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Objective: Hippocampal sclerosis (HS), the most common pathology associated with temporal lobe epilepsy (TLE), is not always visible on magnetic resonance imaging (MRI), causing surgical delays and reduced postsurgical seizure-freedom. We developed an open-source software to characterize and localize HS to aid the presurgical evaluation of children and adults with suspected TLE., Methods: We included a multicenter cohort of 365 participants (154 HS; 90 disease controls; 121 healthy controls). HippUnfold was used to extract morphological surface-based features and volumes of the hippocampus from T1-weighted MRI scans. We characterized pathological hippocampi in patients by comparing them to normative growth charts and analyzing within-subject feature asymmetries. Feature asymmetry scores were used to train a logistic regression classifier to detect and lateralize HS. The classifier was validated on an independent multicenter cohort of 275 patients with HS and 161 healthy and disease controls., Results: HS was characterized by decreased volume, thickness, and gyrification alongside increased mean and intrinsic curvature. The classifier detected 90.1% of unilateral HS patients and lateralized lesions in 97.4%. In patients with MRI-negative histopathologically-confirmed HS, the classifier detected 79.2% (19/24) and lateralized 91.7% (22/24). The model achieved similar performances on the independent cohort, demonstrating its ability to generalize to new data. Individual patient reports contextualize a patient's hippocampal features in relation to normative growth trajectories, visualise feature asymmetries, and report classifier predictions., Interpretation: Automated and Interpretable Detection of Hippocampal Sclerosis (AID-HS) is an open-source pipeline for detecting and lateralizing HS and outputting clinically-relevant reports. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Youth sport specialization is a growing trend in youth sports and is associated with an increased risk of injuries and burnout. However, it is unknown how sport specialization is perceived to be affecting the working environment of secondary school athletic trainers (ATs). The purpose of this paper is to describe how ATs perceive youth sport specialization impacting their workload and whether they perceive it to impact patient safety., Hypothesis: ATs will perceive that youth sport specialization impacts their workload and could impact patient safety., Study Design: A sequential, explanatory mixed methods design with 2 phases: (1) cross-sectional surveys and (2) individual interviews., Level of Evidence: Level 3., Methods: A total of 487 secondary school ATs completed the online survey (access rate, 8.4%; completion rate, 85.4%). The survey consisted of Likert questions and included sections about aspects of workload impacted by specialization, impacts on patient safety, demographics. Ten participants were selected to complete a semi-structured interview via video conference., Results: Approximately two-thirds of ATs perceive that sport specialization impacts their workload. (Somewhat, 38.6%; Quite a bit, 25.5%; A great deal, 5.5%) Attempts to reduce or modify patient activity and a patient's time for rehabilitation were the highest rated aspects of workload impacted by sport specialization. Approximately 30% ATs (29.9%) perceive that sport specialization impacts their workload to where it may influence patient safety (Somewhat, 21.6%; Quite a bit, 6.4%; A great deal, 1.9%). Three themes and subsequent subthemes were identified from the qualitative interviews: (1) current youth sport expectations, (2) conflict between school and club sports, and (3) AT job impacts., Conclusion: Secondary school ATs perceive their workload to be negatively impacted by youth sport specialization and some believe it may impact patient safety., Clinical Relevance: Youth sport specialization is impacting youth sport stakeholders, including ATs, in a variety of ways., Competing Interests: The authors report no potential conflicts of interest in the development and publication of this article.

Background: Malformations of cortical development (MCDs) in children with focal epilepsy pose significant diagnostic challenges, and a precise radiological diagnosis is crucial for surgical planning. New MRI sequences and the use of artificial intelligence (AI) algorithms are considered very promising in this regard, yet studies evaluating the relative contribution of each diagnostic technique are lacking., Methods: The study was conducted using a dedicated "EPI-MCD MR protocol" with a 3 Tesla MRI scanner in patients with focal epilepsy and previously negative MRI. MRI sequences evaluated included 3D FLAIR, 3D T1 MPRAGE, T2 Turbo Spin Echo (TSE), 3D T1 MP2RAGE, and Arterial Spin Labelling (ASL). Two paediatric neuroradiologists scored each sequence for localisation and extension of the lesion. The MELD-FCD AI classifier's performance in identifying pathological findings was also assessed. We only included patients where a diagnosis of MCD was subsequently confirmed on histology and/or sEEG., Results: The 3D FLAIR sequence showed the highest yield in detecting epileptogenic lesions, with 3D T1 MPRAGE, T2 TSE, and 3D T1 MP2RAGE sequences showing moderate to low yield. ASL was the least useful. The MELD-FCD classifier achieved a 69.2% true positive rate. In one case, MELD identified a subtle area of cortical dysplasia overlooked by the neuroradiologists, changing the management of the patient., Conclusions: The 3D FLAIR sequence is the most effective in the MRI-based diagnosis of subtle epileptogenic lesions, outperforming other sequences in localisation and extension. This pilot study emphasizes the importance of careful assessment of the value of additional sequences., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis 1,2 . APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants 3-5 . Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process 6,7 . Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones., (© 2024. The Author(s).)

Objective: To compare rates of adverse pregnancy outcomes in term pregnancies complicated by polyhydramnios between women who had induction of labor (IOB) versus women who had expectant management., Methods: This multicenter retrospective study included term pregnancies complicated by isolated polyhydramnios. Patients who underwent IOB were compared with those who had expectant management. The primary outcome was defined as a composite adverse maternal outcome, and secondary outcomes were various maternal and neonatal adverse outcomes. Univariate analyses were followed by multivariate logistic regression., Results: A total of 865 pregnancies with term isolated polyhydramnios were included: 169 patients underwent IOB (19.5%), while 696 had expectant management and developed spontaneous onset of labor (80.5%). Women who underwent IOB had significantly higher rates of composite adverse maternal outcome (23.1% vs 9.8%, P < 0.01), prolonged hospital stay, perineal tear grade 3/4, intrapartum cesarean, postpartum hemorrhage, blood products transfusion, and neonatal asphyxia compared with expectant management. While the perinatal fetal death rate was similar between the groups (0.6% vs 0.6%, P = 0.98), the timing of the loss was different. Four women in the expectant management group had a stillbirth, while in the induction group one case of intrapartum fetal death occurred due to uterine rupture. Multivariate analyses revealed that IOB was associated with a higher rate of composite adverse maternal outcome (adjusted odds ratio, 2.22 [95% CI, 1.28-3.83]; P < 0.01)., Conclusion: IOB in women with term isolated polyhydramnios is associated with higher rates of adverse maternal outcomes in comparison to expectant management. Further research is needed to determine the optimal approach for the management of isolated polyhydramnios at term., (© 2024 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis., Design: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model., Results: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature., Conclusions: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery might alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning [obtained from IQ tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory and processing speed) and tests of academic attainment (reading, spelling and numeracy)] and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery [median age at surgery = 11.9 years, interquartile range = (7.8, 15.0)] and neuropsychological assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all P-values ≤0.001; e.g. βFSIQ = -1.9, SEFSIQ = 0.3, PFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27%-43% declined by ≥10 points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46%-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all P-values ≥0.128). However, children who became seizure free through surgery showed higher postoperative neuropsychological performance (e.g. rrb-FSIQ = 0.37, P < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g. βFSIQ = 0.9, SEFSIQ = 0.3, PFSIQ = 0.004). Children who had discontinued antiseizure medication treatment at 1-year follow-up showed an 8- to 13-point advantage in postoperative working memory, processing speed and numeracy, and greater improvements in verbal IQ, working memory, reading and spelling (all P-values ≤0.034) over the postoperative period compared with children who were seizure free and still receiving antiseizure medication. In conclusion, by providing seizure freedom and the opportunity for antiseizure medication cessation, epilepsy surgery might not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible or, potentially, to prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

