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Abstract Background The aim of the study was to evaluate the effectiveness of a novel e-learning module in teaching the physical exam of the temporomandibular joint (TMJ) in Juvenile idiopathic arthritis (JIA.). Methods An e-learning module was developed to convey the TMJ physical examination maneuvers that are considered to be best practice in JIA. Pediatric rheumatology fellows were randomized to two groups. One group received an article describing the physical examination skills while the second group received both the article and module. All participants completed a written pre-test, an in-person objective structured clinical examination (OSCE), a written post-test, and a follow-up survey. Results Twenty-two pediatric rheumatology fellows enrolled, with 11 per group. Written test: The two groups improved equally, although there was a trend toward improved defining of maximal incisal opening (MIO) in the module group. OSCE: The mean OSCE score was 11.1 (SD 3.3) in the article group and 13.5 (SD 1.9) in the module group (p = 0.06); significant differences were seen in measuring MIO (p = 0.01), calculating maximal unassisted mouth opening (MUMO; p = 0.01), and assessment of facial symmetry (p = 0.03), all favoring the module. Enjoyment scores in the module group were higher than in the article group (mean 7.7/10 vs. 5.9/10, p = 0.02). The two groups self-reported performing TMJ examinations at comparable rates three months following the intervention. Conclusions The study demonstrated that a formalized educational program improved knowledge of the physical exam of the TMJ in JIA. Learners viewing the module were more adept at obtaining quantitative TMJ measurements.

Serum levels of the tumor marker CA 19–9 are widely utilized in the diagnosis and monitoring pancreatic and biliary malignancies. However, serum levels of CA 19–9 have also been reportedly elevated in non-malignant conditions. Here, we present the rare case of a 65-year-old woman with a history of gallbladder malignancy who was found to have a new hepatic lesion on surveillance CT with an associated elevation in CA 19–9 to 5,866 U/mL. Drainage of the lesion and treatment with antibiotics resulted in a rapid decline in CA 19–9 levels, indicating that the elevation in CA 19–9 was due to a benign hepatic lesion. We review eight similar reported cases of CA 19–9 elevations due to benign hepatic abscesses, thereby highlighting a need to interpret the tumor marker with caution.

Purpose: To describe the visual acuity (VA) outcomes from a telemedicine-enabled pathway allowing for rapid diagnosis and administration of intravenous (IV) thrombolytic treatment for non-arteritic central retinal artery occlusion (naCRAO) within 4.5 hours (4.5 h) of visual loss. Design: Retrospective observational case series. Methods: Setting: A large managed healthcare consortium.Patient Population: Eighty-five patients with naCRAO and vision loss for less than 4.5 h presenting between 2021 and 2023. Thirty-five patients received IV thrombolytic therapy and 50 patients were closely observed.Intervention: A collaborative telemedicine-enabled pathway employing fundus photography was previously established by Ophthalmology, Emergency Medicine, and Stroke services to rapidly evaluate and manage patients presenting with acute painless monocular vision loss and allow for administration of IV tenecteplase (0.25 mg/kg) for eligible consenting patients diagnosed with naCRAO within 4.5 h. Retrospective chart review was conducted to collect data on demographics, vascular risk factors, clinical features, VA outcomes, and adverse events. Comparison was made between patients who received intravenous thrombolysis and those who were observed.Main Outcome Measures: Improvement in VA of at least 0.3 logarithm of the minimum angle of resolution (logMAR) and/or from 20/200 or worse to 20/100 or better. Results: A greater percentage of patients in the treated group had VA improvement of ≥0.3 logMAR (54.3 % vs 28 %, p = .014), and a greater percentage of patients in the untreated group had VA worsening of ≥0.3 logMAR (30 % vs 5.7 %, p = .006). Twice the percentage of treated versus untreated patients had improved VA from 20/200 or worse to 20/100 or better, but this difference was not statistically significant (20 % vs 10 %, p = .192). There was a significantly shorter mean time to treatment for those patients who had VA improvement from 20/200 or worse to 20/100 or better compared to those who did not (118 versus 171 min, p = .031). Two patients experienced intracranial bleeding after IV thrombolysis. Conclusions: The evaluation and treatment of hyperacute naCRAO is possible on a large scale via an integrated telemedicine-enabled approach utilizing fundus photography. The use of IV thrombolytic was associated with better VA outcomes compared to observation alone. Prospective randomized controlled trials are needed to confirm these findings and determine optimal management.

Primary school pupils have difficulty making accurate judgments of learning (JOL) in a digital environment. In two studies, we examined the contribution of metacognitive self-questioning to JOL accuracy in the course of reading literacy (Study 1) and mathematical literacy (Study 2) digital learning programs. Both studies comprised a six-session intervention. In each session fifth-grade students studied a short text (Study 1, N = 65) or story containing mathematical components (Study 2, N = 72), then judged their comprehension by predicting their performance before completing a test. For the experimental groups, metacognitive questioning was incorporated into the study materials. In both studies the experimental groups improved over the six sessions in both performance and calibration (i.e., reducing the gap between judgment and performance). The findings highlight the contribution of metacognitive support to improved performance and judgment accuracy and strengthen the case for incorporating metacognitive practices when teaching literacy in a digital environment.

