effects of climate change will continue to intensify, it is necessary to understand the response and adaptive capacity of individuals and communities. Coastal communities in Ecuador have evolved in an environment of such cyclical climatic variations referred to as El Niño-Southern Oscillation (ENSO) and La Niña. These climatic events are frequently characterized by extreme variations in precipitation, violent storms, and coastal flooding during El Niño and lowered sea water temperatures and drought during La Niña. This paper draws on survey data and long-term ethnographic research in Ecuadorian coastal communities to explore how fishers understand the impacts of ENSO and implications for their livelihood decisions and resilience to climate variability. The results suggest that fishers along the coast of Ecuador understand and respond differentially to the impacts of ENSO depending on social, cultural, environmental, and geographical factors. These differential levels of response suggest that livelihood diversification may uphold social resilience, which has implications for how coastal communities may adapt to the increasingly harsh weather conditions predicted by many climate models. Our findings further suggest that the impacts of El Niño are more salient than the impacts of La Niña; these findings have significant implications for fisheries management and science communication.

Ongoing efforts to improve U.S. Caribbean fisheries management include increased consideration for human dimensions data and increased stakeholder input and engagement. Given the significant pressure that the local fisheries have sustained due to environmental degradation, climate change, storms and hurricanes, and overharvesting, combined with the critical data gaps that exist in both natural and human dimensions, it becomes particularly important to understand fishers’ perceptions and aspects influencing them to promote efforts that will maximize the wellbeing of these social-ecological systems. In this study, data collected through surveys with fishers in the U.S. Virgin Islands were used to develop a correlation model to test relationships between variables using a heuristic model, the Anthropic Impact Assessment Model (AIAM) as the basis. Findings support the application of heuristic models, such as the AIAM, to develop hypotheses and test relationships to understand complex fishery social-ecological systems. The most significant findings with implications for decision making in the region include support for considering fishers’ wellbeing as an indicator of ecosystem health and for using fishers’ local ecological knowledge in the management process, particularly under data-poor conditions, for information that can be used to better target outreach and education efforts, as well as more effective recovery plans to promote resilience and adaptation to environmental change, including the impacts of natural disasters. Results of this study and future analyses using similar approaches can be used to guide the incorporation of human dimensions data into the decision-making process in the U.S. Caribbean and elsewhere.

The adaptable nature of the SARS-CoV-2 virus has led to the emergence of multiple viral variants of concern. This research builds upon a previous demonstration of sampling human hand odor to distinguish SARS-CoV-2 infection status in order to incorporate considerations of the disease variants. This study demonstrates the ability of human odor expression to be implemented as a non-invasive medium for the differentiation of SARS-CoV-2 variants. Volatile organic compounds (VOCs) were extracted from SARS-CoV-2-positive samples using solid phase microextraction (SPME) coupled with gas chromatography–mass spectrometry (GC–MS). Sparse partial least squares discriminant analysis (sPLS-DA) modeling revealed that supervised machine learning could be used to predict the variant identity of a sample using VOC expression alone. The class discrimination of Delta and Omicron BA.5 variant samples was performed with 95.2% (±0.4) accuracy. Omicron BA.2 and Omicron BA.5 variants were correctly classified with 78.5% (±0.8) accuracy. Lastly, Delta and Omicron BA.2 samples were assigned with 71.2% (±1.0) accuracy. This work builds upon the framework of non-invasive techniques producing diagnostics through the analysis of human odor expression, all in support of public health monitoring.

Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92-0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients.

Recruiting participants for research from highly traumatised ethnic and faith communities requires a participatory and trauma-informed approach that considers logistic barriers, as well as trauma-related and culture-specific issues. Active community engagement through every stage of the project and employing community members in research roles can help build trust, identify and mitigate concerns early, prevent re-traumatization, and ensure that findings will be of value to the community. Some of these research challenges are discussed in the context of the Christchurch mosque terror attacks. These insights may be helpful for researchers and clinicians working in similarly challenging environments.