LGBT individuals experience discrimination in health care settings and report difficulty accessing clinically competent healthcare. This study examined the self-assessed knowledge, clinical preparedness, LGBT health focused education received and attitudinal awareness of health care workers (HCW) ( n  = 215) toward LGBT patients at an urban hospital in New York City. HCW completed a one-time survey, that included the Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale. Forty percent of HCW treated LGB patients and 30% treated transgender patients, 11% and 18% reported they were unaware if their patients were LGB or transgender. Seventy-four percent of HCW received less than two hours of formal education in LGBT health. A slight majority of HCW (51%) reported not receiving adequate clinical training to work with transgender clients. Forty-six percent of HCW reported not receiving adequate clinical training to work with LGB clients. A significant difference in LGBT health knowledge, clinical preparedness, and attitudinal awareness was found by LGBT health education received. HCW that reported more LGBT focused health education reported higher basic LGBT health knowledge, felt more clinically prepared, and reported affirming attitudes regarding LGBT patients. This research suggests that more LGBT health focused education of HCW is needed.

Introduction: Despite over 15 years of real-world data that supports the safety and efficacy of the human papillomavirus (HPV) vaccine, in the United States vaccine hesitancy persists. Many studies have focused on vaccine-hesitant parents, but fewer have examined provider perspectives on how to address HPV vaccine hesitancy., Methods: Between July 2021-April 2022, we recruited providers in Maryland and the broader Mid-Atlantic region who practiced pediatrics, primary care, family medicine, or adolescent medicine and who provided outpatient care for children ages 10-17. Semi-structured virtual interviews focused on provider-reported strategies to address HPV vaccine-hesitant parents, as well as perceived barriers to successful vaccination and provider perspectives on specific interventions to address parental hesitancy. Audio recordings were transcribed and analyzed via a combination of deductive and inductive coding. Higher-level themes within the domains of strategies, barriers, and perspectives on specific proposed interventions were identified., Results and Discussion: A total of sixteen providers completed an interview. Within the domain of provider-reported strategies, the following themes emerged: 1) leveraging continuity of care and established parental trust, 2) supporting parental autonomy, 3) tailoring the approach to specific concerns of vaccine-hesitant parents, 4) normalizing the HPV vaccine, and 5) focusing on health prevention and cancer prevention. Barriers providers identified were: 1) limited time, 2) lack of common ground with parents, 3) parent-child decision discordance, 4) availability of misinformation, and 5) parental concerns such as safety and necessity. In the domain for proposed interventions, providers favored interventions that saved time or were not resource-intense, that did not single out the HPV vaccine as different, were patient friendly, and leveraged efficiency through the electronic medical record. The insights from this study can help inform the development of provider-acceptable and feasible tools and interventions to address parental HPV vaccine hesitancy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne Rositch reports a relationship with Hologic Inc that includes: employment. A.F. Rositch is currently an employee of Hologic, which had no role in the current study, as it originated and was primarily conducted while she was an independent faculty researcher at Johns Hopkins University where she maintains an adjunct appointment., (© 2024 Published by Elsevier Ltd.)

Background: The aim of this study was to evaluate evolution of ultra-processed food intake and recurrent weight gain in patients who underwent Roux-en-Y gastric bypass., Materials and Methods: This study is an observational longitudinal study that evaluated patients who underwent metabolic and bariatric surgery at four time points: before surgery and at 3, 12, and 60 months after surgery. Anthropometric and dietary intake data were collected through two 24-h dietary recalls. All foods consumed were classified according to degree of processing. Recurrent weight gain was considered the difference between current weight and nadir weight., Results: The sample consisted of 58 patients with a mean age of 38.7 ± 8.9 years and 68% female. After 60 months, mean excess weight loss and recurrent weight gain were 73.6 ± 27.2% and 22.5 ± 17.4%. Calorie and macronutrient intake decreased significantly between the pre-surgery period, and 3 and 12 months post-surgery; however, there was no significant difference after 60 months. In relation to food groups or macronutrients, no difference was observed between the pre-surgery period and 60 months post-surgery. The contribution of unprocessed or minimally processed foods to calorie intake gradually decreased after 3 months post-surgery., Conclusion: The profile of dietary intake after 60 months of metabolic and bariatric surgery tends to approach that of the pre-surgery period. The contribution of unprocessed and minimally processed foods to calorie intake decreased after 60 months, while ultra-processed food contribution increased., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Analysing complex diseases such as chronic inflammatory joint diseases (CIJDs), where many factors influence the disease evolution over time, is a challenging task. CIJDs are rheumatic diseases that cause the immune system to attack healthy organs, mainly the joints. Different environmental, genetic and demographic factors affect disease development and progression. The Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) Foundation maintains a national database of CIJDs documenting the disease management over time for 19'267 patients. We propose the Disease Activity Score Network (DAS-Net), an explainable multi-task learning model trained on patients' data with different arthritis subtypes, transforming longitudinal patient journeys into comparable representations and predicting multiple disease activity scores. First, we built a modular model composed of feed-forward neural networks, long short-term memory networks and attention layers to process the heterogeneous patient histories and predict future disease activity. Second, we investigated the utility of the model's computed patient representations (latent embeddings) to identify patients with similar disease progression. Third, we enhanced the explainability of our model by analysing the impact of different patient characteristics on disease progression and contrasted our model outcomes with medical expert knowledge. To this end, we explored multiple feature attribution methods including SHAP, attention attribution and feature weighting using case-based similarity. Our model outperforms temporal and non-temporal neural network, tree-based, and naive static baselines in predicting future disease activity scores. To identify similar patients, a k-nearest neighbours regression algorithm applied to the model's computed latent representations outperforms baseline strategies that use raw input features representation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Trottet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose  The biodistribution of gallium-68-dotatate (Ga-68-dotatate) and standardized uptake values (SUVs) using non-time-of-flight (TOF) positron emission tomography/computed tomography (PET/CT) cameras is well established. However, with the eventual retirement of older PET cameras and their replacement with newer, highly sensitive TOF PET/CT cameras, where SUV max measurements are reportedly higher, updated knowledge of normal SUV max range is needed and, to our knowledge, not previously reported. Our objectives are as follows: To establish normal Ga-68-dotatate TOF SUV max database for common structures and to aid the visual detection of abnormalities objectively. To compare SUV max values using the TOF and non-TOF algorithms. Methods  Fifty consecutive patients referred routinely to our nuclear medicine service (20 men, 30 women; median age 55 years) with presumed neuroendocrine tumors underwent Ga-68-dotatate scans on a PET-CT camera having capability of reconstructing both TOF/non-TOF images. Region of interests (ROIs) were drawn around 24 normal structures as well as the primary lesion with abnormal radiotracer uptake and SUV max was measured. The same ROI was analyzed using both algorithms simultaneously and both TOF and non-TOF SUV max values were compared. Results  Twelve hundred ROIs were evaluated. Non-TOF Ga-68-dotatate uptake in normal structures was in alignment with previously published studies. As compared to non-TOF, TOF images had better target to background ratios visually. TOF SUV max was higher for all structures except for lung and brain. TOF SUV max was more than double in adrenals/uncinate process of the pancreas; approximately 1.8 times in abnormal lesions, lymph nodes, pineal gland; and greater than 1.5 times in thyroid, breast, and pancreatic head. Conclusion  Normal database of Ga-68-dotatate TOF SUV max is provided for common structures to aid visual detection of abnormalities objectively. Overall, TOF SUV max measures higher in identical ROIs, with abnormal lesions measuring approximately 1.8 times higher versus non-TOF technology. These findings need to be taken in consideration when comparing patient scans imaged on different PET/CT technologies., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Objectives: Acute atrial fibrillation and flutter (AF/AFL) are common arrhythmias treated in the emergency department (ED). The 2021 CAEP Best Practices Checklist provides clear recommendations for management of patients with acute AF/AFL. This study aimed to evaluate physician compliance to Checklist recommendations for risk assessment and ED management of AF/AFL., Methods: This health records review assessed the management of adult patients presenting to two tertiary care EDs for management of acute AF/AFL from January to August, 2022. All ECGs demonstrating AF/AFL with a heart rate greater than 100 were compiled to capture primary and secondary causes. All visits were assessed for rate and rhythm control management, adverse events, return to ED, and safety criteria. Study physicians classified safety criteria from the Checklist into high and moderate concerns. The primary outcome was the proportion of cases with safety concerns and adverse events occurring during management in the ED. Data were analyzed using simple descriptive statistics., Results: We included 429 patients with a mean age of 67.7 years and 57.1% male. ED management included rate control (20.4%), electrical (40.1%), and pharmacological (20.1%) cardioversion. Adverse events occurred in 9.5% of cases: 12.5% in rate control, 13.4% in electrical cardioversion, and 6.9% in pharmacologic cardioversion. Overall, 7.9% of cases had management safety concerns. Moderate safety concerns occurred in 4.9% of cases including failure to attain recommended heart rate at time of discharge (3.9%). Severe concerns were identified in 3.0% of cases including failure to cardiovert unstable patients (1.2%). The 30-day return-to-ED rate was 16.5% secondary to AF/AFL., Conclusion: ED management of AF/AFL was consistent with the CAEP Checklist and was safe overall. Opportunities for optimizing care include attaining recommended targets during rate control, avoidance of calcium channel and beta blockers in patients with systolic dysfunction, and earlier cardioversion for clinically unstable patients., (© 2024. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Objectives: Acute atrial fibrillation (AF)/flutter (AFL) is a common emergency department (ED) presentation. In 2021, an updated version of CAEP's Acute AF/AFL Best Practices Checklist was published, seeking to guide management. We assessed the alignment with and safety of application of the Checklist, regarding stroke prevention and disposition., Methods: This health records review included adults presenting to two tertiary care academic EDs between January and August 2022 with a diagnosis of acute AF/AFL. Patients were excluded if their initial heart rate was < 100 or if they were hospitalized. Data extracted included: demographics, CHADS-65 score, clinical characteristics, ED treatment and disposition, and outpatient prescriptions and referrals. Our primary outcome was the proportion of patient encounters with one or more identified safety issues. Each case was assessed according to seven predetermined criteria from elements of the CAEP Checklist and either deemed "safe" or to contain one or more safety issues. We used descriptive statistics with 95% confidence intervals., Results: 358 patients met inclusion criteria. The mean age was 66.9 years, 59.2% were male and 77.4% patients had at least one of the CHADS-65 criteria. 169 (47.2%) were not already on anticoagulation and 99 (27.6%) were discharged home with a new prescription for anticoagulation. The primary outcome was identified in 6.4% (95% CI 4.3-9.5) of encounters, representing 28 safety issues in 23 individuals. The safety concerns included: failure to prescribe anticoagulation when indicated (n = 6), inappropriate dosing of a direct oral anticoagulant (DOAC) (n = 2), inappropriate prescription of rate or rhythm control medication (n = 9), and failure to recommend appropriately timed follow-up for new rate control medication (n = 11)., Conclusions: There was a very high level of ED physician alignment with CAEP's Best Practices Checklist regarding disposition and stroke prevention. There are opportunities to further improve care with respect to recommendation of anticoagulation and reducing inappropriate prescriptions of rate or rhythm medications., (© 2024. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Objective: To investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren's disease (SjD)., Methods: In this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders., Results: We identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07-1.6]; OMA HR 1.12 [0.91-1.37]; JAKi HR 0.97 [0.62-1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46-0.84]) and JAKi (HR 0.52 [0.28-0.96])., Conclusion: RA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi., (© 2024. The Author(s).)