This paper focuses on how first-generation Bahá’ís view dreams and visions as confirming their choice to become Bahá’í. It presents life story interviews, highlighting the significance of their dream narratives in religious conversion. The study emphasizes that these dreams integrate their prior religious identity, mainly through the appearance of messengers of God serving as supernatural agents, which conforms to Bahá’í beliefs in progressive revelation. It advocates for anthropological attention to Bahá’í dream accounts, presenting dreams as premonitions or encouragements for conversion and acknowledging leaving a previous faith. The paper calls for investigating dreams’ bridging function, viewed by converts as a nonhuman and non-institutional force aiding conversion. It aims to explore agency in dreams concerning religious conversion by analyzing dream accounts from first-generation Bahá’ís’ life stories, illustrating how dreams influence and transform individual beliefs.

Abstract Primary Health Care (PHC) is the most equitable and cost-effective way to enhance the health of populations and improve health security and is a requirement for achieving universal health coverage (UHC). Vital to advancing the PHC agenda is effective global health partnerships, particularly with Global Health Initiatives (GHIs) which provide financial support for improving population health. Despite progress, GHI support at times remained parallel to rather than embedded in national health strategies. To improve the impact of GHI support, World Health Organization (WHO) member states requested specific guidance to better align GHI support to national health strategies and PHC principles. We present the PHC-GHI Toolbox as a comprehensive set of resources for use by countries to apply the PHC approach to development of plans for securing and optimally utilizing funding received from GHIs, such as Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM); and the Global Financing Facility (GFF) as well as other donors. The PHC-GHI Toolbox includes a PHC resource database, GHI-specific overviews, a database of health system strengthening (HSS) investments, COVID-19 funding rapid assessment tool, and a focal point database for identifying expert technical assistance. This paper describes the process undertaken for Toolbox development and outlines its potential applications.

Religious conversion is a phenomenon that has intrigued scholars, theologians, and sociologists for centuries. As the conscious choice of a particular form of religion over another, it is eminently a form of religious contact. Religious conversion may be approached psychologically, sociologically, and conceptually. The contributions of this special issue show all three approaches and cover a wide array of geographical, social, and religious contexts.

Aims: Individuals of African ancestry (AA) present with lower insulin sensitivity compared to their European counterparts (EA). Studies show ethnic differences in skeletal muscle fiber type (lower type I fibers in AA), muscle fat oxidation capacity (lower in AA), whilst no differences in total skeletal muscle lipids. However, skeletal muscle lipid subtypes have not been examined in this context. We hypothesize that lower insulin sensitivity in AA is due to a greater proportion of type II (non-oxidative) muscle fibers, and that this would result in an ancestry-specific association between muscle lipid subtypes and peripheral insulin sensitivity. To test this hypothesis, we examined the association between insulin sensitivity and muscle lipids in AA and EA adults, and in an animal model of insulin resistance with muscle-specific fiber types. Methods: In this cross-sectional study, muscle biopsies were obtained from individuals with a BMI ranging from normal to overweight with AA (N = 24) and EA (N = 19). Ancestry was assigned via genetic admixture analysis; peripheral insulin sensitivity via hyperinsulinaemic–euglycemic clamp; and myofiber content via myosin heavy chain immunohistochemistry. Further, muscle types with high (soleus) and low (vastus lateralis) type I fiber content were obtained from high-fat diet-induced insulin resistant F1 mice and littermate controls. Insulin sensitivity in mice was assessed via intraperitoneal glucose tolerance test. Mass spectrometry (MS)-based lipidomics was used to measure skeletal muscle lipid. Results: Compared to EA, AA had lower peripheral insulin sensitivity and lower oxidative type 1 myofiber content, with no differences in total skeletal muscle lipid content. Muscles with lower type I fiber content (AA and vastus from mice) showed lower levels of lipids associated with fat oxidation capacity, i.e., cardiolipins, triacylglycerols with low saturation degree and phospholipids, compared to muscles with a higher type 1 fiber content (EA and soleus from mice). Further, we found that muscle diacylglycerol content was inversely associated with insulin sensitivity in EA, who have more type I fiber, whereas no association was found in AA. Similarly, we found that insulin sensitivity in mice was associated with diacylglycerol content in the soleus (high in type I fiber), not in vastus (low in type I fiber).Conclusions; Our data suggest that the lipid contribution to altered insulin sensitivity differs by ethnicity due to myofiber composition, and that this needs to be considered to increase our understanding of underlying mechanisms of altered insulin sensitivity in different ethnic populations.