Category: Midfoot/Forefoot; Basic Sciences/Biologics Introduction/Purpose: Plantar fibromatosis (PFi) is characterized by collagen-containing nodules on the foot along the plantar fascia that can cause pain and functional disability. Current treatments focus on symptom relief, which may become ineffective, or surgery, which can have lengthy recovery times. Collagenase clostridium histolyticum (CCH) is approved for Dupuytren’s and Peyronie’s disease treatment, which are both fibroproliferative disorders that may coexist in patients with PFi. This dose-ranging study assessed the efficacy and safety of CCH treatment of PFi. Methods: In this Phase 1, multicenter study, participants were randomly allocated (1:1:1) to receive 0.6, 1.2, or 2.25 mg/mL CCH. All participants underwent the initial treatment period (ITP) and received 1–2 intralesional injections per nodule on Day 1 with 5 follow-up assessments. Participants with palpable treated nodules could receive additional CCH doses (at 2.25 mg/mL; retreatment period, RP), with follow-up at specified intervals. Assessments included a 5-scale measure of nodule hardness (0 [nonpalpable] to 4 [hard]), and the Foot Function Index-Short Form23 (FFI-SF23) reported as a composite score (0 – 100) of 3 subscale scores (disability, difficulty, and pain subscales). Results: After ITP (n=24), 100% (8/8) of participants receiving 2.25 mg/mL CCH showed improvement in nodule hardness, compared with 87.5% (7/8) and 75% (6/8) of participants receiving 1.2 and 0.6 mg/mL, respectively. FFI-SF23 also showed a negative change from baseline across treatment groups, indicating improvement. Participants that received 2.25 mg/mL reported the largest percent improvement (-83.7%). After RP (n=11), 81.8% (9/11) of participants showed improvement in nodular hardness and an FFI-SF23 score change of -9.3%, indicating further improvement from baseline after ITP. CCH had a consistent safety profile in ITP/RP. Conclusion: CCH caused dose-dependent improvement of nodule hardness after treatment, with 2.25 mg/mL utilized for nodule retreatment; FFI-SF23 scores correlated with this finding, indicating CCH may be a potential nonsurgical intralesional option for PFi treatment.

Category: Midfoot/Forefoot; Basic Sciences/Biologics Introduction/Purpose: Currently, there is no safe and efficacious injectable therapy for symptomatic plantar fibromatosis (PFi) that addresses its pathophysiology. Patients with PFi nodules experience symptoms that reduce quality of life, causing functional disability leading to severe impairment in some patients. Collagenase clostridium histolyticum (CCH) is approved for Dupuytren’s and Peyronie’s disease treatment, which are both fibroproliferative disorders that may coexist in patients with PFi. This first study of CCH treatment for PFi evaluated participant satisfaction and investigator assessment of improvement. Methods: Participants were randomly allocated (1:1:1) in this Phase 1, multicenter study to receive 0.6, 1.2, or 2.25 mg/mL CCH. All participants underwent the initial treatment period (ITP) and received 1–2 intralesional injections per nodule on Day 1 with follow-up assessments at specified intervals. Participants with palpable treated nodules could enter the retreatment period (RP) and receive additional CCH doses (at 2.25 mg/mL), with follow-up at specified intervals. Assessments included the Subject Satisfaction with Treatment Rating Scale (+2: very satisfied; to -2: very dissatisfied), and the Investigator Assessment of Improvement Scale (+3: very much improvement; to -3: very much worse). Results: After ITP, ≥75% of participants reported “very” or “quite” satisfied across all treatment groups, with 2.25 mg/mL group reporting 100% satisfaction. For ≥72.7% of nodules, participants reported satisfaction with outcome. Investigators reported improvement (“minimal”, “much”, or “very much”) in ≥75% of participants and ≥80% of treated nodules. After RP, 63.6% of participants reported treatment satisfaction; participants were satisfied with 66.7% of treated nodules, indicating continued improvement from the ITP. Almost all participants (90.9%) were deemed by investigators to have shown improvement, with 86.7% of treated nodules being assessed as having improvement. Conclusion: CCH-treated PFi participants were satisfied with their improvement; physicians assessed improvement in >90% of participants. Results indicate CCH as a potential nonsurgical intralesional option for PFi treatment.