Background/objective: We evaluated patients with fibromyalgia syndrome (FMS) to determine whether there is a correlation between pain scores based on a 0- to 10-point visual analog scale (VAS) and muscle pressure., Methods: One hundred forty-two patients who satisfied the American College of Rheumatology classification criteria for FMS and 38 non-FMS controls comprised the study groups. Muscle pressure was measured in mm Hg using a pressure gauge attached to a no. 22 needle inserted into the midportion of the trapezius muscle. The muscle pressure was then correlated with the VAS pain score of 0 to 10, some with an increment of 0.5. A second muscle pressure was obtained from 19 patients at a subsequent visit, which was compared with their pain scores., Results: The mean (SD) pain score for 142 patients with FMS was 6.6 (SD, 1.84) on a 0- to 10-point VAS. The mean pain score in the non-FMS subjects was 0.7 (SD, 1.26). The mean muscle pressure in the FMS group was 32.9 (SD, 6.57) mm Hg. The mean muscle pressure in the non-FMS subjects was 10.6 (SD, 3.85) mm Hg. The calculated Pearson correlation coefficient for muscle pressure versus pain score was 0.8312 ( p < 0.0001). This indicates a highly significant association between subjects' muscle pressure and pain scores. For the repeat muscle pressures, the change in muscle pressure was correlated with the change in pain score, and the resulting Pearson correlation coefficient was 0.9255 ( p < 0.0001). These results again indicate a highly significant association between subjects' muscle pressure and pain scores., Conclusion: The results show that increased muscle pressure may be a significant cause of pain in FMS, and the etiology of the pain may have a large peripheral component in addition to a centralized origin of the pain., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The cerebral cortex underlies many of our unique strengths and vulnerabilities, but efforts to understand human cortical organization are challenged by reliance on incompatible measurement methods at different spatial scales. Macroscale features such as cortical folding and functional activation are accessed through spatially dense neuroimaging maps, whereas microscale cellular and molecular features are typically measured with sparse postmortem sampling. Here, we integrate these distinct windows on brain organization by building upon existing postmortem data to impute, validate, and analyze a library of spatially dense neuroimaging-like maps of human cortical gene expression. These maps allow spatially unbiased discovery of cortical zones with extreme transcriptional profiles or unusually rapid transcriptional change which index distinct microstructure and predict neuroimaging measures of cortical folding and functional activation. Modules of spatially coexpressed genes define a family of canonical expression maps that integrate diverse spatial scales and temporal epochs of human brain organization - ranging from protein-protein interactions to large-scale systems for cognitive processing. These module maps also parse neuropsychiatric risk genes into subsets which tag distinct cyto-laminar features and differentially predict the location of altered cortical anatomy and gene expression in patients. Taken together, the methods, resources, and findings described here advance our understanding of human cortical organization and offer flexible bridges to connect scientific fields operating at different spatial scales of human brain research., Competing Interests: KW, SA, JS, SV, TM, RD, AD, TS, SL, PV, AA, DG, AR No competing interests declared, RS receives consulting income from Octave Bioscience and compensation for reviewership duties from the American Medical Association

Purpose: To determine predictive factors associated with a good response (GR) to and efficacy of low-dose radiotherapy (LDRT) in patients with greater trochanteric pain syndrome (GTPS)., Methods: Patients with GTPS were irradiated on a linear accelerator with 0.5-1.0 Gy per fraction to a total dose of 3.0-4.0 Gy per series. The endpoint was subjective good response (GR) to treatment 2 months after completion of the last LDRT series, defined as complete pain relief or marked improvement assessed using the von Pannewitz score. A positive response to steroid injection (SI) was defined as pain relief of at least 7 days. Patient and treatment-related characteristics were evaluated with respect to LDRT outcomes., Results: Outcomes were assessed for 71 peritrochanteric spaces (PTSs; 65 patients, 48 females, with mean age of 63 [44-91] years). Prior SI had been given to 55 (77%) PTSs and 40 PTSs received two series of LDRT. Two months after completion of LDRT, GR was reported in 42 PTSs (59%). Two series of LDRT provided a significantly higher rate of GR than one series (72.5 vs. 42% PTSs, p = 0.015). Temporary pain relief after prior SI predicted GR to LDRT compared with PTSs which had not responded to SI (73 vs. 28% PTSs, p = 0.001). A regional structural abnormality, present in 34 PTSs (48%), was associated with a reduction of GR to LDRT (44 vs. 73% PTSs, p = 0.017)., Conclusion: LDRT is an effective treatment for GTPS. Administration of two LDRT series, prior response to SI, and absence of structural abnormalities may predict significantly better treatment outcomes., (© 2023. The Author(s).)