Abstract Background In Israel there are only 6.53 nurses per 1000 citizens, compared to 8.8 nurses per 1000 citizens in the OECD countries. The nursing shortage is even more severe in peripheral areas, especially in southern Israel. Nurses` professional satisfaction is crucial for preserving the nursing workforce. This study aimed to assess job satisfaction among novice nurses and identify components of professional satisfaction. Methods Cross-sectional study of 216 novice nurses who graduated in 2018–2022 and were approached ten months after graduation. Job satisfaction components were constructed using factor analysis. Results Professional satisfaction was based mainly on the intrinsic characteristics of the occupation related to personal accomplishment and organizational culture. In a multivariable model, a one-point increase in mean satisfaction with the training period during studies in the nursing department was associated with a more than a three-fold elevation in the odds for high and very high professional satisfaction (OR 3.0, 95% CI 1.7–5.1). Odds for high and very high professional satisfaction were more than four-fold and two-fold higher among graduates who rated their level of control over work schedule as high and medium vs. low (OR 4.2, 95% CI 1.0–16.7 and OR 2.8, 95% CI 1.2–6.3, respectively). Work-life balance without disturbance to daily life by work was found significantly associated with higher odds for high and very high satisfaction. Nurses who plan to continue professional development, i.e., an advanced professional course or Master’s degree, had significantly higher mean professional satisfaction scales than others (4.2 vs. 3.7, p = .009 and 4.2 vs. 3.9, p

Osteosarcoma treatment comprises pre-surgical chemotherapy followed by radical surgery and further chemotherapy cycles, but the prognosis has been far from satisfactory. No new drugs or treatment modalities have been developed for clinical use in the last four decades. We describe a nano-hydroxyapatite (HA)-based local drug delivery platform for the delivery of doxorubicin (DOX), a cornerstone drug in osteosarcoma treatment. The efficacy of the developed drug delivery system was evaluated in an orthotopic human osteosarcoma xenograft in the proximal tibia of mice. After tumor development, the tumor was surgically resected and the void filled with the following: (1) No treatment (G1); (2) nHA only (G2); (3) DOX-loaded nHA (G3). In-vivo tumor response was assessed by evaluating the tumor-induced osteolysis at 2 weeks using micro-CT followed by in-vivo PET-CT at 3 weeks and ex-vivo micro-CT and histology. Micro-CT imaging revealed complete destruction of the tibial metaphysis in groups G1 and G2, while the metaphysis was protected from osteolysis in G3. PET-CT imaging using 18F-FDG revealed high metabolic activity in the tumors in G1 and G2, which was significantly reduced in G3. Using histology, we were able to verify that local DOX delivery reduced the bone destruction and the tumor burden compared with G1 and G2. No off-target toxicity in the vital organs could be observed in any of the treatment groups histologically. This study describes a novel local drug adjuvant delivery approach that could potentially improve the prognosis for patients responding poorly to the current osteosarcoma treatment.

Abstract Dynamic interactions of neurons and glia in the ventral midbrain mediate reward and addiction behavior. We studied gene expression in 212,713 ventral midbrain single nuclei from 95 individuals with history of opioid misuse, and individuals without drug exposure. Chronic exposure to opioids was not associated with change in proportions of glial and neuronal subtypes, however glial transcriptomes were broadly altered, involving 9.5 − 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes. Genes associated with activation of the immune response including interferon, NFkB signaling, and cell motility pathways were upregulated, contrasting with down-regulated expression of synaptic signaling and plasticity genes in ventral midbrain non-dopaminergic neurons. Ventral midbrain transcriptomic reprogramming in the context of chronic opioid exposure included 325 genes that previous genome-wide studies had linked to risk of substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry.

Abstract A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.

Abstract Background Partial Tonsillectomy (PT) is an alternative method to treat sleep disordered breathing (SDB) and/or obstructive sleep apnea (OSA). The current guidelines do not differentiate it from traditional tonsillectomy. Thus, children younger than 3 years old undergoing PT are admitted for surveillance similar to traditional tonsillectomy due to possible postoperative complications. The aim of this study is to assess the risks of PT in children 3 years old and younger, compared to older children. Methods Children underwent inpatient partial tonsillectomy and/or adenoidectomy, due to SDB/OSA, from 2018 to 2020. A special protocol was designed, including follow-up at 2-, 4-, 6-, 8- and 24-h after surgery. Variables analyzed included visual analogue pain score, oral intake, oxygen saturation, pulse rate, postoperative hemorrhage, urine output, temperature, analgesics and fluid administration. Furthermore, major interventions were recorded. Comparison of all variables between children younger than 3 years old with older children was performed. Results Ninety-two children were included; mean age of the whole cohort was 44.5 ± 21.9 months. Thirty-five (38%) children were 3-years old or younger and n = 57 (62%) were older than 3 years old, with no significant statistical difference in sex (p = 0.22). Mean age in the younger group was 25.7 ± 6.9 months, and 56.1 ± 20.1 months in the older group. In total we had 7 children with post-operative complications; 4 with fever, 3 with low intake. There were no major interventions recorded in either group. The complications were more common in the older group (n = 5) than the younger group (n = 2) without a statistical significance (p = 0.59). There were no differences in VAS, use of painkillers, oral intake, urine output, oxygen saturation and tachycardia among the two groups. Conclusion This study supports that children undergoing ambulatory PT may be at low risk of complications, regardless of age. Graphical abstract

