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Abstract Background Deficient DNA repair and excessive DNA damage contribute to neurodegenerative disease. However, the role of DNA damage and repair in spinal cord injury (SCI) is unclear. SCI, a debilitating disruption of the structural and biological network of the spinal cord, is characterized by oxidative stress. Nevertheless, the pathophysiological mechanisms leading to neuronal loss following SCI remain incompletely defined. Methods: Using a contusion model, a severe SCI was induced at the L1 spinal level in C57Bl/6J mice. The temporal and spatial presence of DNA damage was then determined via immunolabeling for the DNA damage marker, γH2AX, from 1 h post-injury (hpi) to 28 days post-injury (dpi). Results: Our analysis revealed that increased DNA damage foci were present from 1 hpi to 3 dpi in SCI mice relative to controls (sham surgery and naive), with the damage signal spreading over time longitudinally from the affected area to more rostral and caudal regions. Co-labeling of γH2AX with NeuN revealed neuronal specificity of DNA damage, with increased early cell death (pan-nuclear γH2AX) peaking at 1 dpi and apoptosis (cleaved Caspase-3) arising later at 3 dpi. Conclusion: Our study indicates a possible role of DNA damage in neuronal loss following SCI and highlights the need for early interventions targeting DNA repair to preserve neuronal tissue.

Abstract Background Ameloblastoma is the most prevalent odontogenic tumor of the jaw, with a significant recurrence rate. It was conventionally classified radiographically as unilocular or multilocular. As 3D images become more common, there is a need to reassess this classification. This study aimed to conduct a multi-planar assessment of ameloblastoma using CT images, reclassify the lesions based on locularity, and correlate the locularity with imaging characteristics and recurrence. Methods Panoramic radiographs and CT images of histopathologically confirmed 255 ameloblastoma patients were included. The analysis encompassed imaging features including locularity, expansion, thinning, cortical perforation, and root resorption. Image characteristics associated with recurrence rate were examined, and image features were assessed based on locularity. Results On panoramic radiographs, most ameloblastomas (68.6%) were classified as multilocular, while 31.4% were unilocular. The CT scan demonstrated that 46.3% of the ameloblastomas were pseudo-multilocular, 29.4% were unilocular, and 24.3% were multilocular. Multilocular cases on panoramic radiographs often appeared as pseudo-multilocular on CT. Cortical perforation, root resorption, and size were significantly correlated with CT locularity types (p

Abstract Correct classification of type 1 (T1D) and type 2 diabetes (T2D) is challenging due to overlapping clinical features and the increasingly early onset of T2D, particularly in South Asians. Polygenic risk scores (PRSs) for T1D and T2D have been shown to work relatively well in South Asians, despite being derived from largely European-ancestry samples. Here we used PRSs to investigate the rate of potential misclassification of diabetes amongst British Bangladeshis and Pakistanis. Using linked health records from the Genes & Health cohort (n = 38,344) we defined two reference groups meeting stringent diagnostic criteria: 31 T1D cases, 1842 T2D cases, and after excluding these, two further groups: 839 insulin-treated diabetic individuals with ambiguous features and 5174 non-diabetic controls. Combining these with 307 confirmed T1D cases and 307 controls from India, we calculated ancestry-corrected PRSs for T1D and T2D, with which we estimated the proportion of T1D cases within the ambiguous group at ~ 6%, dropping to ~ 4.5% within the subset who had T2D codes in their health records (and are thus most likely to have been misclassified). We saw no significant association between the T1D or T2D PRS and BMI at diagnosis, time to insulin, or the presence of T1D or T2D diagnostic codes amongst the T2D or ambiguous cases, suggesting that these clinical features are not particularly helpful for aiding diagnosis in ambiguous cases. Our results emphasise that robust identification of T1D cases and appropriate clinical care may require routine measurement of diabetes autoantibodies and C-peptide.

Abstract Selecting appropriate buffers is crucial for evaluating the chemical durability of glass under controlled conditions such as in the EPA 1313 test designed to measure elemental release as a function of pH. The efficacy of two alkali-metal free buffers, TRIS (NH2C(CH2OH)3) and ammonium chloride—ammonia (NH3/NH4Cl), was investigated during EPA 1313 testing of a simulated Hanford low-activity waste borosilicate glass in the alkaline regime (pH 8.5–10.5) at varying temperatures (RT, 40 °C, and 60 °C). While both buffers maintained the desired pH at room temperature, and up to 40 °C, the effectiveness of TRIS decreased at elevated temperatures, particularly at pH 10.5. Although 11B NMR showed evidence of TRIS-B complexation, its effect on the rate of elemental release was found to be negligible under the test conditions. With ammonium buffer, the release of alkali cations was slightly elevated when compared to the same conditions with TRIS at early time points.

Abstract Background The rumen fluke, Calicophoron daubneyi, is the major paramphistome species infecting ruminants within Europe. Adult flukes reside within the rumen where they are in direct contact with a unique collection of microorganisms. Here, we report a 1.76-Gb draft genome for C. daubneyi, the first for any paramphistome species. Results Several gene families have undergone specific expansion in C. daubneyi, including the peptidoglycan-recognition proteins (PGRPs) and DM9 domain-containing proteins, which function as pattern-recognition receptors, as well as the saposin-like proteins with putative antibacterial properties, and are upregulated upon arrival of the fluke in the microbe-rich rumen. We describe the first characterisation of a helminth PGRP and show that a recombinant C. daubneyi PGRP binds to the surface of bacteria, including obligate anaerobes from the rumen, via specific interaction with cell wall peptidoglycan. We reveal that C. daubneyi eggshell proteins lack L-DOPA typically required for eggshell crosslinking in trematodes and propose that C. daubneyi employs atypical eggshell crosslinking chemistry that produces eggs with greater stability. Finally, although extracellular digestion of rumen ciliates occurs within the C. daubneyi gut, unique ultrastructural and biochemical adaptations of the gastrodermal cells suggest that adult flukes also acquire nutrients via uptake of volatile fatty acids from rumen fluid. Conclusions Our findings suggest that unique selective pressures, associated with inhabiting a host environment so rich in microbial diversity, have driven the evolution of molecular and morphological adaptations that enable C. daubneyi to defend itself against microorganisms, feed and reproduce within the rumen.

