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Abstract Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin’ Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.

Abstract Air pollution is a serious environmental health concern for humans and other living organisms. This study analyzes the spatial and temporal characteristics of air pollutant concentrations, changes in the degree of pollution, and the wavelet coherence of the air quality index (AQI) with pollutants in various monitoring stations. The analysis is based on long-term time series data (January 2016 to December 2023) of air pollutants (PM2.5, PM10, and O3) from Korla, an oasis city in the northeastern part of the Tarim Basin, China. The concentrations of PM2.5, PM10, and O3 in Korla showed a cyclical trend from 2016 to 2023; PM10 concentrations exhibited all-season exceedance and PM2.5 exhibited exceedance only in spring. PM2.5 and PM10 showed a seasonal distribution of spring > winter > fall > summer; O3 concentrations showed a seasonal distribution of summer > spring > fall > winter. Strong positive wavelet coherence between PM and Air Quality Index (AQI) data series suggests that the AQI data series can effectively characterize fluctuating trends in PM concentrations. Moreover, PM10 levels IV and VI were maintained at approximately 10%, indicating that sand and dust have a substantial influence on air quality and pose potential threats to the health of urban inhabitants. Based on the results of this study, future efforts must strengthen relative countermeasures for sand prevention and control, select urban greening species with anti-pollution capabilities, rationally expand urban green spaces, and restrict regulations for reducing particulate matter emissions within city areas.

Introduction: Firearm injury remains a public health problem, with nearly 50,000 firearm-related deaths in the US in 2021. Extreme risk protection orders (ERPOs) are civil restraining orders that intend to reduce firearm deaths by temporarily removing firearms from individuals who are threatening violence to themselves or others. We described ERPO use by petitioner type and implementation including firearm removal. Methods: All ERPO petitions filed in Colorado (1/1/2020–12/31/2022) were analyzed using an established abstraction tool and team-based approach. Case data abstracted from petitions and court documents were analyzed descriptively. Results: Over three years, there were 353 ERPO petitions filed in Colorado. Only 39 % percent of granted petitions had documentation of firearms being relinquished. The average number firearms relinquished was 1.8 with a range of 1 to 31 firearms. One third (37.7 %) of petitions mentioned a mental health issue, 10 % had a renewal request, and half (54.6 %) of petitions were filed by law enforcement (LE). LE petitions filed were more likely to be granted temporary ERPOs (94.3 % vs 35.0 %, p

Abstract Drowsiness while driving negatively impacts road safety, especially in truck drivers. The present study investigated the feasibility and alerting effects of a daylight-supplementing in-truck lighting system (DS) providing short-wavelength enriched light before, during, and after driving. In a within-participants design, eight truck drivers drove a fully-loaded truck under wintry Scandinavian conditions (low daylight levels) with a DS or placebo system for five days. Subjective and objective measures of alertness were recorded several times daily, and evening melatonin levels were recorded three times per study condition. DS significantly increased daytime light exposure without causing negative side effects while driving. In addition, no negative carry-over effects were observed on evening melatonin and sleepiness levels or on nighttime sleep quality. Moreover, objective alertness (i.e., psychomotor vigilance) before and after driving was significantly improved by bright light exposure. This effect was accompanied by improved subjective alertness in the morning. This field study demonstrated that DS was able to increase daytime light exposure in low-daylight conditions and to improve alertness in truck drivers before and after driving (e.g., during driving rest periods). Further studies are warranted to investigate the effects of daylight-supplementing in-cabin lighting on driving performance and road safety measures.