Abstract Background and objective Evidence for the treatment of multisystem inflammatory syndrome in children (MIS-C) is lacking. Anakinra, which targets IL-1-mediated inflammation, is reserved for refractory cases of MIS-C; however, its use in the treatment of MIS-C is not clearly established. Patients and methods To examine a role for anakinra in MIS-C, we performed a single center observational cohort study of all MIS-C patients diagnosed at our children’s hospital from May 15 to November 15, 2020. Demographics, clinical features, diagnostic testing, and cardiac function parameters were compared between MIS-C patients treated with intravenous immunoglobulin (IVIG) monotherapy and IVIG with anakinra (IVIG + anakinra). Results Among 46 patients with confirmed MIS-C, 32 (70%) were in the IVIG + anakinra group, of which 9 (28%) were also given corticosteroids (CS). No patients were treated with anakinra alone. MIS-C patients in the IVIG + anakinra group were enriched in a CV shock phenotype (p = 0.02), and those with CV shock were treated with higher doses of anakinra for a longer duration. Furthermore, MIS-C patients in the IVIG + anakinra group exhibited improvements in fever and cardiac function with or without CS. No significant adverse events were observed, and no differences in IL-1β levels were found among MIS-C patients in the IVIG + anakinra group. Conclusions Anakinra treatment, which was co-administered with IVIG primarily in patients with severe MIS-C, was associated with improvements in fever and cardiac function, and demonstrated a favorable side-effect profile. These findings suggest a role for adjunctive anakinra in the treatment of severe MIS-C.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures. Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled “Reverse Engineering of Digital Measures,” was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools. Key Messages: In this paper, we discuss progress and the remaining barriers to widespread use of digital measures for evidence generation in clinical development and care delivery. We also present key discussion points and takeaways in order to continue discourse and provide a basis for dissemination and outreach to the wider community and other stakeholders. The work presented here shows us a blueprint for how and why the patient voice can be thoughtfully integrated into digital measure development and that continued multistakeholder engagement is critical for further progress.

This study compared two professional training courses targeting self-regulated learning (SRL) amongst preservice secondary science teachers in the context of didactic content knowledge for teaching higher-order thinking (HOT-PCK), either with metacognitive scaffolding (Meta group) or without (Control group). Measures included trainees' comprehension and design of HOT-PCK learning tasks, online SRL reflections about learning-teaching events, and self-reported SRL aptitude. Results indicated skill improvement in both groups, but the metacognitive support provided by the IMPROVE self-questioning technique better enhanced the preservice teachers’ (PSTs) development of HOT-PCK, both as students (comprehension skills) and as future teachers (design skills), additionally as their ability to reflect on and control their studying. Findings also revealed significant correlations between SRL assessments (self-reports, event-based reflections) and between SRL and HOT-PCK indices. Consequences for teacher education combining SRL and HOT-PCK contexts are discussed.

Background: Epstein-Barr virus (EBV) is a common human Herpesvirus with worldwide distribution. Primary EBV infection usually occurs early in life and typically presents as infectious mononucleosis consisting of fever, pharyngitis, hepatosplenomegaly, and lymphadenopathy. Usually, the disease course is benign and most patients recover uneventfully without any consequent sequel. Method and results: We present a case of an immunologically normal young male in whom an acute EBV infection caused severe pneumonitis. He was treated empirically with Paracetamol, intravenous Ceftriaxone 1 gr/day plus Azithromycin 500 mg/day. Conclusion: EBV-associated pneumonitis is rare, and treatment is usually supportive, whether antiviral agents (such as acyclovir) or steroids would be beneficial remains to be determined.

IntroductionPhysical Activity (PA) levels for individuals with spinal cord injury (SCI) peak during rehabilitation and sharply decline post-discharge. The ProACTIVE SCI intervention has previously demonstrated very large-sized effects on PA; however, it has not been adapted for use at this critically understudied timepoint. The objective is to evaluate the reach, effectiveness, adoption, implementation, and maintenance of the ProACTIVE SCI intervention delivered by physiotherapists and SCI peer coaches during the transition from rehabilitation to community.MethodsA single-group, within-subjects, repeated measures design was employed. The implementation intervention consisted of PA counseling training, champion support, prompts and cues, and follow-up training/community of practice sessions. Physiotherapists conducted counseling sessions in hospital, then referred patients to SCI peer coaches to continue counseling for 1-year post-discharge in the community. The RE-AIM Framework was used to guide intervention evaluation.ResultsReach: 82.3% of patients at the rehabilitation hospital were reached by the intervention. Effectiveness: Interventionists (physiotherapists and SCI peer coaches) perceived that PA counseling was beneficial for patients. Adoption: 100% of eligible interventionists attended at least one training session. Implementation: Interventionists demonstrated high fidelity to the intervention. Intervention strategy highlights included a feasible physiotherapist to SCI peer coach referral process, flexibility in timepoint for intervening, and time efficiency. Maintenance: Ongoing training, PA counseling tracking forms, and the ability to refer to SCI peer coaches at discharge are core components needed to sustain this intervention.DiscussionThe ProACTIVE SCI intervention was successfully adapted for use by physiotherapists and SCI peer coaches during the transition from rehabilitation to community. Findings are important for informing intervention sustainability and scale-up.