Category: Midfoot/Forefoot; Basic Sciences/Biologics Introduction/Purpose: Plantar fibromatosis (PFi) is a functionally disabling disorder characterized by fibrous collagen-containing nodules along the plantar fascia. Collagenase clostridium histolyticum (CCH) is a nonsurgical treatment approved for Dupuytren’s and Peyronie’s disease; both can coexist with PFi. Composed of two collagenases, CCH specifically hydrolyzes certain collagen types and may disrupt the nodule when injected directly. This proof-of-concept study evaluated pharmacokinetics, immunogenicity, and assessed tolerability and safety of CCH treatment of PFi. Methods: In this Phase 1, multicenter study, participants were randomly allocated (1:1:1) to receive 0.6, 1.2, or 2.25 mg/mL CCH. All participants underwent the initial treatment period (ITP) and received 1–2 intralesional injections per nodule on Day 1 with pharmacokinetic samples collected over 24hrs, followed by 5 follow-up visits. Post-ITP, participants with a remaining, palpable nodule could enter the retreatment period (RP) and receive additional CCH doses (at 2.25 mg/mL) with follow-up at specified intervals. Immunogenicity test sampling occurred at screening and at the end of ITP/RP. Adverse events (AEs) were monitored throughout. Results: Twenty-four participants enrolled into ITP, with 11 continuing into RP. Pharmacokinetic and immunogenicity findings were consistent with previous CCH studies in other therapeutic areas. CCH treatment was generally well tolerated, with no serious treatment emergent adverse events (TEAEs), drug discontinuations, or study withdrawals by study end. Over 70% of participants during ITP (19/24) and RP (8/11) reported at least 1 TEAE. Eighty-six TEAEs occurred during ITP and 35 in RP; most were mild in severity (73%, ITP; 83%, RP), and 67% of ITP and 49% of RP TEAEs were treatment related. TEAEs were reportedly injection site- related, with injection site bruising, pain, and swelling frequently recorded. Conclusion: CCH had an expected pharmacokinetics/immunogenicity profile and was safe and well tolerated in participants with PFi. CCH may be a potential nonsurgical intralesional option for PFi treatment.

Summary: Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.

Background The evidence base for racemic ketamine treatment for treatment-resistant major depressive disorder (TRD) continues to expand, but there are major challenges translating this evidence base into routine clinical care. Aim To prepare guidelines for ketamine treatment of TRD that are suitable for routine use by publicly funded specialist mental health services. Method We consulted with senior leadership, clinical pharmacy, psychiatrists, nursing, service users and Māori mental health workers on issues relating to ketamine treatment. We prepared treatment guidelines taking the evidence base for ketamine treatment and the consultation into account. Results Ketamine treatment guidance is reported. This offers two treatment pathways, including a test of ketamine responsiveness with intramuscular ketamine and the dominant use of oral ketamine for a 3-month course to maximise the opportunity for the short-term benefits of ketamine to accumulate. Conclusions We have responded to the challenges of translating the evidence base for ketamine treatment into a form suitable for routine care.

Purpose: Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer. Methods and Materials: Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board–approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review. Results: Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage (P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics (P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics (P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were “per protocol” or met “variation acceptable” ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes. Conclusions: A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace.

We are writing in response to comments made by Shah and Ramasamy [...]

Bipolar disorder (BD) is a serious mental health condition that is clinically complex to monitor and manage. While best practice guidelines exist, they vary internationally lacking consensus. Indigenous peoples, including Māori in New Zealand, experience higher community rates of BD. While New Zealand practice guidelines recommend providing culturally responsive care to Māori, studies show that Māori do not receive best practice. This qualitative study aimed to share the evidence about patterns of health service use and Māori patient experiences with focus group participants involved in the design and delivery of BD services, to discuss and develop guidelines for best practice for Māori with BD and address areas of unmet need. Three focus groups were conducted with 22 participants involved in the delivery of services to Māori with BD across three sites. Willing participants were sent background information and three focus group questions framed to elicit priority solutions to improve clinical, structural and organisational features of mental health service delivery for Māori patients with BD and their whānau (family). The nominal group technique was used to synthesise responses, and then develop a prioritised list of proposed solutions. Results identified system-level changes required at the clinical, structural and organisational levels of healthcare. Findings further evidence the need for healthcare reform in New Zealand, to be responsive to Māori with BD.