Abstract During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

Abstract Background Falls are a common problem experienced by people living with HIV yet predictive models specific to this population remain underdeveloped. We aimed to identify, assess and stratify the predictive strength of various physiological, behavioral, and HIV-specific factors associated with falls among people living with HIV and inform a predictive model for fall prevention. Methods Systematic review and meta-analysis were conducted to explore predictors of falls in people living with HIV. Data was sourced, screened, extracted, and analyzed by two independent reviewers from eight databases up to January 2nd, 2024, following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocol. Evidence quality and bias were assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and the Mixed Method Appraisal Tool (MMAT), respectively. Pooled odds ratios (OR) with 95% confidence intervals (CI) were computed using random-effects models to establish associations between predictors and falls risk. We applied established criteria (Bradford Hill’s criteria, Rothman’s and Nweke’s viewpoints) to stratify risk factors and create a weighted predictive algorithm. Results This review included 12 studies on falls/balance dysfunction in 117,638 participants (54,513 people living with HIV), with varying ages (45–50 years), sample sizes (32 − 26,373), study durations (6 months to 15 years), disease stages (CD4 + counts 347.2 cells/mm³ to ≥ 500 cells/µL) and fall definitions (self-reported histories to real-time reporting). Some predictors of falls in people living with HIV including depression, cannabis use, cognitive impairment/neurocognitive adverse effects (NCAE), hypertension, and stavudine—showed perfect risk responsiveness (Ri = 1), indicating their strong association with falls. Notably, cannabis use demonstrated the highest risk weight (Rw = 3.0, p

Abstract Background Intestinal schistosomiasis was confirmed endemic in Mangochi District, Malawi, in May of 2018 following an unexpected encounter with discreet populations of Biomphalaria spp. freshwater snails during routine malacological surveillance activities. Since then, only limited malacological surveillance of Biomphalaria has been carried out, and so the distribution of Biomphalaria populations in this area is currently unclear. Additionally, sites of active Schistosoma mansoni transmission in this area are also unknown. In the present study, through extensive malacological surveillance, we aimed to formally document the distribution of Biomphalaria in Mangochi District. We also aimed to identify active intestinal schistosomiasis transmission sites in this area through subjecting all collected Biomphalaria to a recently developed S. mansoni-specific molecular xenomonitoring PCR. Methods Three malacological surveys were carried out along the southern shoreline of Lake Malawi, Mangochi District, Malawi, in November 2021, July 2022 and October/November 2022. All collected Biomphalaria were subjected to cercarial shedding analysis to identify active Schistosoma infections. Shed cercariae were then genotyped to species level using a standard multi-locus PCR and Sanger sequencing protocol. Following this, a subset of Biomphalaria from each collection site were also genotyped to species level using a standard PCR and Sanger sequencing protocol. All collected Biomphalaria were then subjected to a recently developed S. mansoni-specific molecular xenomonitoring PCR to identify infected, but non-shedding, Biomphalaria. Results A total of 589 Biomphalaria were collected across all three surveys. One single Biomphalaria (0.17%) specimen was found to be actively shedding Schistosoma cercariae, which were molecularly confirmed as S. mansoni. All genotyped Biomphalaria (n = 42) were molecularly identified as B. pfeifferi. A further 19 Biomphalaria specimens, collected from four different surveillance sites, were found to be infected with S. mansoni through molecular xenomonitoring. Intestinal schistosomiasis transmission was therefore identified at four different foci in Mangochi District. Conclusions Our study highlights the importance of molecular approaches to investigate Biomphalaria populations and monitor Biomphalaria-associated intestinal schistosomiasis transmission in endemic areas. As such, the continued development and use of such approaches, in particular the development and use of molecular xenomonitoring assays that can be carried out in resource-poor schistosomiasis-endemic settings, is encouraged. The revision of ongoing schistosomiasis control programmes in Mangochi District, in line with WHO recommendations, is also encouraged. Graphical abstract

Abstract Background The policy shift towards person-centred integrated primary care systems drives interest in primary care across higher education programs. In Flanders, the Primary Care Academy (PCA) is established to support this policy shift. The PCA focusses on the concepts of goal-oriented care, self-management, and interprofessional collaboration to support the shift towards integrated care and to integrate them in curricula in order to strengthen and develop a futureproof health system. Therefore, the aim of this study is if and how lecturers implement these concepts in the curriculum and what they need for a successful implementation. Methods A sequential explanatory mixed method study design was used combining quantitative and qualitative data. A cross-sectional survey was sent to 276 Flemish health care education programs. Qualitative data was collected through focus groups in which lecturers participated. Results The results showed that 89% of the higher education programs address goal-oriented care, self-management, and interprofessional collaboration with regard to primary care. Further analysis of courses within the programs reveals that the concept of self-management is covered in only 58%, while goal-oriented care (73%) and interprofessional collaboration (80%) appear more frequently. The level at which the themes are addressed in the courses are often limited to an introduction. The focus groups revealed that primary care is present in education programs, however lecturers are limited aware where primary care is integrated in their own and other programs. Lectures expressed a need for more collaboration between research, education and practice in developing educational content. When new concepts are introduced, lecturers want them to be translated into educational content, learning objectives and competencies. Conclusions The study shows that the concepts of goal-oriented care, self-management, and interprofessional collaboration are present in higher education programs to a varying degree. Lecturers are eager to implement these new primary concepts but they lack collaboration between education, research and practice. Lecturers indicate the need for a competence profile for primary care professionals as common framework to guide curriculum development.

Abstract Background Bladder cancer is the 10th most common malignancy and carries the highest treatment cost among all cancers. The elevated cost stems from its high recurrence rate, which necessitates frequent surveillance. White light cystoscopy (WLC), the standard of care surveillance tool to examine the bladder for lesions, has limited sensitivity for early-stage bladder cancer. Blue light cystoscopy (BLC) utilizes a fluorescent dye to induce contrast in cancerous regions, improving the sensitivity of detection by 43%. Nevertheless, the added equipment cost and lengthy dwell time of the dye limits the availability of BLC. Methods Here, we report the first demonstration of digital staining as a promising strategy to convert WLC images collected with standard-of-care clinical equipment into accurate BLC-like images, providing enhanced sensitivity for WLC without the associated labor or equipment cost. Results By introducing key pre-processing steps to circumvent color and brightness variations in clinical datasets needed for successful model performance, the results achieve a staining accuracy of 80.58% and show excellent qualitative and quantitative agreement of the digitally stained WLC (dsWLC) images with ground truth BLC images, including color consistency. Conclusions In short, dsWLC can affordably provide the fluorescent contrast needed to improve the detection sensitivity of bladder cancer, thereby increasing the accessibility of BLC contrast for bladder cancer surveillance. The broader implications of this work suggest digital staining is a cost-effective alternative to contrast-based endoscopy for other clinical scenarios outside of urology that can democratize access to better healthcare.