An essential step in devising measures to improve road safety is road accident prediction. In particular, it is important to identify the risk factors that increase the likelihood of severe injuries in the event of an accident. There are two distinct ways of analyzing data in order to produce predictions: machine learning and statistical methods. This study explores the severity of road traffic injuries sustained by pedestrians through the use of machine-learning methodology.In general, the goal of the statistician is to model and understand the connections between variables, whereas machine learning focuses on more intricate and expansive datasets, with the aim of creating algorithms that can recognize patterns and make predictions without being explicitly programmed. The ability to handle very large datasets constitutes a distinct advantage of machine learning over statistical techniques. In addition, machine-learning models can be adapted to a wide range of data sources and problem domains, and can be utilized for numerous tasks, from image identification to natural language processing. Machine-learning models may be taught to recognize patterns and make predictions automatically, minimizing the need for manual involvement and enabling rapid data processing of enormous quantities of data. The use of new data to retrain or fine-tune a machine-learning model allows the model to adapt to changing conditions and enhances its accuracy over time. Finally, while non-linear interactions between variables can be difficult to predict using conventional statistical techniques, they can be recognized by machine-learning models.The study begins by compiling an inventory of features linked to both the accident and the environment, focusing on those that exert the greatest influence on the severity of pedestrian injuries. The “optimal” algorithm is then chosen based on its superior levels of accuracy, precision, recall, and F1 score. The developed model should not be regarded as fixed; it should be updated and retrained on a regular basis using new traffic accident data that mirror the evolving interplay between the road environment, driver characteristics, and pedestrian conduct. Having been constructed using Israeli data, the current model is predictive of injury outcomes within Israel. For broader applicability, the model should undergo retraining and reassessment using traffic accident data from the pertinent country or region.

Abstract In this work, we consider the case of a strongly coupled dark/hidden sector, which extends the Standard Model (SM) by adding an additional non-Abelian gauge group. These extensions generally contain matter fields, much like the SM quarks, and gauge fields similar to the SM gluons. We focus on the exploration of such sectors where the dark particles are produced at the LHC through a portal and undergo rapid hadronization within the dark sector before decaying back, at least in part and potentially with sizeable lifetimes, to SM particles, giving a range of possibly spectacular signatures such as emerging or semi-visible jets. Other, non-QCD-like scenarios leading to soft unclustered energy patterns or glueballs are also discussed. After a review of the theory, existing benchmarks and constraints, this work addresses how to build consistent benchmarks from the underlying physical parameters and present new developments for the pythia Hidden Valley module, along with jet substructure studies. Finally, a series of improved search strategies is presented in order to pave the way for a better exploration of the dark showers at the LHC.

Although the value of patient and public involvement and engagement (PPIE) activities in the development of new interventions and tools is well known, little guidance exists on how to perform these activities in a meaningful way. This is particularly true within large research consortia that target multiple objectives, include multiple patient groups, and work across many countries. Without clear guidance, there is a risk that PPIE may not capture patient opinions and needs correctly, thereby reducing the usefulness and effectiveness of new tools. Mobilise-D is an example of a large research consortium that aims to develop new digital outcome measures for real-world walking in 4 patient cohorts. Mobility is an important indicator of physical health. As such, there is potential clinical value in being able to accurately measure a person’s mobility in their daily life environment to help researchers and clinicians better track changes and patterns in a person’s daily life and activities. To achieve this, there is a need to create new ways of measuring walking. Recent advancements in digital technology help researchers meet this need. However, before any new measure can be used, researchers, health care professionals, and regulators need to know that the digital method is accurate and both accepted by and produces meaningful outcomes for patients and clinicians. Therefore, this paper outlines how PPIE structures were developed in the Mobilise-D consortium, providing details about the steps taken to implement PPIE, the experiences PPIE contributors had within this process, the lessons learned from the experiences, and recommendations for others who may want to do similar work in the future. The work outlined in this paper provided the Mobilise-D consortium with a foundation from which future PPIE tasks can be created and managed with clearly defined collaboration between researchers and patient representatives across Europe. This paper provides guidance on the work required to set up PPIE structures within a large consortium to promote and support the creation of meaningful and efficient PPIE related to the development of digital mobility outcomes.

Abstract Background Urologic chronic pelvic pain syndrome (UCPPS) encompasses several common, costly, diagnoses including interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome that are poorly understood and inadequately treated with conventional medical therapies. Behavioral strategies, recommended as a first-line treatment for managing symptoms, are largely inaccessible, time and labor intensive, and technically complex. The Easing Pelvic Pain Interventions Clinical Research Program (EPPIC) is a clinical trial examining the efficacy of low-intensity cognitive behavioral therapy (Minimal Contact CBT or MC-CBT) for UCPPS and its durability 3 and 6 months post treatment. Additional aims include characterizing the operative processes (e.g., cognitive distancing, context sensitivity, coping flexibility, repetitive negative thought) that drive MC-CBT-induced symptom relief and pre-treatment patient variables that moderate differential response. Methods UCPPS patients (240) ages 18–70 years, any gender, ethnicity, and race, will be randomized to 4-session MC-CBT or a credible, non-specific education comparator (EDU) that controls for the generic effects from simply going to treatment. Efficacy assessments will be administered at pre-treatment, 2 weeks, and 3 and 6 months post treatment-week acute phase. A novel statistical approach applied to micro-analytic mediator assessment schedule will permit the specification of the most effective CBT component(s) that drive symptom relief. Discussion Empirical validation of a low-intensity self-management therapy transdiagnostic in scope has the potential to improve the health of chronic pelvic pain patients refractory to medical therapies, reduce social and economic costs, conserve health care resources, as well as inform evidence-based practice guidelines. Identification of change mechanisms and moderators of treatment effects can provide proactive patient-treatment matching fundamental to goals of personalized medicine. Trial Registration Clinicaltrials.gov NCT05127616. Registered on 9/19/21.