Key Clinical Message A plunging ranula may present initially as an extensive vallecular cyst and correct diagnosis may be reached with the use of ultrasound, fluid aspiration for amylase detection, and MRI imaging. Abstract The ranula is a pseudocyst of the sublingual salivary gland and can be divided into two known subtypes. The simple ranula and plunging ranula. While the simple type can be found in the floor of the mouth, the plunging ranula usually pervades the mylohoid muscle and presents as a cervical swelling. The presented case should outline the difficulties in diagnostic and treatment of an uncommon expression of a mucocele above the mylohoid muscle without presenting either a cervical or an intraoral swelling, only extending towards the vallecula. We present a previously unreported clinical manifestation of a ranula of an 18‐year old male, which extends posteriorly, remaining confined in the supramylohyoid muscle space. The cystic lesion protrudes in the oropharynx, and clinically appears as an extensive vallecular cyst. On magnetic resonance imaging the initial suspected diagnosis of a vallecular cyst was changed to the final diagnosis of a plunging ranula. The marsupialization of the cyst sac was performed. Outpatient follow‐up revealed a persisting ostium, indicating a continuous extravasation of the sublingual gland. The present case report describes an unusual clinical presentation of a plunging ranula, remaining above the mylohyoid muscle and protruding into the oropharynx, misdirecting to the first suspected diagnosis of a vallecular cyst. The case highlights the useful contribution of the MRI imaging for differential diagnoses and the need for criteria to indicate further investigations.

Background: Biomechanical analysis of the sagittal alignment of the lumbar spine and pelvis on radiographs is common in clinical practices including chiropractic, physical therapy, scoliosis-related thoraco-lumbo-sacral orthosis (TLSO) management, orthopedics, and neurosurgery. Of specific interest is the assessment of pelvic morphology and the relationship between angle of pelvic incidence, sacral slope, and lumbar lordosis to pain, disability, and clinical treatment of spine conditions. The current state of the literature on the reliability of common methods quantifying these parameters on radiographs is limited. Methods: The objective of this systematic review is to identify and review the available studies on the reliability of different methods of biomechanical analysis of sagittal lumbo-pelvic parameters used in clinical practice. Our review followed the recommendations of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The design of this systematic review was registered with PROSPERO (CRD42023379873). Results: The search strategy yielded a total of 2387 articles. A total of 1539 articles were screened after deduplication and exclusion by automation tools, leaving 473 full-text articles that were retrieved. After exclusion, 64 articles met the inclusion criteria. The preponderance of the evidence showed good to excellent reliability for biomechanical assessment of sagittal lumbo-pelvic spine alignment. Conclusions: The results of this systematic review of the literature show that sagittal radiographic analysis of spinal biomechanics and alignment of the human lumbo-pelvic spine is a reliable tool for aiding diagnosis and management in clinical settings.

Abstract Evidence-based indication for tonsil surgery in patients with recurrent acute tonsillitis (RAT) is an ongoing matter of debate. Since introduction of the German tonsillitis guideline in 2015, the indication criteria for tonsil surgery have become much stricter. It is unclear, if this has changed the indication policy. A retrospective population-based study was performed including all 1398 patients with RAT admitted for tonsil surgery in all Thuringian hospitals in 2011, 2015, and 2019. Changes over the years concerning patients’ characteristics, number of tonsillitis episodes in the last 12 months treated with antibiotics (T12), and decision for tonsillectomy or tonsillotomy were analyzed using univariable and multivariable statistics. The surgical rates decreased from 28.56/100,000 population in 2011 to 23.57 in 2015, and to 11.60 in 2019. The relative amount of patients with ≥ 6 T12 increased from 14.1% in 2011 over 13.3% in 2015 to 35.9% in 2019. Most patients received a tonsillectomy (98% of all surgeries). Decision for tonsillotomy was seldom (1.2%). Multinomial logistic regression analysis with the year 2011 as reference showed that compared to the year 2015, the age of the patients undergoing surgery increased in 2015 (Odds ratio [OR] = 1.024; 95% confidence interval [CI] = 1.014–1.034; p