Abstract Background Darier disease is a genodermatosis which manifests as hyperkeratotic papules and superficial erosions mainly in seborrheic skin areas. This retrospective registry-based cohort study aimed to estimate the association between Darier disease and skin cancer. Results Patients diagnosed with Darier disease were identified from the patient registry of Sahlgrenska University Hospital (Gothenburg, Sweden) in 2016–2020. The local cohort included 13 patients. Verification of Darier disease diagnosis in the National Patient Registry showed positive predictive value of more than 90%. National Patient Registry was searched for Darier disease in 2001–2020, Swedish Cancer Registry for cancers and Prescribed Drug Register for medications. The national cohort included 770 patients and tenfold matched control cohort. Patients with Darier disease had an increased relative risk of keratinocyte carcinoma (basal cell carcinoma and cutaneous squamous cell carcinoma combined) (hazard ratio [HR], 1.6, 95% confidence interval [CI], 1.0-2.5, P = 0.036). The risk increase was significant for basal cell carcinoma (HR, 1.8, 95% CI, 1.1–2.9, P = 0.012), whereas there was a trend for cutaneous squamous cell carcinoma, (HR, 1.9, 95% CI, 0.9–4.1, P = 0.086) and cutaneous melanoma (HR, 2.4, 95% CI, 0.9–6.2, P = 0.083). Standardized incidence ratio for keratinocyte cancers was 2.9 (95% CI, 2.4–3.3. The results were consistent in two subgroup analyses adjusting for use of retinoid and/or immunosuppressive drugs. Conclusion Patients with Darier disease have an increased risk of skin cancer, particularly keratinocyte carcinoma. This risk was consistent even when known risk modifiers for keratinocyte carcinoma were excluded in sensitivity analyses. The results support previously proposed molecular links between Darier disease and skin cancer, but further investigations are needed. Additional studies are also required to develop clinical management recommendations for Darier disease. In the meantime, dermatologists should be aware of the cancer risk in these patients and remain vigilant, as detecting cancer can be challenging in hyperkeratotic and/or eroded skin.

BACKGROUND: In acute ischemic stroke (AIS), cerebral autoregulation becomes dysfunctional, impacting the brain’s ability to maintain cerebral blood flow (CBF) at adequate levels. Reperfusion of affected and nearby brain tissue in AIS is currently the aim of treatment in AIS, but the effectiveness of fluid resuscitation on increasing the CBF is debated. OBJECTIVE: We investigated the hypothesis that early fluid resuscitation with normal saline bolus would improve CBF velocity in the initial resuscitation of patients with AIS. METHODS: We conducted a prospective, quasi-experimental study on 30 patients in the early stages of AIS management. Patients had a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher. Patients met inclusion criteria if they were 18–90 years old and had time of stroke onset within 12 h. Patients with a severe underlying disability, hemorrhagic stroke, advanced directives for comfort care/hospice, as well as pregnant patients were excluded. Noninvasive hemodynamic monitoring was performed. We performed transcranial Doppler (TCD) insonation of the middle cerebral arteries (MCAs) to measure CBF velocity. Each patient received a 500-ml normal saline crystalloid bolus as a standardized intervention, then had hemodynamic and TCD measurements repeated. Analysis was limited to patients with stroke confirmed with neuroimaging. Mean flow velocity (MFV) was compared before and postreceiving the bolus in the MCA ipsilateral to the ischemic location. RESULTS: Thirty patients were analyzed who had confirmed AIS. The mean age was 53 ± 13 years, 50% were female, and the median NIHSS was 6 (interquartile range: 4–7). Outcomes measured included various cerebrovascular and cardiovascular parameters. Infusion of 500-mL normal saline bolus produced increases in systolic blood pressure (+7 mmHg, 95% confidence interval [CI] 0.6–13 mmHg) and stroke volume (SV) index (+2.2 ml/m2, 95% CI 0.3–4.1 ml/m2). The mean change in MFV was not statistically significant (+0.3 cm/s, 95% CI-3.7–4.3 cm/s). An adjusted model showed higher age and lower baseline SV index were not associated with improved MFV following administration of the fluid bolus. CONCLUSION: Our prospective study of AIS patients revealed that a fluid bolus improves hemodynamic parameters, but did not significantly increase CBF velocity. TRIAL REGISTRATION: clinicaltrials.gov (identifier: NCT02056821).

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Abstract A tendency to merge mental representations of self and other is thought to underpin the intense and unstable relationships that feature in Borderline Personality Disorder (BPD). However, clinical theories of BPD do not specify, in computational terms, how the perspectives of self and other might become confused. To address this question, we used a probabilistic false belief task (p-FBT) to examine how individuals with BPD (N = 38) and matched controls from the general population (N = 74) selectively assigned beliefs to self or other. The p-FBT requires participants to track a gradually changing quantity, whilst also predicting another person’s belief about that quantity. We found that BPD participants showed less selectivity in belief assignment compared with controls (Cohen’s d = 0.64). Behaviourally, participants with BPD tended to predict that others’ beliefs resembled their own. Modelling analysis revealed that BPD participants were prone to generalise their own learning signals to others. Furthermore, this generalising tendency correlated with BPD symptomatology across participants, even when controlling for demographic factors and affective psychopathology. Our results support a computational account of self-other mergence, based on a generalisation of learning across agents. Self-other generalisation in learning purports to explain key clinical features of BPD, and suggests a potential transdiagnostic marker of mentalising capability.

Abstract Light profoundly impacts many aspects of human physiology and behaviour, including the synchronization of the circadian clock, the production of melatonin, and cognition. These effects of light, termed the non-visual effects of light, have been primarily investigated in laboratory settings, where light intensity, spectrum and timing can be carefully controlled to draw associations with physiological outcomes of interest. Recently, the increasing availability of wearable light loggers has opened the possibility of studying personal light exposure in free-living conditions where people engage in activities of daily living, yielding findings associating aspects of light exposure and health outcomes, supporting the importance of adequate light exposure at appropriate times for human health. However, comprehensive protocols capturing environmental (e.g., geographical location, season, climate, photoperiod) and individual factors (e.g., culture, personal habits, behaviour, commute type, profession) contributing to the measured light exposure are currently lacking. Here, we present a protocol that combines smartphone-based experience sampling (experience sampling implementing Karolinska Sleepiness Scale, KSS ratings) and high-quality light exposure data collection at three body sites (near-corneal plane between the two eyes mounted on spectacle, neck-worn pendant/badge, and wrist-worn watch-like design) to capture daily factors related to individuals’ light exposure. We will implement the protocol in an international multi-centre study to investigate the environmental and socio-cultural factors influencing light exposure patterns in Germany, Ghana, Netherlands, Spain, Sweden, and Turkey (minimum n = 15, target n = 30 per site, minimum n = 90, target n = 180 across all sites). With the resulting dataset, lifestyle and context-specific factors that contribute to healthy light exposure will be identified. This information is essential in designing effective public health interventions.