Predicting the severity of injuries caused by traffic accidents is an important undertaking because it may lead to establishing regulations increasing road-user safety. Bicyclists are a particularly susceptible category of road users, which is especially troubling considering the environmental, financial, and health benefits of this mode of transportation. As a result, this study aims to apply machine learning to identify risk variables that may result in serious biker injuries in the case of an accident.Machine-learning models make no assumptions about the connections between variables. Hence, it has been argued that machine-learning approaches produce better outcomes than statistical procedures. This study selects the “best” machine-learning classification system from a vast pool of similar algorithms to predict the severity of bicycling injuries. Machine learning allows the system to learn from experience and improve without being too programmed.We first use a variety of feature selection algorithms to identify a list of features related to the accident and the environment that have the greatest impact on the severity of bicyclist injuries. This feature list is then used as input data to various machine-learning algorithms that predict the class of bicyclist injury severity at one of three levels (fatal, serious, and slight). The “best” machine-learning algorithm is identified on the basis of having the highest levels of accuracy, precision, recall, and F1 score. The current models were developed and trained based on Israeli road-traffic accident data from 2009 to 2019, meaning that new models would need to be developed for other geographical locations. In addition, the models would need to be updated to take account of the changing relationships between motorists, bicyclists, and the environment. Nevertheless, the proposed methodology has universal applicability.

Abstract The translation of research findings into clinical practice is challenging, especially fields like in pediatric rheumatology, where the evidence base is limited, there are few clinical trials, and the conditions are rare and heterogeneous. Implementation science methodologies have been shown to reduce the research- to- practice gap in other clinical settings may have similar utility in pediatric rheumatology. This paper describes the key discussion points from the inaugural Childhood Arthritis and Rheumatology Research Alliance Implementation Science retreat held in February 2020. The aim of this report is to synthesize those findings into an Implementation Science Roadmap for pediatric rheumatology research. This roadmap is based on three foundational principles: fostering curiosity and ensuring discovery, integration of research and quality improvement, and patient-centeredness. We include six key steps anchored in the principles of implementation science. Applying this roadmap will enable researchers to evaluate the full range of research activities, from the initial clinical design and evidence acquisition to the application of those findings in pediatric rheumatology clinics and direct patient care.

Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to pediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behavior of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn’s disease, a non-histiocytic inflammatory disease. We observed that interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endo- and exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate extracellular vesicles in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumor niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.

Objectives While service integration has gained prominence as an objective of many global initiatives, there is no widely recognised single definition of integration nor a clear understanding of how programmes are integrated into health systems to achieve improved health outcomes. This study aims to review measurement approaches for integrated antenatal care (ANC) services, propose and operationalise indicators for measuring ANC service integration and inform an integrated ANC indicator recommendation for use in low-income and middle-income countries (LMICs).Design Feasibility study.Setting Burkina Faso, Kenya, Malawi, Senegal and Sierra Leone.Methods Our six-step approach included: (1) conceptualise ANC service integration models; (2) conduct a targeted literature review on measurement of ANC service integration; (3) develop criteria for ANC service integration indicators; (4) propose indicators for ANC service integration; (5) use extant data to operationalise the indicators; and (6) synthesise information to make an integrated ANC indicator recommendation for use in LMICs.Results Given the multidimensionality of integration, we outlined three models for conceptualising ANC service integration: integrated health systems, continuity of care and coordinated care. Looking across ANC service integration estimates, there were large differences between estimates for ANC service integration depending on the model used, and in some countries, the ANC integration indicator definition within a model. No one integrated ANC indicator was consistently the highest estimate for ANC service integration. However, continuity of care was consistently the lowest estimate for ANC service integration.Conclusions Integrated ANC services are foundational to ensuring universal health coverage. However, our findings demonstrate the complexities in monitoring indicators of ANC service quality using extant data in LMICs. Given the challenges, it is recommended that countries focus on monitoring measures of service quality. In addition, efforts should be made to improve data collection tools and routine health information systems to better capture measures of service integration.

Antologin Reforming Child Welfare in the Post-Soviet Space: Institutional Change in Russia behandlar Rysslands satsning under senare år på att etablera ett fosterhemssystem i stället för de ökända institutionerna för omhändertagna barn. Den praktiska implementeringen redogörs för från olika aktörers perspektiv, myndighets- och NGO-personal såväl som fosterföräldrar och barn, med fokus både på institutionella bromsklossar och reformens mer välfungerande aspekter.