BackgroundDepression and anxiety are common and debilitating mental disorders with severe negative repercussions at both individual and societal levels. Although virtual reality (VR) has emerged as a safe and effective tool for the treatment of anxiety disorders, studies of the therapeutic application of VR to treat depression are more limited. ObjectiveThe purpose of this study was to test whether a novel type of individualized VR (iVR) can be used to improve self-compassion and decrease depressive symptoms and to evaluate the usability and acceptability of this approach, as rated by participants. The iVR system was designed and developed based on the feedback obtained from a previous study, with improved appearance and feel of the avatar and enhanced graphical quality. MethodsA total of 36 young adult participants were recruited from a university community social media site. Participants were aware that the study was investigating a treatment for depression but were not recruited based on depression diagnosis. Participants were asked to complete 2 iVR sessions, spaced 2 weeks apart. At baseline and upon completion of each iVR session, participants were asked to complete validated measures of self-compassion and depression. Upon completion of both iVR sessions, additional measures were administered to assess participants’ perceptions about the perceived usability and system acceptability of the iVR approach. ResultsSelf-compassion was assessed at the beginning of session 1 (preintervention baseline) and at the end of session 1 (postintervention assessment). Owing to COVID-19 constraints, 36% (13/36) of the participants were unable to complete the follow-up iVR session. Self-compassion was assessed again for the remaining 64% (23/36) of the participants at the end of session 2 (postintervention assessment). Within-group analyses revealed that self-compassion was significantly increased at the end of both session 1 (P=.01) and session 2 (P=.03) relative to baseline. There was also a nonsignificant trend for depressive symptoms to be low at the end of session 2 relative to baseline. Both quantitative and qualitative participant data supported the iVR approach as being acceptable and usable. ConclusionsAlthough these data must be treated as preliminary owing to the small sample size and potential selection bias, the data provide encouraging initial evidence that iVR might be a useful tool to enhance self-compassion and reduce depressive symptoms, highlighting the need for randomized controlled trials in the future.

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.

Chronic kidney disease-associated pruritus is linked with decreased health-related quality of life assessed using disease-specific instruments. The extent to which worsening pruritus reduces generic quality of life assessed using the EQ-5D instrument is unknown. Prevalent kidney failure patients receiving in-centre haemodialysis from 5 centres completed the EQ-5D-5L quality of life measure, worst Itching Intensity Numerical Rating Scale and 5-D itch pruritus instruments. Latent class models were used to identify clusters of patients with similarly affected body parts, and mixture models were used to map the pruritus measures to the EQ-5D. Data on 487 respondents were obtained. Latent class analysis identified 3 groups of patients who had progressively worsening severity and an increasing number of body parts affected. Although the worst itching intensity numerical rating scale and 5-D itch instruments correlated with each other, only the latter had a strong relationship with EQ-5D. When controlling for age, sex, diabetes and years receiving dialysis, the meanpredicted EQ-5D utility (1: perfect health, 0: dead) decreased progressively from 0.69 to 0.41. These findings suggest that pruritus instruments that include domains capturing how the individual is physically, mentally and socially affected by their pruritus, in addition to severity, more closely approximate the EQ-5D generic quality of life measure.

Introduction Our previous research has demonstrated significant cognitive effects of earthquake exposure 2–3 years following the Canterbury earthquake sequence of 2011. Such impairment has major implications for a population trying to recover, and to rebuild, a devastated city. This study aims to examine psychological, cognitive and biological factors that may contribute to subjective cognitive difficulties in a large group of individuals exposed to the Canterbury earthquake sequence.Methods and analysis Two-hundred earthquake-exposed participants from an existing large cohort study (Christchurch Health and Development Study, CHDS) will be recruited. Inclusion is based on results of online screening of the CHDS cohort, using the Cognitive Failures Questionnaire. Individuals scoring the highest (n=100) and lowest (n=100), representing the highest and lowest levels of subjective cognitive impairment, are selected. Exclusions are: psychotic/bipolar disorders, serious substance/alcohol dependence, chronic medical conditions, pregnancy and previous serious head injury. Participants will undergo a half-day assessment including clinician-rated interviews, self-report measures, objective and subjective cognitive assessments, blood sample collection and physical measurements. The primary analysis will compare cognitive, psychological and biological measures in ‘high’ and ‘low’ subjective cognitive impairment groups. The study will have power (p