Cerebral hyperperfusion syndrome is a rare complication that can occur following carotid artery revascularization procedures in patients with chronic carotid artery stenosis. Cases of hyperperfusion syndrome resulting solely from intravenous tissue plasminogen activator administration, without a history of revascularization, are extremely rare. Only four of such cases have been reported with imaging evidence. This report presents a case of early neurological deterioration in acute ischemic stroke, identified as a form of hyperperfusion syndrome. Imaging evidence supports this diagnosis, and highlights the occurrence of hyperperfusion syndrome after intravenous tissue plasminogen activator administration.

Abstract Positional coding along the anterior-posterior axis is regulated by HOX genes, whose 3’ to 5’ expression correlates with location along this axis. The precise utilisation of HOX genes in different human cell types is not fully understood. Here, we use single-cell and spatial-transcriptomics, along with in-situ sequencing, to create a developmental atlas of the human fetal spine. We analyse HOX gene expression across cell types during development, finding that neural-crest derivatives unexpectedly retain the anatomical HOX code of their origin while also adopting the code of their destination. This trend is confirmed across multiple organs. In the axial plane of the spinal cord, we find distinct patterns in the ventral and dorsal domains, providing insights into motor pool organisation and loss of collinearity in HOXB genes. Our findings shed new light on HOX gene expression in the developing spine, highlighting a HOX gene ‘source code’ in neural-crest cell derivatives.

Abstract Sixteen color additives (tar colors) were detected in 128 food samples (macarons, meringue cookies, and coque macarons) using HPLC with a photodiode array detector at 420 nm, 520 nm, and 620 nm for the yellow, red, and blue and green color types, respectively. The tar color recovery rates ranged from 81.3 to 95.6%, and their limits of detection (LOD) and quantification (LOQ) were 0.001–0.049 mg/kg and 0.004–0.147 mg/kg, respectively. Seven tar colors (Y4, Y5, R3, R40, R102, B1, and B2) were detected in 129 samples. All the samples did not contain nine tar colors (R2, G3, Azo, R106, QY, ORII, BBN, PBV, and GS). The quantity of tar colors (Y4, Y5, R40, and B1) in 15 samples exceeded the Korean Ministry of Food and Drug Safety (MFDS) standard. Ninety samples (70%) used a mixture of two or more tar colors, and the amount used was 11.0–1643.3 mg/kg. The quantity of combined tar colors in 15 samples exceeded 300 mg/kg. Through these findings, this study aims to contribute to the development of safer and more reliable desserts containing tar colors, by enhancing safety measures and ensuring improved quality control for consumer protection.

Abstract Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.

Abstract The establishment of industrial hemp (Cannabis sativa L.) fields near row crops has raised concerns about the potential adverse effects of herbicide drift on hemp production. This study examined hemp susceptibility to drift of herbicides registered for use in corn and/or soybeans. Herbicide solutions (2,4-D, dicamba, glufosinate, glyphosate, imazethapyr, lactofen, mesotrione) were applied separately in the wind tunnel (3.6 m s−1 airspeed), simulating drift scenarios, with conventional TP95015EVS (TP) and air inclusion AI95015EVS (AI) flat fan nozzles calibrated to deliver 140 L ha−1 carrier volume at 230 kPa. Mylar cards and hemp plants (20–25 cm tall) were placed downwind up to 12 m. Spray deposition from mylar cards was quantified using fluorometry and hemp biomass was collected 21 post application. Results indicated the nozzle design influenced downwind deposition; 5% of spray deposits from the TP nozzle reached 5.9 m downwind versus 2.0 m for the AI nozzle. Glyphosate, glufosinate, and mesotrione caused the highest biomass reductions, with 50% reductions observed at 19.3 (inferred), 8.7, and 9.3 m downwind for TP nozzle, and 4.1, 4.0, and 2.9 m for AI nozzle. These findings suggest herbicide applications at airspeeds of 3.6 m s−1 or greater present a risk to nearby hemp fields.

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Abstract Deep-sea coral frameworks are understudied in the Red Sea, where conditions in the deep are conspicuously warm and saline compared to other basins. Habitat suitability models can be used to predict the distribution pattern of species or assemblages where direct observation is difficult. Here we show how coral frameworks, built by species within the families Caryophylliidae and Dendrophylliidae, are distributed between water depths of 150 m and 700 m in the northern Red Sea and Gulf of Aqaba. To extrapolate the known (ground-truthed) positions of these deep frameworks, we use environmental and geomorphometric variables to inform well-performing maximum entropy models. Over 250 km2 of seafloor in our study area are identified as suitable for such frameworks, equivalent to at least 35% of the area of photic-zone coral reefs in the same region. We hence contend that deep-water coral frameworks are an important and underappreciated repository of Red Sea biodiversity.

Abstract Background Typhoid fever remains a significant public health problem contributing to significant misapplication of antibiotics in Ghana. However, there is little data on the accuracy of the commonly used serology based rapid diagnostic Typhidot test kit (Typhidot RDT) for confirming typhoid fever. Methods We conducted a study to assess the diagnostic accuracy of Typhidot RDT in seven clinical facilities across five regions in Southern Ghana. A total of 258 participants, clinically diagnosed with typhoid fever, were enrolled in this study. Blood and stool samples were obtained for culture, Typhidot and PCR assays. Disc diffusion antibiotic sensitivity was performed to determine the resistance pattern of Salmonella enterica isolates from positive blood and stool cultures. Results Recovery of S. enterica isolates was higher from stool samples (14.7%) in comparison to blood samples (1.6%). The sensitivity and specificity of Typhidot compared to blood and stool cultures was 35% (19.94%—52.65%) and 45% (38.67%—51.45%), respectively. Compared to PCR, the Typhidot had a sensitivity and a specificity of 61% and 53%, respectively. Resistance phenotyping of isolates showed broad sensitivity to the front-line antibiotics used. Resistance to ampicillin (10%), cotrimoxazole (7%), azithromycin and ciprofloxacin (