Abstract Gene fusions and MET exon skipping drive oncogenesis in 8–9% and 3% of non-small cell lung cancers (NSCLC) respectively. Their detection are essential for the management of patients since they confer sensitivity to specific targeted therapies with significant clinical benefit over conventional chemotherapy. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) account for historical reference techniques however molecular-based technologies (RNA-based sequencing and RT-PCR) are emerging as alternative or complementary methods. Here, we evaluated the analytical performance of the fully-automated RT-PCR Idylla GeneFusion assay compared to reference methods using 35 fixed NSCLC samples. Idylla demonstrated overall agreement, sensitivity and specificity of 100% compared to RNASeq. Interestingly, it succeeded in retrieving 10 out of 11 samples with inconclusive results due to insufficient RNA quality for sequencing. Idylla showed an overall agreement, sensitivity and specificity of 90.32%, 91.67% and 89.47% compared to IHC/FISH respectively. Using commercial standards, the limit of detection of the Idylla system for the most frequent fusions and exon skipping ranges between 5 and 10 ng RNA input. These results support that the Idylla assay is a reliable and rapid option for the detection of these alterations, however a particular attention is needed for the interpretation of the expression imbalance.

Background: Cardiogenic shock (CS) following an out-of-hospital cardiac arrest (OHCA) poses significant management challenges, exacerbated by inflammatory responses and infectious complications. This study investigates the microbiological profiles and impacts of mechanical circulatory support (MCS) on inflammation and infection in OHCA patients. Methods: We retrospectively analyzed microbiological data from various specimens of 372 OHCA patients, who were treated at the Cardiac Arrest Center of the University Hospital of Marburg from January 2018 to December 2022. Clinical outcomes were evaluated to investigate the potential impact of MCS on infection and inflammation. Results: Of the study cohort, 115 patients received MCS. The microbiological analysis revealed a higher incidence of positive blood cultures in the MCS group vs. the non-MCS group (39% vs. 27.7%, p = 0.037), with predominantly Gram-positive bacteria. Patients with positive microbiological findings had longer in-hospital stays and prolonged periods of mechanical ventilation. The levels of inflammatory markers such as C-reactive protein (CRP) and procalcitonin (PCT) differed, suggesting a more pronounced inflammatory response in MCS patients, especially in the later ICU stages. Notably, despite the higher infection rate in the MCS group, the survival rates did not significantly differ in the two groups. Conclusions: MCS appears to influence the microbiological and inflammatory landscape in OHCA patients, increasing the susceptibility to certain infections but not affecting the overall mortality. This study underscores the complexity of managing post-resuscitation care and highlights the need for tailored therapeutic strategies to effectively mitigate infectious and inflammatory complications.

This prospective cohort study aimed to characterise the impact of oxaliplatin-based chemotherapy and its neurotoxic side effects (i.e., chemotherapy-induced neuropathy) on functional fall-risk and falls. Twenty chemotherapy-naïve participants (mean age, 59 years; 16 males) were consecutively included. A multimodal fall risk assessment was performed at four time points within 6 months. Polyneuropathy was assessed using the Neurologic Disability Scale; the fall risk was assessed by functional tests (Tinetti Test, Chair-Rising Test, and Timed up and Go Test). Patient-reported outcomes comprised the Hospitality Anxiety and Depression Scale (HADS), the Falls Efficacy Scale – International (FES-I) to assess the fear of falling, and the Physical Activity for the Elderly (PASE) questionnaire. Three falls occurred during the study. All fallen participants had a high fall risk-index (≥4 more risk factors) compared to only 30% of the non-fallen participants (p = 0.03) and suffered more frequently from pre-existing mild polyneuropathy (p = 0.049). Study discontinuation (n = 12) was associated with a higher rate of polypharmacy (p = 0.045), anxiety (HADS-A, p = 0.03), and specific fear of falling (FES-I, p = 0.025). In contrast, study completers (n = 8) reported an improvement in physical activity (PASE) (p = 0.018). In summary, pre-existing fall-risk factors impacted more falls than chemotherapy. A fall risk index offers a time-efficient screening option in an outpatient oncological setting.