Aim: To evaluate a lesion detection algorithm designed to detect focal cortical dysplasia (FCD) in children undergoing stereoelectroencephalography (SEEG) as part of their presurgical evaluation for drug-resistant epilepsy., Method: This was a prospective, single-arm, interventional study (Idea, Development, Exploration, Assessment, and Long-Term Follow-Up phase 1/2a). After routine SEEG planning, structural magnetic resonance imaging sequences were run through an FCD lesion detection algorithm to identify putative clusters. If the top three clusters were not already sampled, up to three additional SEEG electrodes were added. The primary outcome measure was the proportion of patients who had additional electrode contacts in the SEEG-defined seizure-onset zone (SOZ)., Results: Twenty patients (median age 12 years, range 4-18 years) were enrolled, one of whom did not undergo SEEG. Additional electrode contacts were part of the SOZ in 1 out of 19 patients while 3 out of 19 patients had clusters that were part of the SOZ but they were already implanted. A total of 16 additional electrodes were implanted in nine patients and there were no adverse events from the additional electrodes., Interpretation: We demonstrate early-stage prospective clinical validation of a machine learning lesion detection algorithm used to aid the identification of the SOZ in children undergoing SEEG. We share key lessons learnt from this evaluation and emphasize the importance of robust prospective evaluation before routine clinical adoption of such algorithms., What This Paper Adds: The focal cortical dysplasia detection algorithm collocated with the seizure-onset zone (SOZ) in 4 out of 19 patients. The algorithm changed the resection boundaries in 1 of 19 patients undergoing stereoelectroencephalography for drug-resistant epilepsy. The patient with an altered resection due to the algorithm was seizure-free 1 year after resective surgery. Overall, the algorithm did not increase the proportion of patients in whom SOZ was identified., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

The immune-mediated small vessel vasculitis is known as Schoenlein-Henoch purpura predominantly from pediatrics and in these cases occurs more frequently after infections of the upper airways. In adults, immunoglobulin A (IgA) vasculitis often proceeds more severely und recurrently with the classical tetrad of skin manifestations in the sense of leukocytoclastic vasculitis, joint affection, gastrointestinal involvement and IgA nephritis, in contrast to the mostly mild and self-limiting course in children. The background of this systemic vasculitis with formation of IgA immune complexes is considered to be an altered glycosylation of IgA, as this causes the exposure of binding sites for autoantibodies so that an immune complex reaction can be elicited. This ultimately leads to perivascular deposition of IgA and a further activation of neutrophils. Groundbreaking in the diagnostics is the histological detection of leukocytoclastic vasculitis and in cases of renal manifestations a kidney biopsy with characteristic deposits of immune complexes, which cannot be clearly differentiated from IgA nephropathy. The treatment is aimed at the respective manifestation and is mostly based on consensus recommendations due to the lack of randomized studies. In addition to immunosuppressive medication, in the presence of a chronic kidney disease general nephroprotection is becoming increasingly more important also by inhibition of sodium-glucose transporter 2 (SGLT2). The type and extent of kidney involvement and also rare cardiac manifestations are the main determinants of the prognosis. Continuous medical accompaniment of those affected is necessary due to the possible progression of the disease and the risk of recurrence., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

This interdisciplinary study examined the relationship between bone density and drilling forces required during trans-pedicular access to the vertebra using fresh-frozen thoraco-lumbar vertebrae from two female body donors (A, B). Before and after biomechanical examination, samples underwent high-resolution CT-quantification of total bone density followed by software-based evaluation and processing. CT density measurements (n = 4818) were calculated as gray values (GV), which were highest in T12 for both subjects (GV maxA  = 3483.24, GV maxB  = 3160.33). Trans-pedicular drilling forces F (Newton N) were highest in L3 (F maxB  = 5.67 N) and L4 (F maxA  = 5.65 N). In 12 out of 13 specimens, GVs significantly (p < 0.001) correlated with force measurements. Among these, Spearman correlations r were poor in two lumbar vertebrae, fair in five specimens, and moderately strong in another five specimens, and highest for T11 (r A  = 0.721) and L5 (r B  = 0.690). Our results indicate that CT-based analysis of vertebral bone density acquired in anatomical specimens is a promising approach to predict the drilling force appearance as surrogate parameter of its biomechanical properties by e.g., linear regression analysis. The study may be of value as basis for biomechanical investigations to improve planning of the optimal trajectory and to define safety margins for drilling forces during robotic-assisted trans-pedicular interventions on the spine in the future., (© 2024. The Author(s).)

This paper summarizes key shifts in judicial decisions relating to public health powers during the pandemic and the implications of those decisions for public health practice. Then, it gives a preview and call for partnership in developing a legal framework for authority that guides public health to better activities, processes, and accountability in service of the public's health.