Abstract Background The clinical utility of whole genome sequencing (WGS) in paediatric cancer has been demonstrated in recent years. WGS has been routinely available in the National Health Service (NHS) England for all children with cancer in England since 2021, but its uptake has been variable geographically. To explore the underlying barriers to routine use of WGS in this population across England and more widely in the United Kingdom (UK) and the Republic of Ireland (ROI), a one-day workshop was held in Cambridge, United Kingdom in October 2022. Methods Following a series of talks, delegates participated in open, round-table discussions to outline local and broader challenges limiting routine WGS for diagnostic work-up for children with cancer in their Principal Treatment Centres (PTCs) and Genomic Laboratory Hubs (GLHs). Within smaller groups, delegates answered structured questions regarding clinical capability, education and training needs, and workforce competence and requirements. Data was recorded, centrally collated, and analysed following the event using thematic analysis. Results Sixty participants attended the workshop with broad representation from the 20 PTCs across the UK and ROI and the seven GLHs in England. All healthcare professionals involved in the WGS pathway were represented, including paediatric oncologists, clinical geneticists, clinical scientists, and histopathologists. The main themes highlighted by the group in ensuring equitable access to WGS identified were: lack of knowledge equity between NHS trusts, with a perception of WGS being for research only; and perception of lack of financial support for the clinical process surrounding WGS, including lack of time to take informed consent from patients. The latter also included limited trained staff available for data interpretation, affecting the turnaround time for reporting. Finally, the need for an integrated digital pathway to order, track, and return data to clinicians was highlighted. Conclusion At the workshop, the general motivation for including WGS in the diagnostic work up for children with cancer was high throughout the UK, however a perceived lack of resources and education opportunities limit the widespread use of this commissioned assay. This workshop has led to some recommendations to increase access to WGS in this population in England and more widely in the devolved national of the UK and the ROI.

Abstract Tropical forests dominate terrestrial photosynthesis, yet there are major contradictions in our understanding due to a lack of field studies, especially outside the tropical Americas. A recent field study indicated that West African forests have among the highest forests gross primary productivity (GPP) yet observed, contradicting models that rank them lower than Amazonian forests. Here, we show possible reasons for this data-model mismatch. We found that biometric GPP measurements are on average 56.3% higher than multiple global GPP products at the study sites. The underestimation of GPP largely disappears when a standard photosynthesis model is informed by local field-measured values of (a) fractional absorbed photosynthetic radiation (fAPAR), and (b) photosynthetic traits. Remote sensing products systematically underestimate fAPAR (33.9% on average at study sites) due to cloud contamination issues. The study highlights the potential widespread underestimation of tropical forests GPP and carbon cycling and hints at the ways forward for model and input data improvement.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of unknown etiology that commonly affects adolescents, imposing significant socioeconomic burdens. Effective management necessitates a comprehensive approach that takes into account multiple factors, including growth potential and psychological issues. Despite significant advancements in AIS management, several questions regarding optimal treatment strategies persist. Recent technological advancements are transforming the treatment landscape, encompassing advancements in bracing, robotic-assisted deformity corrections, and other interventions. This review explores current issues debated in the literature concerning the treatment of AIS, focusing on contemporary high-level evidence (e.g., meta-analyses and randomized controlled trials). Furthermore, this review explores cutting-edge developments and future directions in AIS management, including the integration of artificial intelligence and augmented reality.

Background: /purposeIn cases where oral squamous cell carcinoma (OSCC) invades the jawbone, clinicians frequently observe abnormal attenuation on computed tomography (CT) and pathologic signal intensity (SI) on magnetic resonance (MR) imaging of the affected underlying bone marrow. This study introduced a concept of “underlying bone change” to examine its association with clinicopathological features and prognosis of OSCC, as well as its correlation with medullary invasion. Materials and methods: We enrolled 93 consecutive patients diagnosed with OSCC, who underwent mandibulectomy between 2010 and 2016. CT and MR images, along with electronic medical records, were reviewed to evaluate correlations between underlying bone changes, clinicopathological features, five-year overall survival, and medullary invasion. Results: Of the 93 patients, 69 (74.2%) exhibited underlying bone sclerosis on CT, and 74 (79.6%) displayed pathological SI on MR images. These underlying bone changes correlated with the T stage and recurrence, but not with overall survival.Medullary invasion, observed in 61 (65.6%) patients, was strongly associated with T and TNM stages and was linked to poorer overall survival.The underlying bone changes on CT and MR images were positively associated with medullary invasion; however, no significant differences were found in the occurrence of underlying bone changes between the subtypes based on the extent of medullary invasion. Conclusion: Underlying bone changes on CT and MR images can provide valuable insights into the aggressiveness of bone invasion by OSCC. Accurate interpretation of these imaging findings might be crucial for correctly delineating surgical margins and preventing the overestimation of tumor extent.

Background/purpose: Cognitive flexibility is a personality trait, which can influence how effectively a healthcare professional can manage a challenging clinical situation. This study explored the cognitive flexibility of undergraduate dental hygiene students at two universities in Asia to gather baseline information in order to consider whether there was an educational need for pre-clinical students with regards to this personality factor. Materials and methods: Participants were all undergraduate dental hygiene students in the 2022 academic year at Tokyo Medical and Dental University (TMDU; n = 79) and Taipei Medical University (TMU; n = 88). An anonymous questionnaire was distributed, which included questions on demographic information and the Cognitive Flexibility Inventory (CFI). Results: The response rates were 97.5% (TMDU) and 89.8% (TMU). The CFI total scores were 91.77 for TMDU and 95.87 for TMU, and there was no significant difference between the two schools. The Alternatives scores were significantly higher in TMU than TMDU (P = 0.044), but there were no significant differences in the Control scores between the two schools. There were also no significant differences between school years of both universities. Conclusion: The dental hygiene students from both dental schools exhibit moderate cognitive flexibility. The educators in both dental schools may consider whether they should investigate and develop this personality factor further during the undergraduate training of their dental hygiene students.