Abstract Background In 2018, USAID published a report based on Demographic and Health Surveys data on the relationship between men’s involvement and women and children’s health outcomes. Using a flawed operationalization of “men’s involvement,” USAID’s analysis implies that Senegalese men are not involved in women and children’s health. Methods The findings of this study come from 12 months of ethnographic research in Dakar, Senegal that examined the roles and responsibilities of expectant fathers. Research participants included 32 pregnant women and 27 expectant partners recruited from three maternity wards. Research methods included long-term, immersive participant observation and semi-structured interviews. Results Pregnant women in Senegal are surrounded by a kin-based network of care providers called the entourage who share responsibilities for support. Expectant fathers, as members of the entourage, are expected to provide financial and emotional support, while other members of the entourage are expected to undertake the responsibilities which USAID have designated as “men’s involvement.” Men typically do not undertake additional forms of care and support because they are considered “women’s business,” meaning that women actively discourage men from doing those things, in order to preserve women’s autonomy. Conclusion This research demonstrates that expectant fathers are involved in antenatal care in ways that USAID does not track through DHS. Further, I argue that USAID’s heterosexist, monogamous, and nuclear operationalization of “men’s involvement” aligns with a long history of Eurocentrism in development discourse which may be potentially harmful and obstructive to improving maternal and child health when the problem that is targeted is not a problem at all. This study is yet another case that demonstrates an urgent need of public and global health engagement with local stakeholders and ethnographic researchers.

This paper analyses EU-Central Asia trade and EU economic assistance to Central Asia. Some EU companies have had a high profile in individual countries or in energy projects (reflected in trade relations between parent and host country), but overall EU companies have lagged the higher profile of Russian companies and the increasing Chinese economic presence. Central Asia had low priority in EU external economic policies towards Soviet successor states. After 2007 the EU became more active in designing a Central Asia strategy, but funding has been limited and the impact small. A significant development for EU-Central Asian economic relations has been the expansion of Eurasian rail services. This has a firm economic foundation and, if currently important routes are disrupted by events in Russia, alternatives will be found. The paper concludes with discussion of prospects for EU-Central Asian relations with new presidents in Uzbekistan since 2016 and Kazakhstan since 2019.

After a year of record international trade in 2022, it is uncertain whether the future of the global economy is fragmentation or a new institutional structure. The challenges are to re-establish a dispute resolution mechanism, as the WTO process currently allows decisions to be appealed into oblivion, and to extend the coverage of world trade law to address changes in world trade since 1995. This paper argues that the best option for a beyond-WTO institutional order is an expanded Comprehensive and Progressive Trans-Pacific Partnership (CPTPP) and that, absent a functioning WTO appeal system, the Multi-Party Interim Appeal Arbitration Arrangement (MPIA) is a way to resolve appeals. This could lead to a three-tier global trade system as the expanded CPTPP membership observes the highest standard world trade rules, a second group accepts WTO rules but no more, and a third group has no interest in being bound by world trade rules. On the post-2017 record, the USA could be in any of these three groups. The leading Asian trading nations have a key role to play in ensuring that the first group accounts for the majority of world trade, and to encourage countries to want to follow CPTPP standards and to be at the table when extensions to these standards are discussed.

Setting up data structures, parallelizing code, and creating visualizations are tasks in almost any project aiming to develop healthcare AI solutions based on heterogeneous, high-dimensional data structures. While toolkits for individual parts of this workflow exist, a solution that provides integration of all steps is rarely found. We present the Diagnostic Expert Advisor, a platform for machine learning research on heterogeneous medical time-series data that aims to provide a robust environment for the rapid development of AI applications. It integrates a local web app through which whole patient cohorts, as well as the disease evolution of individual patients, can be analyzed with integrated tools for data handling, visualization, and parallelization. The platform provides sensible defaults while being flexible and extensible to fit various projects and working styles.