(1) Background: This study assessed the relationship between cervical spine parameters taken on standing full-spine lateral radiographic images compared to sectional lateral cervical radiographs. (2) Methods: Full-spine (FS) and sectional lateral cervical (LC) radiographs from four spine treatment facilities across the USA retrospectively provided data collected on 220 persons to assess the comparison of three sagittal cervical radiographic measurements between the two views. The measures included cervical lordosis using the absolute rotation angle from C2-C7, sagittal cervical translation of C2-C7, and atlas plane angle to horizontal. Linear correlation and R2 models were used for statistical comparison of the measures for the two views. (3) Results: The mean values of the three measurements were statistically different from each other: C2-C7 translation (FS = 19.84 ± 11.98 vs. LC = 21.18 ± 11.8), C2-C7 lordosis (FS = −15.3 ± 14.63 vs. LC = −18.32 ± 13.16), and atlas plane (FS = −19.99 ± 8.88 vs. LC = −22.56 ± 8.93), where all values were p < 0.001. Weak-to-moderate-to-strong correlations existed between the full-spine and sectional lateral cervical radiographic variables. The R2 values varied based on the measurement were R2 = 0.768 (p < 0.001) for sagittal cervical translation of C2-C7 (strong), R2 = 0.613 (p < 0.001) for the absolute rotation angle C2-C7 (moderate), and R2 = 0.406 (p < 0.001) for the atlas plane line (weak). Though a linear correlation was identified, there were consistent intra-person differences between the measurements on the full spine versus sectional lateral cervical radiographic views, where the full-spine view consistently underestimated the magnitude of the variables. (4) Conclusion: Key sagittal cervical radiographic measurements on the full spine versus sectional lateral cervical radiographic views show striking intra-person differences. The findings of this study confirm that full spine versus sectional lateral cervical radiographic views provide different biomechanical magnitudes of cervical sagittal alignment, and caution should be exercised by health care providers as these are not interchangeable. We recommend the LC view for measurement of cervical sagittal alignment variables.

Background: Measures of lumbar lordosis (LL) and elliptical modeling variables have been shown to discriminate between normal and chronic low back pain (CLBP) patients. Pelvic morphology influences an individual’s sagittal lumbar alignment. Our purpose is to investigate the sensitivity and specificity of lumbar sagittal radiographic alignment and modeling variables to identify if these can discriminate between normal controls and CLBP patients. Methods: We conducted a computer analysis of digitized vertebral body corners on lateral lumbar radiographs of normal controls and CLBP patients. Fifty normal controls were attained from a required pre-employment physical examination (29 men; 21 women; mean age of 27.7 ± 8.5 years), with no history of low back pain, a normal spinal examination, no pathologies, anomalies, or instability. Additionally, 50 CLBP patients (29 men; 29.5 ± 8 years of age) were randomly chosen and matched to the characteristics of the controls. The inclusion criteria required no abnormalities on lumbar spine radiographs. The parameters included the following: ARA L1-L5 lordosis, ARA T12-S1 lordosis, Cobb T12-S1, b/a elliptical modelling ratio, sacral base angle (SBA), and S1 posterior tangent to vertical (PTS1). Two measures of pelvic morphology were determined for each person—the angle of pelvic incidence (API) and posterior tangent pelvic incidence angle (PTPIA)—and the relationships between API − ARA T12-S1, API − Cobb T12-S1, and API − ARA L1-5 was determined. Descriptive statistics and correlations among the primary variables were determined. The receiver operating characteristic curves (ROC curves) for primary variables were analyzed. Results: The mean values of LL were statistically different between the normal and CLBP groups (p < 0.001), indicating a hypo-lordotic lumbar spine for the CLBP group. The mean b/a ratio was lower in the chronic pain group (p = 0.0066). The pelvic morphology variables were similar between the groups (p > 0.05). API had a stronger correlation to the SBA and Cobb T12-S1 than PTPIA did, while PTPIA had a stronger correlation to the S1 tangent and ARA T12-S1 than API did. While CLBP patients had a stronger correlation of ARA T12-S1 and Cobb T12-S1 relative to the pelvic morphology, they also had a reduced correlation of ARA L1-L5 lordosis relative to their SBA and pelvic morphology measures. API − T12-S1, API − L1-L5, and API − Cobb T12-S1 were statistically different between the groups, p < 0.001. Using ROC curve analyses, it was identified that ARA L1-L5 lordosis of 36° and ARA T12-S1 of 68° have a good sensitivity and specificity to discriminate between normal and CLBP patients. ROC curve analyses identified that lordosis ARAT12-S1 < 68° (AUC = 0.83), lordosis ARAL1-L5 < 36° (AUC = 0.78), API − ARA T12-S1 < −18° (AUC = 0.75), API − ARAL1-L5 > 35° (AUC = 0.71), and API − Cobb T12-S1 < −5° (AUC = 0.69) had moderate to good discrimination between groups (AUC = 0.83, 0.78, 0.75, and 0.72). Conclusions: Pelvic morphology is similar between normal and CLBP patients. CLBP patients have an abnormal ‘fit’ of their API − ARAT12-S1 and L1-L5 lumbar lordosis relative to their pelvic morphology and sacral tilt shown as a hypolordosis.