Background: Hemoglobin assessments in children and women have been conducted annually in Chad since 2016 through the Standardized Monitoring and Assessment of Relief and Transitions (SMART) cross-sectional surveys. This analysis aims to characterize national and sub-national trends in anemia among children under five and women of reproductive age from 2016 to 2021 and to compare risk factors for anemia before and during the COVID-19 pandemic., Methods: Hemoglobin concentrations were measured in approximately half of the 12,000 to 15,000 included households each year, except for 2020 when hemoglobin tests were omitted. For children 6 to 59 months of age, anemia was defined as hemoglobin less than 11.0 g/dL. Anemia was defined as hemoglobin less than 11.0 g/dL and 12.0 g/dL for pregnant women and non-pregnant women, respectively. Trends were stratified by agroecological zone, and tests of proportions were used to assess statistical significance. Simple and multivariate logistic regression models were conducted for 2019 and 2021 to identify risk factors for anemia., Results: Reductions in anemia over the 6-year period were significant among women (47.6-30.8%, p = 0.000) and children (68.6-59.6%, p = 0.000). The Sudanian zone had consistently higher rates, particularly in children, compared to the Sahelian and Saharan zones. Significant declines in women's anemia were observed in all zones from 2019 to 2021, but this global decline was not observed among children, where rates in the Saharan zone significantly increased. In 2019, only minimum dietary diversity significantly reduced the odds of anemia in children (AOR: 0.65, 95%CI: 0.46-0.92), whereas in 2021, improvements in all diet indicators were associated with lower odds of anemia. Improved household socio-economic factors, including head of household literacy, were associated with lower odds of anemia in children (2019 AOR: 0.76, 95%CI: 0.67, 0.88) and women (2019 AOR: 0.75, 95%CI: 0.65, 0.87; 2021 AOR: 0.81, 95%CI: 0.70, 0.93)., Conclusions: Anemia declined significantly in Chad among women of reproductive age and children from 2016 to 2021, but the national prevalence of 60% among children remains unacceptably high. Sub-national differences in anemia rates underline the need to identify and address regional causes of anemia while strengthening national level programs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Organoids, combined with genetic editing strategies, have the potential to offer rapid and efficient investigation of gene function in many models of human disease. However, to date, the editing efficiency of organoids with the use of non-viral electroporation methods has only been up to 30%, with implications for the subsequent need for selection, including turnaround time and exhaustion or adaptation of the organoid population. Here, we describe an efficient method for intestinal organoid editing using a ribonucleoprotein-based CRISPR approach. Editing efficiencies of up to 98% in target genes were robustly achieved across different gut anatomical locations and developmental timepoints from multiple patient samples with no observed off-target editing. The method allowed us to study the effect of loss of the tumour suppressor gene PTEN in normal human intestinal cells. Analysis of PTEN-deficient organoids defined phenotypes that likely relate to its tumour suppressive function in vivo, such as a proliferative advantage and increased organoid budding. Transcriptional profiling revealed differential expression of genes in pathways commonly known to be associated with PTEN loss, including mTORC1 activation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Although whey protein isolate (WPI) has been shown to be immunomodulatory, its ability to modulate production of a broad array of inflammatory markers has not previously been investigated in healthy adults. We investigated the effects of daily supplementation with 35 g of WPI for 3 weeks on inflammatory marker concentrations in the blood serum and feces of 14 older adult subjects (mean age: 59). Serum was analyzed using a multiplex assay to quantify the cytokines IFN-γ, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A and TNF-α. Fecal samples were analyzed using an ELISA for the inflammatory markers calprotectin and lactoferrin. Our results yielded high inter-subject variability and a significant proportion of cytokine concentrations that were below our method's limit of quantification. We observed decreases in serum IL-12p70 in the washout phase compared with baseline, as well as the washout stage for fecal lactoferrin relative to the intervention stage. Serum IL-13 was also significantly reduced during the intervention and washout stages. Our data suggest that whey protein supplementation did not significantly alter most inflammatory markers measured but can alter concentrations of some inflammatory markers in healthy older adults. However, our study power of 35% suggests the number of participants was too low to draw strong conclusions from our data.

Background: Cross-sectional surveys using the Standardized Monitoring and Assessment of Relief and Transitions methodology have been conducted annually in Chad since 2015 to evaluate population-level nutritional status., Objective: This analysis characterizes national and subnational trends in child wasting and women's thinness from 2015 to 2021 in Chad and identifies risk factors during the COVID-19 pandemic., Methods: Annual survey data with 12,000 to 15,000 households were included. Wasting was estimated for children 6 to 59 months using the WHO child growth standards, and among women 15 to 49 years, thinness was defined as mid-upper arm circumference <23 cm. Trends were stratified by agroecological zone, and chi-square tests used to assess statistical significance. Simple and multivariate logistic regression models were conducted for 2020 and 2021 to identify risk factors of wasting and thinness., Results: About 11,958 to 17,897 children and 9883 to 15,535 women contributed values each year. National wasting and thinness rates did not significantly decrease over the 7-year period (wasting: 14.1% to 12.1%, P = .43; thinness: 15.2% to 13.4%, P = .51) and wasting rose from 2020 to 2021. The Saharan and Sahelian zones had consistently higher rates compared to the Sudanian zone. Younger age, male sex, inadequate infant and young child feeding practices, and poorer household socio-economic factors were associated with greater odds of child wasting. For women, younger age, lack of nutrition knowledge, and poorer household socio-economic factors increased the odds of thinness., Conclusions: Undernutrition in Chad has not improved since 2015, and the COVID-19 pandemic likely exacerbated the crisis among children nationally and among women subnationally. Multisectoral approaches and regional targeting of interventions are recommended.

Background: Osteosarcoma (OS) is an aggressive pediatric cancer with unmet therapeutic needs. Glutaminase 1 (GLS1) inhibition, alone and in combination with metformin, disrupts the bioenergetic demands of tumor progression and metastasis, showing promise for clinical translation. Materials and Methods: Three positron emission tomography (PET) clinical imaging agents, [ 18 F]fluoro-2-deoxy-2-D-glucose ([ 18 F]FDG), 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT), and (2S, 4R)-4-[ 18 F]fluoroglutamine ([ 18 F]GLN), were evaluated in the MG63.3 human OS xenograft mouse model, as companion imaging biomarkers after treatment for 7 d with a selective GLS1 inhibitor (CB-839, telaglenastat) and metformin, alone and in combination. Imaging and biodistribution data were collected from tumors and reference tissues before and after treatment. Results: Drug treatment altered tumor uptake of all three PET agents. Relative [ 18 F]FDG uptake decreased significantly after telaglenastat treatment, but not within control and metformin-only groups. [ 18 F]FLT tumor uptake appears to be negatively affected by tumor size. Evidence of a flare effect was seen with [ 18 F]FLT imaging after treatment. Telaglenastat had a broad influence on [ 18 F]GLN uptake in tumor and normal tissues. Conclusions: Image-based tumor volume quantification is recommended for this paratibial tumor model. The performance of [ 18 F]FLT and [ 18 F]GLN was affected by tumor size. [ 18 F]FDG may be useful in detecting telaglenastat's impact on glycolysis. Exploration of kinetic tracer uptake protocols is needed to define clinically relevant patterns of [ 18 F]GLN uptake in patients receiving telaglenastat.