Desertification reversal is globally significant for the sustainable development of land resources. However, the mechanisms of desertification reversal at the level of plant community are still unclear. We hypothesized that desertification reversal has clear effects on plant community composition, plant functional types (PFTs), and other vegetation characteristics, including plant diversity and biomass, and their changes in the early stages of reversal are more dramatic than in later stages. We investigated the vegetation of four to five different stages of desertification reversal at each of seven large study sites in southwestern Mu Us Sandy Land, China. The results show that the dominant species in very severe desertification areas were replaced by perennial grasses in potential desertification areas. The importance values of annual forbs and perennial sub-shrubs decreased dramatically (from 42.59 and 32.98 to 22.13 and 5.54, respectively), whereas those of perennial grasses and perennial forbs increased prominently (from 13.26 and 2.71 to 53.94 and 11.79, respectively) with the reversal of desertification. Desertification reversal increased the complexity of plant community composition by increasing plant species in each PFT, and C3 plants replaced C4 plants to become the dominant PFT with reversal. Plant species richness and species diversity rose overall, and aboveground plant biomass significantly (p < 0.05) increased with the reversal of desertification. Most vegetation characteristics changed more strikingly in the early stages of desertification reversal than in later stages. Our results indicate that the type and composition of the plant community were dramatically affected by desertification reversal. Anthropogenic measures are more applicable to being employed in early stages than in later stages, and Amaranthaceae C4 plants are suggested to be planted in mobile dunes for the acceleration of desertification reversal. This study is useful for designing strategies of land management and ecological restoration in arid and semiarid regions.

Responses of agriculture and fisheries to climate change are interlinked, yet rarely studied together. Here, the authors analyse more than 3000 households from 5 tropical countries and forecast mid-century climate change impacts, finding that communities with higher fishery dependence and lower socioeconomic status communities face greater losses.

Biotic homogenization, which is increased similarity in the composition of species among communities, is rising due to human activities. Using North American mammal fossil records from the past 30,000 years, this study shows that this phenomenon is ancient, beginning between 12,000 and 10,000 years ago with the extinction of the mammal megafauna.

Abstract Background The PULSE (PostUraL tachycardia Syndrome Exercise) study is a randomised controlled trial assessing the feasibility of conducting a multicentre RCT testing supervised exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with Postural Tachycardia Syndrome (PoTS). The original trial protocol was published in BMC Pilot & Feasibility Studies (accessible at https://doi.org/10.1186/s40814-020-00702-1 ). The PULSE intervention consists of (1) individual assessment; (2) 12-week, twice-weekly, supervised exercise training; (3) behavioural and motivational support; and (4) guided lifestyle physical activity. The control intervention is best-practice usual care with a single 30-min, one-to-one practitioner appointment, and general advice on safe and effective physical activity. Sixty-two people (aged 18–60 years) with a confirmed diagnosis of PoTS will be invited to enrol on a feasibility RCT with an embedded qualitative study. The primary outcome will be feasibility; process-related measures will include eligibility, recruitment, randomisation and withdrawal rates, along with indicators of exercise programme adherence and acceptability. Secondary physiological, clinical and health-related outcomes will be assessed. In response to the COVID-19 pandemic, here we describe amendments to the trial protocol. Methods Restrictions imposed by the COVID-19 pandemic meant it was necessary to change the delivery of the PULSE and control interventions. These changes reflected the need to limit the risk of COVID-19 transmission in a clinical population, some of whom were at increased risk of contracting the virus and suffering serious illness. The major change was that the originally intended centre-based PULSE and control interventions would now be delivered remotely on-line. Subsequently, there were minor changes to the participant eligibility criteria. These decisions followed an on-line co-creation session with people affected by PoTS, and relevant public and professional stakeholders. Conclusions We present an update of the original trial protocol in response to the COVID-19 pandemic. No participants were recruited to the original protocol; thus, results will reflect the on-line delivery of the intervention. PULSE will be the first randomised trial to assess the feasibility of conducting a definitive multi-centre RCT testing supervised on-line exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with PoTS. Trial registration ISRCTN45323485 registered on 7 April 2020.