Abstract Conventional radiography (CR) is primarily utilized for fracture diagnosis. Artificial intelligence (AI) for CR is a rapidly growing field aimed at enhancing efficiency and increasing diagnostic accuracy. However, the diagnostic performance of commercially available AI fracture detection solutions (CAAI-FDS) for CR in various anatomical regions, their synergy with human assessment, as well as the influence of industry funding on reported accuracy are unknown. Peer-reviewed diagnostic test accuracy (DTA) studies were identified through a systematic review on Pubmed and Embase. Diagnostic performance measures were extracted especially for different subgroups such as product, type of rater (stand-alone AI, human unaided, human aided), funding, and anatomical region. Pooled measures were obtained with a bivariate random effects model. The impact of rater was evaluated with comparative meta-analysis. Seventeen DTA studies of seven CAAI-FDS analyzing 38,978 x-rays with 8,150 fractures were included. Stand-alone AI studies (n = 15) evaluated five CAAI-FDS; four with good sensitivities (> 90%) and moderate specificities (80–90%) and one with very poor sensitivity ( 95%). Pooled sensitivities were good to excellent, and specificities were moderate to good in all anatomical regions (n = 7) apart from ribs (n = 4; poor sensitivity / moderate specificity) and spine (n = 4; excellent sensitivity / poor specificity). Funded studies (n = 4) had higher sensitivity (+ 5%) and lower specificity (-4%) than non-funded studies (n = 11). Sensitivity did not differ significantly between stand-alone AI and human AI aided ratings (p = 0.316) but specificity was significantly higher the latter group (p

Abstract Usutu virus (USUV) and West Nile virus (WNV) are two closely related emerging mosquito-borne flaviviruses. Their natural hosts are wild birds, but they can also cause severe neurological disorders in humans. Both viruses are efficiently suppressed by type I interferon (IFN), which interferes with viral replication, dissemination, pathogenesis and transmission. Here, we show that the replication of USUV and WNV are inhibited through a common set of IFN–induced genes (ISGs), with the notable exception of ISG20, which USUV is resistant to. Strikingly, USUV was the only virus among all the other tested mosquito-borne flaviviruses that demonstrated resistance to the 3′–5′ exonuclease activity of ISG20. Our findings highlight that the intrinsic resistance of the USUV genome, irrespective of the presence of cellular or viral proteins or protective post-transcriptional modifications, relies on a unique sequence present in its 3′ untranslated region. Importantly, this genomic region alone can confer ISG20 resistance to a susceptible flavivirus, without compromising its infectivity, suggesting that it could be acquired by other flaviviruses. This study provides new insights into the strategy employed by emerging flaviviruses to overcome host defense mechanisms.

Abstract Cannabis use disorder (CUD) is associated with adverse mental health effects, as well as social and cognitive impairment. Given prevalence rates of CUD are increasing, there is considerable efforts, and need, to identify prognostic markers which may aid in minimising any harm associated with this condition. Previous neuroimaging studies have revealed changes in white matter (WM) organization in people with CUD, though, the findings are mixed. In this study, we applied MRI-based analysis techniques that offer complimentary mechanistic insights, i.e., a connectome approach and fixel-based analysis (FBA) to investigate properties of individual WM fibre populations and their microstructure across the entire brain, providing a highly sensitive approach to detect subtle changes and overcome limitations of previous diffusion models. We compared 56 individuals with CUD (median age 25 years) to a sample of 38 healthy individuals (median age 31.5 years). Compared to controls, those with CUD had significantly increased structural connectivity strength (FDR corrected) across 9 edges between the right parietal cortex and several cortical and subcortical regions, including left orbitofrontal, left temporal pole, and left hippocampus and putamen. Utilizing FBA, WM density was significantly higher in those with CUD (FWE-corrected) across the splenium of the corpus callosum, and lower in the bilateral cingulum and right cerebellum. We observed significant correlation between cannabis use over the past month and connectivity strength of the frontoparietal edge, and between age of regular use and WM density of the bilateral cingulum and right cerebellum. Our findings enhance the understanding of WM architecture alterations associated with CUD.

Abstract Macaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here solve the cryo-electron microscopy structure of mNTCP. Superposing on the human NTCP (hNTCP)-preS1 complex structure shows that Arg158 of mNTCP causes steric clash to prevent preS1 from embedding onto the bile acid tunnel of NTCP. Cell-based mutation analysis confirms that only Gly158 permitted preS1 binding, in contrast to robust bile acid transport among mutations. As the second determinant, Asn86 on the extracellular surface of mNTCP shows less capacity to restrain preS1 from dynamic fluctuation than Lys86 of hNTCP, resulting in unstable preS1 binding. Additionally, presence of long-chain conjugated-bile acids in the tunnel induces steric hindrance with preS1 through their tailed-chain. This study presents structural basis in which multiple sites in mNTCP constitute a molecular barrier to strictly restrict HBV.

Abstract Synthetic data promise privacy-preserving data sharing for healthcare research and development. Compared with other privacy-enhancing approaches—such as federated learning—analyses performed on synthetic data can be applied downstream without modification, such that synthetic data can act in place of real data for a wide range of use cases. However, the role that synthetic data might play in all aspects of clinical model development remains unknown. In this work, we used state-of-the-art generators explicitly designed for privacy preservation to create a synthetic version of ever-smokers in the UK Biobank before building prognostic models for lung cancer under several data release assumptions. We demonstrate that synthetic data can be effectively used throughout the medical prognostic modeling pipeline even without eventual access to the real data. Furthermore, we show the implications of different data release approaches on how synthetic biobank data could be deployed within the healthcare system.

Abstract Brainstem cerebral cavernous malformations (CCM) are clinically more aggressive compared to superficial CCMs. Due to their location, resection can be challenging, making stereotactic radiosurgery (SRS) an attractive alternative for symptomatic patient. Brainstem CCM patients (n = 170) were treated with Gamma Knife SRS at 11 radiosurgical centers. Hemorrhagic risk reduction, risk factors of post-SRS hemorrhage, and clinical outcomes were retrospectively analyzed. Most patients had a single (165/170 patients) brainstem CCMs treated; the majority of CCMs (165/181) presented with bleeding. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM (HR: 0.17, p 13 Gy (HR = 2.57, p = 0.044). Adverse radiation effect (ARE) occurred in 9 patients (5.3%) and was symptomatic in four (2.4%). At a median follow-up of 3.4 years (Inter-quartile range: 5.4), 13 patients (8.0%) had a worsened clinical status, with the treated CCM being the cause in 5.6% (10) of the patients. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM and conveyed this benefit with a low risk of advrse radiation effects (ARE) and worsening clinical status.

Abstract The integration of next-generation sequencing into clinical diagnostics and surveillance initiatives is impeded by the lack of data analysis pipelines that align with privacy legislation and laboratory certification protocols. To address these challenges, we developed Jovian, an open-source, virus-focused, metagenomic analysis workflow for Illumina data. Jovian generates scaffolds enriched with pertinent annotations, including taxonomic classification, combined with metrics needed for quality assessment (coverage depth, average GC content, localization of open reading frames, minority single nucleotide polymorphisms), and incorporates host and disease metadata. Interactive web-based reports with an audit trail are generated. Jovian was employed on four systems, hosted by three institutes, utilizing grid-computers, a high-performance compute singular server, and a Windows10 laptop. All systems yielded identical results with matching MD5sums. Comparison with a commercial online reference tool using viral gastroenteritis samples confirmed the identification of the same pathogens. Jovian provides comparable results to a commercially available online reference tool and generates identical results at different institutes with different IT architectures, proving it is portable and reproducible. Jovian addresses bottlenecks in the deployment of metagenomics within public health and clinical laboratories and has the potential to enhance the breadth of surveillance and testing programs, thereby fostering more effective public health interventions.