Objective: Neurosurgery is a safe and effective form of treatment for select children with drug-resistant epilepsy. Still, there is concern that it remains underutilized, and that seizure freedom rates have not improved over time. We investigated referral and surgical practices, patient characteristics, and postoperative outcomes over the past two decades., Methods: We performed a retrospective cohort study of children referred for epilepsy surgery at a tertiary center between 2000 and 2018. We extracted information from medical records and analyzed temporal trends using regression analyses., Results: A total of 1443 children were evaluated for surgery. Of these, 859 (402 females) underwent surgical resection or disconnection at a median age of 8.5 years (interquartile range [IQR] = 4.6-13.4). Excluding palliative procedures, 67% of patients were seizure-free and 15% were on no antiseizure medication (ASM) at 1-year follow-up. There was an annual increase in the number of referrals (7%, 95% confidence interval [CI] = 5.3-8.6; p < .001) and surgeries (4% [95% CI = 2.9-5.6], p < .001) over time. Duration of epilepsy and total number of different ASMs trialed from epilepsy onset to surgery were, however, unchanged, and continued to exceed guidelines. Seizure freedom rates were also unchanged overall but showed improvement (odds ratio [OR] 1.09, 95% CI = 1.01-1.18; p = .027) after adjustment for an observed increase in complex cases. Children who underwent surgery more recently were more likely to be off ASMs postoperatively (OR 1.04, 95% CI = 1.01-1.08; p = .013). There was a 17% annual increase (95% CI = 8.4-28.4, p < .001) in children identified to have a genetic cause of epilepsy, which was associated with poor outcome., Significance: Children with drug-resistant epilepsy continue to be put forward for surgery late, despite national and international guidelines urging prompt referral. Seizure freedom rates have improved over the past decades, but only after adjustment for a concurrent increase in complex cases. Finally, genetic testing in epilepsy surgery patients has expanded considerably over time and shows promise in identifying patients in whom surgery is less likely to be successful., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The accurate prediction of seizure freedom after epilepsy surgery remains challenging. We investigated if (1) training more complex models, (2) recruiting larger sample sizes, or (3) using data-driven selection of clinical predictors would improve our ability to predict postoperative seizure outcome using clinical features. We also conducted the first substantial external validation of a machine learning model trained to predict postoperative seizure outcome., Methods: We performed a retrospective cohort study of 797 children who had undergone resective or disconnective epilepsy surgery at a tertiary center. We extracted patient information from medical records and trained three models-a logistic regression, a multilayer perceptron, and an XGBoost model-to predict 1-year postoperative seizure outcome on our data set. We evaluated the performance of a recently published XGBoost model on the same patients. We further investigated the impact of sample size on model performance, using learning curve analysis to estimate performance at samples up to N = 2000. Finally, we examined the impact of predictor selection on model performance., Results: Our logistic regression achieved an accuracy of 72% (95% confidence interval [CI] = 68%-75%, area under the curve [AUC] = .72), whereas our multilayer perceptron and XGBoost both achieved accuracies of 71% (95% CI MLP  = 67%-74%, AUC MLP  = .70; 95% CI XGBoost own  = 68%-75%, AUC XGBoost own  = .70). There was no significant difference in performance between our three models (all p > .4) and they all performed better than the external XGBoost, which achieved an accuracy of 63% (95% CI = 59%-67%, AUC = .62; p LR  = .005, p MLP  = .01, p XGBoost own  = .01) on our data. All models showed improved performance with increasing sample size, but limited improvements beyond our current sample. The best model performance was achieved with data-driven feature selection., Significance: We show that neither the deployment of complex machine learning models nor the assembly of thousands of patients alone is likely to generate significant improvements in our ability to predict postoperative seizure freedom. We instead propose that improved feature selection alongside collaboration, data standardization, and model sharing is required to advance the field., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In this study, we developed an automated workflow using a deep learning model (DL) to measure the lateral ventricle linearly in fetal brain MRI, which are subsequently classified into normal or ventriculomegaly, defined as a diameter wider than 10 mm at the level of the thalamus and choroid plexus. To accomplish this, we first trained a UNet-based deep learning model to segment the brain of a fetus into seven different tissue categories using a public dataset (FeTA 2022) consisting of fetal T2-weighted images. Then, an automatic workflow was developed to perform lateral ventricle measurement at the level of the thalamus and choroid plexus. The test dataset included 22 cases of normal and abnormal T2-weighted fetal brain MRIs. Measurements performed by our AI model were compared with manual measurements performed by a general radiologist and a neuroradiologist. The AI model correctly classified 95% of fetal brain MRI cases into normal or ventriculomegaly. It could measure the lateral ventricle diameter in 95% of cases with less than a 1.7 mm error. The average difference between measurements was 0.90 mm in AI vs. general radiologists and 0.82 mm in AI vs. neuroradiologists, which are comparable to the difference between the two radiologists, 0.51 mm. In addition, the AI model also enabled the researchers to create 3D-reconstructed images, which better represent real anatomy than 2D images. When a manual measurement is performed, it could also provide both the right and left ventricles in just one cut, instead of two. The measurement difference between the general radiologist and the algorithm ( p = 0.9827), and between the neuroradiologist and the algorithm ( p = 0.2378), was not statistically significant. In contrast, the difference between general radiologists vs. neuroradiologists was statistically significant ( p = 0.0043). To the best of our knowledge, this is the first study that performs 2D linear measurement of ventriculomegaly with a 3D model based on an artificial intelligence approach. The paper presents a step-by-step approach for designing an AI model based on several radiological criteria. Overall, this study showed that AI can automatically calculate the lateral ventricle in fetal brain MRIs and accurately classify them as abnormal or normal.

The outer membrane (OM) protects Gram-negative bacteria from harsh environmental conditions and provides intrinsic resistance to many antimicrobial compounds. The asymmetric OM is characterized by phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. Previous reports suggested an involvement of the signaling nucleotide ppGpp in cell envelope homeostasis in Escherichia coli . Here, we investigated the effect of ppGpp on OM biosynthesis. We found that ppGpp inhibits the activity of LpxA, the first enzyme of LPS biosynthesis, in a fluorometric in vitro assay. Moreover, overproduction of LpxA resulted in elongated cells and shedding of outer membrane vesicles (OMVs) with altered LPS content. These effects were markedly stronger in a ppGpp-deficient background. We further show that RnhB, an RNase H isoenzyme, binds ppGpp, interacts with LpxA, and modulates its activity. Overall, our study uncovered new regulatory players in the early steps of LPS biosynthesis, an essential process with many implications in the physiology and susceptibility to antibiotics of Gram-negative commensals and pathogens., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Aims of the Study: To assess current practices in diagnosing, treating, and following-up giant-cell arteritis by specialists in Switzerland and to identify the main barriers to using diagnostic tools., Methods: We performed a national survey of specialists potentially caring for patients with giant-cell arteritis. The survey was sent by email to all members of the Swiss Societies of Rheumatology and for Allergy and Immunology. A reminder was sent to nonresponders after 4 and 12 weeks. Its questions covered the following dimensions: respondents' main characteristics, diagnosis, treatment, and imaging's role during follow-up. The main study results were summarized using descriptive statistics., Results: Ninety-one specialists, primarily aged 46-65 years (n = 53/89; 59%), working in academic or nonacademic hospitals or private practice, and treating a median of 7.5 (interquartile range [IQR]: 3-12) patients with giant-cell arteritis per year participated in this survey. Ultrasound of temporal arteries/large vessels (n = 75/90; 83%) and positron-emission-tomography-computed tomography (n = 52/91; 57%) or magnetic resonance imaging (n = 46/90; 51%) of the aorta/extracranial arteries were the most common techniques used to diagnose giant-cell arteritis with cranial or large vessel involvement, respectively. Most participants reported a short time to obtain imaging tests or arterial biopsy. The glucocorticoid tapering scheme, glucocorticoid-sparing agent, and glucocorticoid-sparing treatment duration varied among the participants. Most physicians did not follow a predefined repeat imaging scheme for follow-up and mainly relied on structural changes (vascular thickening, stenosis, or dilatation) to drive treatment choice., Conclusions: This survey indicates that imaging and temporal biopsy are rapidly accessible for diagnosing giant-cell arteritis in Switzerland but highlights heterogeneous practice in many disease management areas.

Background: Sexual and gender minority (SGM) persons are at a higher risk for some cancers and may have poorer health outcomes as a result of ongoing minority stress, social stigma, and cisnormative, heteronormative healthcare environments. This study compared patient and provider experiences of affirming environmental and behavioral cues and also examined provider-reported knowledge, attitudes, behaviors, and clinical preparedness in caring for SGM patients among a convenience sample., Methods: National convenience samples of oncology providers ( n = 107) and patients ( n = 88) were recruited separately via snowball sampling. No incentives were provided. After reverse coding of appropriate items for unidirectional analysis, lower scores on items indicated greater knowledge, more affirming attitudes or behaviors, and greater confidence in clinical preparedness to care for SGM patients. Pearson chi-square tests compared dichotomous variables and independent samples t -tests compared continuous variables. Other results were reported using descriptive frequencies., Results: Both patient and provider samples were predominantly female sex assigned at birth, cisgender, and heterosexual. Providers were more likely than patients to report affirming cues in clinic, as well as the ability for patients to easily document their name in use and pronouns. Providers were more likely to report asking about patient values and preferences of care versus patients' recollection of being asked. Patients were more likely to report understanding why they were asked about both sex assigned at birth and gender identity compared to providers' perceptions that patients would understand being asked about both. Patients were also more likely to report comfort with providers asking about sex assigned at birth and gender identity compared to providers' perceptions of patient comfort. SGM providers had greater knowledge of SGM patient social determinants of health and cancer risks; felt more prepared to care for gay patients; were more likely to endorse the importance of knowing patient sexual orientation and gender identity; and were more likely to indicate a responsibility to learn about SGM patient needs and champion positive system changes for SGM patients compared to heterosexual/cisgender peers. Overall, providers wished for more SGM-specific training., Conclusion: Differences between patient and provider reports of affirming environments as well as differences between SGM and heterosexual/cisgender provider care support the need for expanded professional training specific to SGM cancer care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pratt-Chapman, Wang, Quinn, Shirima, Adler, Brazinskaite, Kamen, Radix, Warren, Eckstrand and Lopez.)