Background Long-term adherence to exercise is often poor for people with coronary heart disease (CHD) who have completed supervised, centre-based cardiac rehabilitation. The aim of this study is to assess the feasibility of a remotely prescribed, delivered and monitored cardiac rehabilitation intervention using a wearable device to support long-term adherence to exercise and physical activity during maintenance of cardiac rehabilitation. Methods After completing cardiac rehabilitation, 30 participants with CHD, will be randomised (1:1) to an intervention ( n = 15) or a usual care group ( n = 15) in a 12-month feasibility randomised controlled trial (RCT). The intervention will comprise of an exercise consultation, personalised exercise prescription delivered via a wearable activity monitor using biometric feedback, regular monitoring via check-ins, and feedback text-messages for 6-months. Participants will be assessed at baseline (following completion of cardiac rehabilitation) and at three-, six-, and 12-months post-randomisation. The primary outcome will be feasibility, including assessment of eligibility, recruitment, adherence, and acceptability. Secondary outcomes will include exercise capacity, physical activity behaviours, cardiovascular disease risk and quality of life. Semi-structured interviews will be conducted at three-, six-, and 12-months post-randomisation (and with those who drop-out) to explore the acceptability of the study intervention and procedures. A questionnaire will be offered to those who decline participation. Discussion The MAINTAIN study will evaluate the feasibility of conducting a future definitive multi-centre RCT testing a remotely prescribed and monitored long-term mHealth maintenance exercise programme, versus usual care, for people with CHD who have completed cardiac rehabilitation. Trial registration number ClinicalTrials.gov, NCT05292287. Registered on 22/03/2022

Purpose This paper reports the evaluation of an ongoing intervention, the GROW Programme, aimed at meeting the needs of 15–18-year-old pupils who were unable to attend school in England for periods during 2020–2021. The aim of the paper is to theorize the underlying basis of practice in such a lockdown context to inform future responses. Design/Approach/Methods Thematic analysis of a mixed-method evaluation, using surveys and interviews of teachers and mentors, and pupil focus groups, of the remote mentoring of pupils and their learning during lockdown, is further analyzed by means of Bernstein's knowledge codes and concept of open schools, to identify the form of knowledge inherent in online mentoring. Findings The analysis offers a framework for open schooling valuable to schools in uncertain times and identifies the shift to metacognition and self-regulated learning as holding particular benefits for learning under disruption. Originality/Value The paper takes a novel view of the disruption brought about by the partial closure of schools and offers a methodology for evaluating its effects by means of a unique intervention. It makes visible the characteristics and the potential benefits of alternative approaches in order that schools can make informed choices.

Background: Empathic communication skills have a growing presence in graduate medical education to empower trainees in serious illness communication. Objective: Evaluate the impact, feasibility, and acceptability of a shared communication training intervention for residents of different specialties. Design: A randomized controlled study of standard education v. our empathic communication skills-building intervention: VitalTalk-powered workshop and formative bedside feedback using a validated observable behavioral checklist. Setting/Subjects: During the 2018?2019 academic year, our intervention was implemented at a large single-academic medical center in the United States involving 149 internal medicine and general surgery residents. Measurements: Impact outcomes included observable communication skills measured in standardized patient encounters (SPEs), and self-reported communication confidence and burnout collected by surveys. Analyses included descriptive and inferential statistics, including independent and paired t tests and multiple regression model to predict post-SPE performance. Results: Of residents randomized to the intervention, 96% (n?=?71/74) completed the VitalTalk-powered workshop and 42% (n?=?30/71) of those residents completed the formative bedside feedback. The intervention demonstrated a 33% increase of observable behaviors (p?0.001) with improvement in all eight skill categories, compared with the control who only showed improvement in five. Intervention residents demonstrated improved confidence in performing all elicited communication skills such as express empathy, elicit values, and manage uncertainty (p?

Wild boar (Sus scrofa L.) is one of the most discussed game species, distributed across Europe, therefore the management of this species is considered important. This management should be based on data presented, population quality and preferences and craniometric dimensions show the development of the individual and its prosperity. A sample of 148 male and 153 female wild boar mandibles was studied to compare differences in craniometric measurements, especially to find out wild boar environmental demands and population trends. The width of the caput mandibulae and angle of the mandible showed significant difference between males and females. Measurements analysed with forest area size and other data also showed that larger craniometric dimensions were reached in hunting areas with at least 200 ha of forested area, which may be due to the wild boar's need for safety and vegetative cover in the first months of piglet development with respect to its home range. The development of young wild boar is dependent on rest and shelter in the first months of life. A forest cover of at least 200 ha appears to be sufficient in this respect. Information on habitat preferences and individual development can lead to improvements in wild boar management.