Objective To explore UK public decisions around whether or not to get COVID-19 vaccines, and the facilitators and barriers behind participants’ decisions. Design This qualitative study consisted of six online focus groups conducted between 15th March and 22nd April 2021. Data were analysed using a framework approach. Setting Focus groups took place via online videoconferencing (Zoom). Participants Participants (n = 29) were a diverse group (by ethnicity, age and gender) UK residents aged 18 years and older. Results We used the World Health Organization’s vaccine hesitancy continuum model to look for, and explore, three main types of decisions related to COVID-19 vaccines: vaccine acceptance, vaccine refusal and vaccine hesitancy (or vaccine delay). Two reasons for vaccine delay were identified: delay due to a perceived need for more information and delay until vaccine was “required” in the future. Nine themes were identified: three main facilitators (Vaccination as a social norm; Vaccination as a necessity; Trust in science) and six main barriers (Preference for “natural immunity”; Concerns over possible side effects; Perceived lack of information; Distrust in government;; Conspiracy theories; “Covid echo chambers”) to vaccine uptake. Conclusion In order to address vaccine uptake and vaccine hesitancy, it is useful to understand the reasons behind people’s decisions to accept or refuse an offer of a vaccine, and to listen to them and engage with, rather than dismiss, these reasons. Those working in public health or health communication around vaccines, including COVID-19 vaccines, in and beyond the UK, might benefit from incorporating the facilitators and barriers found in this study.

Purpose: Exome sequencing (ES) is a powerful tool that facilitates the diagnosis of patients with rare Mendelian syndromes. In 2018 the Israeli Ministry of Health initiated a national pilot program that funds ES for outpatients with global developmental delay (GDD). Here, we describe the 3-year impact of this program on patient care in a single tertiary hospital. Methods: From 2018 to 2020, trio ES was performed on 170 participants fulfilling Israeli Ministry of Health criteria: (1) moderate to severe GDD and (2) mild GDD with epilepsy or a major congenital anomaly. We retrospectively analyzed this cohort. Results: A diagnosis was achieved in 74 individuals (43%). There were 82 clinically significant variants, the majority being novel. Consanguinity was reported in 22% and was not associated with a higher diagnostic rate. The presence of autism spectrum was associated with a lower diagnostic rate of 8/33 (24%). Autosomal dominant inheritance was identified in 14% of participants, and the parental phenotype ranged between fully affected and asymptomatic. Among the diagnosed participants, 16% had an unexpected diagnosis that did not fit the typical clinical presentation. In 9%, the diagnosis changed short-term active clinical management, in 19%, the surveillance recommendations, and in 23%, the family-focused outcomes. Conclusion: The introduction of a national program that funds ES for GDD has transformed patient care, leading to a significant effect on medical management and treatment. The high rate of an unexpected inheritance mode and variable phenotypes emphasizes the diagnostic complexity of neurodevelopmental disorders and the strength of a non-targeted approach.

Hydroxyapatite (HA) has been widely used as a bone substitute and more recently as a carrier for local delivery of bone targeted drugs. Majority of the approved HA based biomaterials and drug carriers comprise of micrometer sized particulate HA (mHA) or granules and can therefore only be used for extracellular drug release. This shortcoming could be overcome with the use of cell penetrating HA nanoparticles (nHA) but a major concern with the clinical use of nHA is the lack of data on its in vivo biodistribution after implantation. In this study, we aimed to study the in vivo biodistribution of locally implanted nHA in a clinically relevant tibial void in rats and compare it with mHA or a combination of mHA and nHA. To enable in vivo tracking, HA particles were first labelled with 14C-zoledronic acid (14C-ZA), known to have a high binding affinity to HA. The labelled particles were then implanted in the animals and the radioactivity in the proximal tibia and vital organs was detected at various time points (Day 1, 7 and 28) post-implantation using scintillation counting. The local distribution of the particles in the bone was studied with micro-CT. We found that majority (>99.9%) of the implanted HA particles, irrespective of the size, stayed locally at the implantation site even after 28 days and the findings were confirmed using micro-CT. Less than 0.1% radioactivity was observed in the kidney and the spleen at later time points of day 7 and 28. No pathological changes in any of the vital organs could be observed histologically. This is the first longitudinal in vivo HA biodistribution study showing that the local implantation of nHA particles in bone is safe and that nHA could potentially be used for localized drug delivery.

High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.

PurposeEmpathy has been widely theorized as an important ability in professions such as policing, in which to perform well individuals require multiple and interacting abilities, not least when resolving conflict situations. Even so, there are few studies investigating how subconstructs of empathy relate to other constructs such as general cognitive ability. The purpose of this paper is to establish, after evaluating psychometric properties, relationships among measures of empathy and cognitive ability in a sample of Swedish police students (n = 157).Design/methodology/approachMultiple latent variable models of how the different measures work to predict tasks that can be seen as proxies for the ability to understand another person’s situation and intentions are evaluated to determine the most robust relationship(s) within the data.FindingsWe find support for the psychometric properties reported in previous studies with the used instruments. We also find support for perspective-taking, a cognitive empathy subconstruct predicting the ability to recognize emotions, and also the affective part of empathy, predicting general cognitive ability. These findings are discussed at length in the paper.Originality/valueThis research adds more knowledge to the issue of how general cognitive ability relates to cognitive empathy and other subconstructs of empathy or Theory of Mind.