This study compared the effects of an increasing-intensity (UP) and a decreasing-intensity (DOWN) resistance training protocol on affective responses across six training sessions. Novice participants (Mage 43.5 ± 13.7 years) were randomly assigned to UP (n = 18) or DOWN (n = 17) resistance training groups. Linear mixed-effects models showed that the evolution of affective valence within each training session was significantly moderated by the group (b = -0.45, p ≤ .001), with participants in the UP group reporting a decline in pleasure during each session (b = -0.82) and the DOWN group reporting an improvement (b = 0.97; ps < .001). Remembered pleasure was significantly higher in the DOWN group compared to the UP group (b = 0.57, p = .004). These findings indicate that a pattern of decreasing intensity throughout a resistance exercise session can elicit more positive affective responses and retrospective affective evaluations of resistance training.

Background: Lyme borreliosis is the most prevalent vector-borne disease in Europe and the USA. Doxycycline for 10 days is the primary treatment recommendation for erythema migrans. To reduce potentially harmful antibiotic overuse by identifying shorter effective treatments, we aimed to assess whether oral doxycycline for 7 days is non-inferior to 14 days in adults with solitary erythema migrans., Methods: In this randomised open-label non-inferiority trial, we enrolled patients with a solitary erythema at the University Medical Centre in Ljubljana, Slovenia. Patients were excluded if they were pregnant or lactating, immunosuppressed, allergic to doxycycline, or had received antibiotics with anti-borrelial activity within 10 days preceding enrolment or had additional manifestations of Lyme borreliosis Adults were randomly allocated 1:1 to receive oral doxycycline 100 mg twice a day for 7 days or 14 days. The primary efficacy endpoint was the difference in proportion of patients with treatment failure, defined as persistent erythema, new objective signs of Lyme borreliosis, or borrelial isolation on skin re-biopsy at 2 months, in a per-protocol analysis (the population that completed the assigned doxycycline regimen according to the study protocol and did not receive any other antibiotics with anti-borrelial activity until the 2-month visit). The non-inferiority margin was 6 percentage points. Safety was assessed in all randomly assigned patients who followed the study protocol and were evaluable at the 14-day visit. This study is registered with ClinicalTrials.gov, NCT03153267., Findings: Between July 3, 2017, and Oct 2, 2018, we enrolled 300 patients (150 per group: median age 56 years [IQR 47-65]; 126 [45%] of 300 male; skin culture positive 72 [30%] of 239 assessed). 295 patients completed antibiotic therapy as per protocol and 294 (98%) patients were evaluable 2 months post-enrolment. Five (3%) of 147 patients from the 7-day group versus 3 (2%) of 147 patients from the 14-day group (one patient did not attend the 2-month visit and was unreachable by telephone) had treatment failure manifesting as persistence of erythema (difference 1·4 percentage points; upper limit of one-sided 95% CI 5·2 percentage points; p=0·64). No patients developed new objective manifestations of Lyme borreliosis during follow-up or had positive repeat skin biopsies. Two (1%) of 150 patients in the 7-day and one (1%) of 150 patients in the 14-day group discontinued therapy due to adverse events., Interpretation: Our data support 7 days of oral doxycycline for adult European patients with solitary erythema migrans, permitting less antibiotic exposure than current guideline-driven therapy., Funding: Slovenian Research Agency and the University Medical Centre Ljubljana., Competing Interests: Declaration of interests DS received support to speak at educational events sponsored by Merck & Co, Sanofi, and Madison Pharma. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

INTRODUCTION: A study was performed to evaluate a cockpit flight simulation suite for measuring moderate altitude effects in a limited subject group. Objectives were to determine whether the apparatus can detect subtle deterioration, record physiological processes throughout hypobaric exposure, and assess recovery. METHODS: Eight subjects trained to perform precision instrument control (PICT) flight and unusual attitude recovery (UAR) and completed chamber flights dedicated to the PICT and UAR, respectively. Each flight comprised five epochs, including ground level pressure (GLP), ascent through altitude plateaus at 10,000, 14,000, and 17,500 ft (3050, 4270, and 5338 m), then postexposure recovery. PICT performance was assessed using control error (FSE) and time-out-of-bounds (TOOB) when pilots exited the flight corridor. UARs were assessed using response times needed to initiate correction and to achieve wings-level attitude. Physiological indices included S p o₂, heart rate (HR), end tidal O₂ and CO₂ pressures, and respiration metrics. RESULTS: Seven subjects completed both flights. PICT performance deteriorated at altitude: FSE increased 33% at 17,513 ft and 21% in Recovery vs. GLP. Mean TOOB increased from 11 s at GLP to 60 s in Recovery. UAR effects were less clear, with some evidence of accelerated responses during and after ascent. CONCLUSIONS: The test paradigm was shown to be effective; piloting impairment was detected during and after exposure. Physiological channels recorded a combination of hypoxia, elevated ventilation, and hypocapnia during ascent, followed by respiratory slowing in recovery. Findings indicate precision piloting and respiration are subject to changes during moderate altitude exposure and may remain altered after S p o₂ recovers, and changes may be linked to hypocapnia. Beer J, Morse B, Dart T, Adler S, Sherman P. Lingering altitude effects during piloting and navigation in a synthetic cockpit . Aerosp Med Hum Perform. 2023; 94(3):135-141.

Background The PINNACLE FLX (Protection Against Embolism for Non-valvular AF [Atrial Fibrillation] Patients: Investigational Device Evaluation of the Watchman FLX LAA [Left Atrial Appendage] Closure Technology) trial evaluated the safety and efficacy of a next-generation left atrial appendage closure device (WATCHMAN FLX; Boston Scientific, Marlborough, MA). At 1 year, the study met the primary end points of safety and anatomical efficacy/appendage closure. This final report of the PINNACLE FLX trial includes the prespecified secondary end point of ischemic stroke or systemic embolism at 2 years, also making it the first report of 2-year outcomes with this next-generation left atrial appendage closure device. Methods and Results Patients with nonvalvular atrial fibrillation with CHA 2 DS 2 -VASc score ≥2 (men) or ≥3 (women), with an appropriate rationale for left atrial appendage closure, were enrolled to receive the left atrial appendage closure device at 29 US centers. Adverse events were assessed by an independent clinical events committee, and imaging was assessed by independent core laboratories. Among 395 implanted patients (36% women; mean age, 74 years; CHA 2 DS 2 -VASc, 4.2±1.5), the secondary efficacy end point of 2-year ischemic stroke or systemic embolism was met, with an absolute rate of 3.4% (annualized rate, 1.7%) and an upper 1-sided 95% confidence bound of 5.3%, which was superior to the 8.7% performance goal. Two-year rates of adverse events were as follows: 9.3% all-cause mortality, 5.5% cardiovascular death, 3.4% all stroke, and 10.1% major bleeding (Bleeding Academic Research Consortium 3 or 5). There were no additional systemic embolisms, device embolizations, pericardial effusions, or symptomatic device-related thrombi after 1 year. Conclusions The secondary end point of 2-year stroke or systemic embolism was met at 3.4%. In these final results of the PINNACLE FLX trial, the next-generation WATCHMAN FLX device demonstrated favorable safety and efficacy outcomes.