Summary Background Dichotomisation of statistical significance, rather than interpretation of effect sizes supported by confidence intervals, is a long-standing problem. Methods We distributed an online survey to clinical trial statisticians across the UK, Australia and Canada asking about their experiences, perspectives and practices with respect to interpretation of statistical findings from randomised trials. We report a descriptive analysis of the closed-ended questions and a thematic analysis of the open-ended questions. Results We obtained 101 responses across a broad range of career stages (24% professors; 51% senior lecturers; 22% junior statisticians) and areas of work (28% early phase trials; 44% drug trials; 38% health service trials). The majority (93%) believed that statistical findings should be interpreted by considering (minimal) clinical importance of treatment effects, but many (61%) said quantifying clinically important effect sizes was difficult, and fewer (54%) followed this approach in practice. Thematic analysis identified several barriers to forming a consensus on the statistical interpretation of the study findings, including: the dynamics within teams, lack of knowledge or difficulties in communicating that knowledge, as well as external pressures. External pressures included the pressure to publish definitive findings and statistical review which can sometimes be unhelpful but can at times be a saving grace. However, the concept of the minimally important difference was identified as a particularly poorly defined, even nebulous, construct which lies at the heart of much disagreement and confusion in the field. Conclusion The majority of participating statisticians believed that it is important to interpret statistical findings based on the clinically important effect size, but report this is difficult to operationalise. Reaching a consensus on the interpretation of a study is a social process involving disparate members of the research team along with editors and reviewers, as well as patients who likely have a role in the elicitation of minimally important differences.

Abstract Background In view of the conflicting results from previous studies, the benefit of paclitaxel-coated balloons for arteriovenous fistulas is uncertain and equipoise remains. Although an industry-led trial testing the efficacy of sirolimus-coated balloons in AVFs is in progress, the benefit of sirolimus-coated balloons for arteriovenous fistulas is currently unknown. The purpose of this trial is to compare the efficacy of additional paclitaxel-coated or sirolimus-coated balloons on outcomes after a plain balloon fistuloplasty to preserve the patency of arteriovenous fistulae used for haemodialysis. Methods The study design is a multicentre randomised controlled trial. Following a successful plain balloon fistuloplasty, participants will be randomised to further treatment with a paclitaxel-coated balloon, a sirolimus-coated balloon, or an uncoated control balloon. We will recruit 642 patients, each with one or two treatment segments, over a 3-year period. Patients will remain in the trial and be followed up for 1 year. The primary endpoint is time to loss of treatment segment primary patency. Cox-proportional hazards models will be used to estimate hazard ratios for the time to loss of treatment segment primary patency for each treatment group relative to the control group. Analysis of the primary endpoint will be based on treatment segments rather than participants and a shared frailty will be estimated to account for the clustering of treatment segments within patients. Secondary endpoints are time to loss of primary patency at any treatment segment; time to end of access circuit primary patency; time to AVF abandonment; number of radiological or surgical interventions; adverse events; intima-media thickness and degree of stenosis at 3 months on ultrasound; and patient quality of life assessed by EQ-5D-5L and VASQoL. Discussion The three-armed design in this proposal will provide an answer on the efficacy of both paclitaxel- and sirolimus-coated balloons in the same trial. This trial is likely to provide a clear answer regarding the efficacy of drug-coated balloons for arteriovenous fistulas. Trial registration ISRCTN ISRCTN40182296. Registered on 4 August 2023.

Abstract Controlling the succession of chemical processes with high specificity in complex systems is advantageous for widespread applications, from biomedical research to drug manufacturing. Despite synthetic advances in bioorthogonal and photochemical methodologies, there is a need for generic chemical approaches that can universally modulate photodynamic reactivity in organic photosensitizers. Herein we present a strategy to fine-tune the production of singlet oxygen in multiple photosensitive scaffolds under the activation of bioresponsive and bioorthogonal stimuli. We demonstrate that the photocatalytic activity of nitrobenzoselenadiazoles can be fully blocked by site-selective incorporation of electron-withdrawing carbamate moieties and restored on demand upon uncaging with a wide range of molecular triggers, including abiotic transition-metal catalysts. We also prove that this strategy can be expanded to most photosensitizers, including diverse structures and spectral properties. Finally, we show that such advanced control of singlet oxygen generation can be broadly applied to the photodynamic ablation of human cells as well as to regulate the release of singlet oxygen in the semi-synthesis of natural product drugs.

Abstract Background Control of humeral torsion can present a challenge, especially intraoperatively during closed reduction and fixation of humeral shaft fractures or 2-part surgical neck fractures of the proximal humerus. The objective of this study is to develop and validate an indirect method for the assessment of humeral torsion using an index that is linearly correlated with rotational arm position and can be derived from only a single plain radiographic image of the proximal humerus. Methods The Humeral Head Offset Index (HHOI) is calculated as the ratio of the medial and lateral offset of the humeral head measured from the outer cortices of the shaft on a plain radiographic or fluoroscopic image. The relationship of HHOI with humeral torsion was first verified on a sawbone model with radiopaque characteristics under fluoroscopic control. Different degrees of retroversion were simulated through manual rotation of the humerus with a digital protractor in 5° increments until 40° internally rotated and then in 5° increments until 40° externally rotated from the neutral position. The same procedure was subsequently performed digitally on Digitally Reconstructed Radiographs (DRRs) from computed tomography (CT) dataset of the sawbone. Next, the HHOI index was applied to eight randomly selected patients with total humerus CT using the same method. Spearman’s rho was calculated for the bivariate analysis of correlation between the simulated degree of retroversion and the HHOI. Strength of correlation was classified according to Koo and Li. Interrater and intrarater reliability of three blinded observers with repetition of measurement after three months were analyzed by assessing the intraclass correlation coefficient (ICC). Results Both in the sawbone model and in DRRs, we demonstrated a high to very high significant linear correlation between simulated retroversion and the HHOI. ICC values demonstrated excellent interrater reliability and excellent intrarater reliability for measurement of the HHOI. Conclusions The HHOI is a new, simple, reliable index that has a linear relationship to the rotation of the humerus and can therefore allow an indirect control of humeral torsion in comparison to the contralateral side.