T cells expressing chimeric antigen receptors (CARs) are at the forefront of clinical treatment of cancers. Still, the nanoscale organization of CARs at the interface of CAR-Ts with target cells, which is essential for TCR-mediated T cell activation, remains poorly understood. Here, we studied the nanoscale organization of CARs targeting CD138 proteoglycans in such fixed and live interfaces, generated optimally for single-molecule localization microscopy. CARs showed significant self-association in nanoclusters that was enhanced in interfaces with on-target cells (SKOV-3, CAG, FaDu) relative to negative cells (OVCAR-3). CARs also segregated more efficiently from the abundant membrane phosphatase CD45 in CAR-T cells forming such interfaces. CAR clustering and segregation from CD45 correlated with the effector functions of Ca++ influx and target cell killing. Our results shed new light on the nanoscale organization of CARs on the surfaces of CAR-Ts engaging on- and off-target cells, and its potential significance for CAR-Ts’ efficacy and safety.

As various regions around the world implement carbon taxes, we assert that the competitiveness of steel products in the marketplace will shift according to individual manufacturers’ ability to reduce CO2 emissions as measured by cradle-to-gate Life Cycle Analysis (LCA). This study was performed by using LCA and cost estimate research to compare the CO2 emissions and the additional cost applied to the production of various decarbonized materials used in sheet for automotive industry applications using the bending stiffness-based weight reduction factor. The pre-pandemic year 2019 was used as a baseline for cost estimates. This paper discusses the future cost scenarios based on carbon taxes and hydrogen cost. The pathways to decarbonize steel and alternative materials such as aluminum and reinforced polymer composites were evaluated. Normalized global warming potential (nGWP) estimates were calculated assuming inputs from the current USA electricity grid, and a hypothetical renewables-based grid. For a current electricity grid mix in the US (with 61% fossil fuels, 19% nuclear, 20% renewables), the lowest nGWP was found to be secondary aluminum and 100% recycled scrap melting of steel. This is followed by the natural gas Direct Reduced Iron–Electric Arc Furnace (DRI-EAF) route with carbon capture and the Blast Furnace-Basic Oxygen Furnace (BF-BOF) route with carbon capture. From the cost point of view, the current cheapest decarbonized production route is natural gas DRI-EAF with Carbon Capture and Storage (CCS). For a renewable electricity grid (50% solar photovoltaic and 50% wind), the lowest GWP was found to be 100% recycled scrap melting of steel and secondary aluminum. This is followed by the hydrogen-based DRI-EAF route and natural gas DRI-EAF with carbon capture. The results indicate that, when applying technologies available today, decarbonized steel will remain competitive, at least in the context of automotive sheet selection compared to aluminum and composites.

Abstract Background Chronic anterior uveitis is a sight-threatening complication of juvenile idiopathic arthritis (JIA) and a primary contributor to long-term morbidity in people with JIA. Levels of knowledge about uveitis among JIA patients and their parents are unknown. A survey of JIA patients and parents was conducted to assess knowledge about uveitis complications and recommended screening. Methods A survey was developed consisting of six demographic questions, six arthritis/uveitis history questions, and nine uveitis knowledge questions. The survey was administered to JIA patients age 14 and older and parents of patients with JIA at three pediatric rheumatology practices and online through the Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) network. ANOVA, chi-square and Fisher’s exact tests were used to look for relationships between survey questions and demographic variables. Results Thirty-three patients and 111 parents completed the survey. Overall, 17.4% reported a history of uveitis, and 89.6% had heard of uveitis. The mean composite knowledge score was 6.46 ± 2.6 out of 9. Patients and parents with a history of uveitis had higher composite knowledge scores than their counterparts without a uveitis history (p = 0.01 and p

This study tested the potential of a technological intervention procedure for promoting letter-naming and initial-phoneme detection skills among preschoolers at risk for Specific Learning Disorder. The study rational is based on evidence for paired associated learning of visual-verbal stimuli, integrated with the use of a tangible technological device (educational floor robot) as means for promoting letter knowledge. Two intervention groups (N = 60) participated. The intervention lasted for eight sessions of phonological training; each dedicated to one target letter. Participants were asked to navigate the robot's path from a current stopping point to the next according to phonological information processing. Both groups went through the same procedure, but using a different type of mat (one with and one without a visual form of the letter). A control group (N = 30) of at-risk preschoolers received no intervention except for their preschool educational routine. We found that children who participated in phonological training with linkage to the visual form of the letter scored higher in post-intervention tests. Among other proposed explanations, we mention the advantages of using a tangible robot and seemingly three-dimensional letters, along with the tendency to consider visual features while processing language stimulus among children with dyslexia.

Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals.Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome.Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder.Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician’s diagnostic toolbox and may aid in facilitating identification of affected individuals.