Evidence suggests that monovalent vaccine formulations are less effective against the Omicron SARS-CoV-2 than against previous variants. In this retrospective cohort study of hospitalized adults with PCR-confirmed COVID-19 during the Delta (October-November 2021) and Omicron (January-April 2022) variant predominant periods in Slovenia, we assessed the association between primary vaccination against SARS-CoV-2 and progression to critically severe disease (mechanical ventilation or death). Compared with the 529 patients hospitalized for acute COVID-19 during the Delta period (median age 65 years; 58.4% men), the 407 patients hospitalized during the Omicron period (median age 75 years; 50.6% men) were older, more often resided in long-term care facilities, and had higher Charlson comorbidity index scores. After adjusting for age, sex, the Charlson comorbidity index, the presence of immunocompromising conditions, and vaccination status, the patients admitted during the Omicron period had comparable odds of progressing to critically severe disease to those admitted during the Delta period. The 334/936 (35.7%) patients completing at least primary vaccination had lower odds of progression to critically severe disease and shorter hospital stay than unvaccinated patients; however, the protective effect of vaccination was less pronounced during the Omicron than during the Delta period. Although the Omicron variant appeared to better evade immunity induced by monovalent vaccines than the Delta variant, vaccination against SARS-CoV-2 remained an effective intervention to decrease morbidity and mortality in COVID-19 patients infected with the Omicron variant.

Introduction: The University of Texas at Austin College of Pharmacy transitioned the prospective student interview process for the incoming Class of 2025 from an onsite to a virtual Zoom interview. Differences between the two processes were assessed to determine utility of virtual interviews in the future. The objective was to compare preference, impact, and barriers to onsite and virtual interview experiences for prospective students., Methods: A survey to assess interviewees' opinions regarding the interview process, preference, and barriers to participation was emailed to candidates following the 2020-2021 interviews. Responses were evaluated using descriptive statistics, chi-square, Mann-Whitney U tests, and constant comparison thematic analysis., Results: The survey response rate was 40%. Of these, 54% preferred virtual interviews. Travel, lodging, and time were identified as barriers, with 80.5% of interviewees reporting at least one of these barriers. Respondents who chose time or had more barriers were more likely to prefer virtual interviews. Hosting a pre-interview day helped candidates prepare. Having a pharmacy student in the breakout room helped reduce stress. Interviewees were able to engage, showcase their personality, and learn the culture of the college despite the virtual nature., Conclusions: From an interviewee perspective, the virtual interview process is a viable method to continue. Virtual interviews decrease barriers to access for candidates unable to attend onsite interviews while still allowing candidates to feel engaged, learn about the program, and have a positive experience. Pharmacy institutions may consider virtual interviews as an alternative or supplement to onsite interviews., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR., Methods: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m 2 , or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia., Discussion: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR., Trial Registration: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018., (© 2022. The Author(s).)

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Elective admission to the epilepsy monitoring unit (EMU) is an essential service provided by epilepsy centers, particularly for those with drug-resistant epilepsy. Given previously characterized racial and socioeconomic healthcare disparities in the management of epilepsy, we sought to understand access and utilization of this service in New Jersey (NJ). We examined epilepsy hospitalizations in NJ between 2014 and 2016 using state inpatient and emergency department (ED) databases. We stratified admissions by race/ethnicity and primary payer and used these to estimate and compare (1) admission rates per capita in NJ, as well as (2) admission rates per number of ED visits for each group. Patients without insurance underwent elective EMU admission at the lowest rates across all racial/ethnic groups and payer types studied. Black patients with Medicaid and private insurance were admitted at disproportionately low rates relative to their number of ED visits. Hispanic/Latino and Asian/Pacific Islanders with private insurance, Hispanic/Latinos with Medicaid, and Asian/Pacific Islanders with Medicare were also admitted at low rates per capita within each respective payer category. Future studies should focus on addressing causal factors driving healthcare disparities in epilepsy, particularly for patients without adequate health insurance coverage and those who have been historically underserved by the healthcare system., Competing Interests: Declaration of Competing Interest Dr. Zhang has received honorariums from Lundbeck Biopharmaceuticals, Board Vitals, and Fieve Clinical Research. He collaborates with Headache Science Incorporated without receiving financial support. He has ownership interest in Cymbeline LLC. The other authors do not have competing interests to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The human papillomavirus (HPV) vaccine is highly effective at preventing HPV-associated cancers in both males and females, yet vaccination rates remain sub-optimal in part due to vaccine hesitancy. This study sought to assess which strategies vaccine-hesitant parents perceive as most likely to motivate them to vaccinate their children against HPV., Methods: In 2021, we recruited parents with children ages 10-17 years old who were not vaccinated against HPV and who felt unsure or hesitant about their decision to vaccinate their child. Participants were recruited through an online patient portal within a single institution. A screening survey assessed for vaccine hesitancy. Semi-structured interviews focused on HPV vaccine decision-making, motivators, and potential strategies to improve vaccination rates in hesitant parents. Audio recordings were transcribed and analyzed via a combination of deductive and inductive codes., Results and Discussion: A total of twenty-two vaccine-hesitant parents were interviewed. The major themes identified were a lack of confidence in vaccine decision-making, a desire for more information, and dissatisfaction with provider encounters. Parents reported that their hesitancy was driven by concerns about safety and necessity, often based on negative anecdotal reports. Although pediatricians were the most often cited source of vaccine information, many parents were dissatisfied with the encounters they had regarding the vaccine. Parents expressed a desire for detailed information on both the benefits and risks of the vaccine, and resources that allowed them to actively participate in vaccine discussions with providers. Suggested modes of delivery for this information included in-depth pediatrician discussions, written materials provided by pediatricians, and facilitation tools, such as a list of questions to help parents prepare for pediatrician visits. Thus, strategies that empower parents to feel informed and confident in their decision to vaccinate their children could be useful in motivating vaccine-hesitant parents to vaccinate their children against HPV., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objectives: To determine whether radiographic measures of tumor aggressiveness differ by smoking status., Materials and Methods: All patients diagnosed with non-small-cell lung cancer(NSCLC) ≤ 30 mm in maximum diameter, without clinical evidence of metastasis who had both pre-treatment PET scans and two CT scans at least 90 days apart in a prospective cohort, the Initiative for Early Lung Cancer Research on Treatment(IELCART) at Mount Sinai between 2016 and 2020 were identified. Comparison of two measures of tumor aggressiveness, positron emission tomography(PET) SUVmax and tumor volume doubling time(VDT) by smoking status was performed., Results: Of 417 patients identified, 158 patients had pre-treatment PET scans and at least two CT scans available. The two measures of tumor aggressiveness, SUVmax and VDT values were significantly different between patients who had never smoked and those who smoked: patients who never smoked had lower median SUVmax[2.5(IQR: 1.1-4.8) vs. 4.2(IQR:2.1-9.2),p = 0.002] and longer median VDT[(372.6 days vs. 225.6 days,p = 0.001)] compared to those who smoked. Using multivariable analyses, when adjusting for age and sex alone, SUVmax(p = 0.004) and VDT(p = 0.0001) remained significantly different by smoking status. The final multivariable analysis, adjusted for all three co-variates(sex, age and tumor histology) showed no significant difference in SUVmax and VDT by smoking status [SUVmax(p = 0.25) and VDT(p = 0.06)]., Conclusion: Smoking history does not influence VDT or PET SUVmax measures of lung cancer aggressiveness., (Copyright © 2022 Elsevier B.V. All rights reserved.)