Abstract Objective Improving care transitions for older adults can reduce emergency department (ED) revisits, and the strain placed upon caregivers. We analyzed whether caregivers felt a change in burden following a care transition, and what may be improved to reduce it. Methods This mixed-methods observational study nested within LEARNING WISDOM included caregivers of older patients who experienced an ED care transition. Burden was collected with the brief Zarit Burden Interview (ZBI-12), and caregivers also commented on the care transition. A qualitative coding scheme of patient care transitions was created to reflect themes important to caregivers. Comments were randomly analyzed until saturation and themes were extracted from the data. We followed both the SRQR and STROBE checklists. Results Comments from 581 caregivers (mean age (SD) 64.5 (12.3), 68% women) caring for patients (mean age (SD) 77.2 (7.54), 48% women) were analyzed. Caregivers overwhelmingly reported dissatisfaction and unmet service expectations, particularly with home care and domestic help. Communication and follow-up from the ED emerged as an area for improvement. Caregivers who reported an increased level of burden following a patient’s care transition had significantly higher ZBI scores than caregivers who self-reported stable burden levels. Conclusion Caregivers with increasing, stable, and improved levels of subjective burden all reported areas for improvement in the care transition process. Themes centering on the capacity to live at home and inadequate communication were most frequently mentioned and may represent serious challenges to caregivers. Addressing these challenges could improve both caregiver burden and ED care transitions.

Abstract Background Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5’phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. Results Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. Conclusion Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

Background & objectives: Malaria remains a complex challenge in India due to its diverse epidemiology, multi-ethnic population, and multiplicity of malaria vectors. While progress has been made in reducing malaria nationally, persistent pockets hinder elimination efforts. These challenges include hidden reservoirs, inadequate healthcare, suboptimal surveillance, non-compliance, and subclinical infections. Shortage of grassroot level and primary care health staff, transportation issues and general inaccessibility and unavailability of healthcare services are additional challenges. Methods: Mobile healthcare vans have been tried and found useful in enhancing healthcare availability in several health conditions in different settings. Nuh district in Haryana, India is a malaria endemic region; it is indeed one of the districts included by India’s NITI Aayog in the Aspirational Districts Programme, a government initiative that focuses on rapidly transforming and developing the most underdeveloped districts in country. With an aim to improve the healthcare seeking behavior of malaria-endemic community of selected villages of Nuh district, we carried out a study using interventions in two villages of the district, that had mobile malaria clinics and toll-free telephone services in enhancing healthcare access. Results: We found that Sangel village had higher literacy rates (60.6%) as compared to 39.4% in Naushera. Similarly, the unemployment rate was higher for Naushera. It the mobile malaria clinic was deployed from December 2019 to July 2020 and a total of 269 phone calls were received from both the villages. A similar number of rapid tests and microscopy smears were examined and all were negative for malaria. The febrile patients were referred to the nearest healthcare facility. Interpretation & conclusion: The study shows that the community is open to using these healthcare interventions. These initiatives of mobile malaria clinics and toll-free telephone services can bridge healthcare gaps, especially in malaria-endemic regions, aligning with India’s malaria elimination and equitable healthcare access goals.

Abstract Young children receiving outpatient cancer care are vulnerable to undermanaged pain. App‐based solutions that provide pain treatment advice to parents in real‐time and in all environments may improve access to quality pain care. We used a parent co‐design approach involving iterative rounds of user testing and software modification to develop a usable Pain Caregiver Resource (PainCaRe) real‐time pediatric cancer pain management app. Parents of children (2–11 years) with cancer completed three standardized modules using a PainCaRe prototype. App usability and acceptability were evaluated using the validated System Usability Scale and a thematic analysis of app testing sessions and interviews. Iterative testing sessions were conducted until data saturation. Interview themes were synthesized into action items that guided revisions to PainCaRe and additional testing rounds were conducted as necessary. Twenty‐two parents participated in three testing cycles. Overall, parents described PainCaRe as an acceptable and potentially clinically useful pain management tool. Mean system usability scores were in the acceptable scale range during each testing cycle. Usability issues identified and resolved included those related to software malfunction, complicated app navigation logic, lack of clarity on pain assessment questions, and the need for pain management advice specifically tailored to child developmental stage. Using co‐design methods, the PainCaRe cancer pain management app was successfully refined for its acceptability and utility to parents. Next steps will include a PainCaRe pilot study before evaluating the impact of the app on younger children's pain outcomes in a randomized controlled trial.

The realm of digital property is a new area in the world of technology that must be addressed in different fields, especially law. In our country, the legislator has not yet provided an explicit text regarding the Digital inheritance property. In addition, like intellectual property rights, although digital property is immaterial, they will have a material effect, including patent rights and author's rights, which are recognized in Iranian law; like intellectual property, virtual properties are not physically tangible, but they have the same financial effects and can be classified as property and inheritance. The findings indicate that so far, the Digital inheritance assets have not yet penetrated Iran's laws, and the internal laws in this regard have not been legislated, despite the need and necessity due to the widespread use of these properties, there was no change in the recognition of digital assets. In this case, do digital properties have a place in Iran's law to be recognized as property or not? The Vice President of New Technologies of the Central Bank published a draft of the requirements and regulations in the field of cryptocurrencies in February 2017, and the bill that was recently submitted to the parliament is an attempt to the legal framework and define the rules of digital property in property can be considered with indulgence. According to the general rules governing material property, the digital property can also be considered as part of the property, be inherited, and at the same time be demanded, divided, and traded. The research method in this article is descriptive-analytical.

Wilms tumors (WT) are characterized by variable contributions of blastemal, epithelial and stromal elements, reflecting their diverse cellular origins and genetic drivers. In vitro models remain rare, despite a growing need to better characterize tumor biology and evaluate new treatments. Using three approaches, we have now established a large collection of long-term cultures that represent this diversity. Adherent WT cultures are predominated by stromal cells, 3D spheroids model blastema, and patient-derived organoid cultures of both tumor and healthy kidney tissue result in the preferential growth of epithelial cells. Adherent, spheroid and organoid cultures are also clearly distinguishable by their transcriptome. Preclinical drug screening experiments revealed sensitivity to a range of inhibitors, that are highly effective in other childhood solid tumors. Sensitivity was related to MYCN status, a marker associated with adverse outcome across human cancers including WT. The combination of the three culture techniques represents a promising tool to both explore tumor heterogeneity in vitro and to facilitate characterization of candidate driver genes, in order to improve treatment regimens in the future.