Background: Forward head posture (FHP) and altered cervical lordotic curvatures are common spine displacements often associated with neck pain and disability. Two primary categories for determining FHP exist: radiographic and postural measurements. Methods: This study investigated the correlation between the craniovertebral angle (CVA), the radiographically measured C2–C7 sagittal vertical axis (SVA), and cervical lordosis (absolute rotation angle: ARA C2–C7) in a sample of participants with chronic myofascial pain (CMP). In 120 participants, we performed both a postural measurement of the CVA and a lateral cervical radiograph, where the C2–C7 SVA and ARA C2–C7 were measured. A linear-regression R2 value to assess the correlation between the CVA, C2–C7 SVA, and ARA C2–C7 was sought. Results: A statistically significant weak linear fit was identified (Spearman’s r = 0.549; R2 = 0.30, p < 0.001) between the CVA and C2–C7 SVA, having considerable variation between the two measures. A statistically significant linear fit (very weak) was identified for the lordosis ARA C2–C7 and the CVA: Spearman’s r = 0.524; R2 = 0.275; p < 0.001. A value of 50° for the CVA corresponded to a value of 20 mm for the C2–C7 SVA on an X-ray. Conclusion: While the CVA and radiographic C2–C7 SVA are weakly correlated in an individual, they seem to represent different aspects of sagittal cervical balance. The CVA cannot replace radiographically measured cervical lordosis. We recommend that more emphasis be given to radiographic measures of sagittal cervical alignment than the CVA when considering patient interventions.

(1) Background: Clinically useful prediction models for chronic postsurgical pain (CPSP) in knee replacement (TKA) are lacking. (2) Methods: In our prospective, multicenter study, a wide-ranging set of 91 variables was collected from 933 TKA patients at eight time points up to one year after surgery. Based on this extensive data pool, simple and complex prediction models were calculated for the preoperative time point and for 6 months after surgery, using least absolute shrinkage and selection operator (LASSO) 1se and LASSO min, respectively. (3) Results: Using preoperative data only, LASSO 1se selected age, the Revised Life Orientation Test on pessimism, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)—subscore pain and the Timed “Up and Go” Test for prediction, resulting in an area under the curve (AUC) of 0.617 and a Brier score of 0.201, expressing low predictive power only. Using data up to 6 months after surgery, LASSO 1se included preoperative Patient Health Questionnaire-4, Knee Injury and Osteoarthritis Outcome Score (KOOS)—subscore pain (pain) 3 months after surgery (month), WOMAC pain 3 and 6 months, KOOS subscore symptoms 6 months, KOOS subscore sport 6 months and KOOS subscore Quality of Life 6 months. This improved the predictive power to an intermediate one (AUC 0.755, Brier score 0.168). More complex models computed using LASSO min did little to further improve the strength of prediction. (4) Conclusions: Even using multiple variables and complex calculation methods, the possibility of individual prediction of CPSP after TKA remains limited.

Summary: Background: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. Methods: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.gov NCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. Findings: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40–266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94–277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69–4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52–3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. Interpretation: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. Funding: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

Background Transgender and gender non-binary (TNB) youth living in the USA report elevated levels of substance use compared with their cisgender counterparts, with previous literature pointing to minority stressors as some of the factors that could facilitate such elevated levels. Yet, substance use and misuse prevalence and associated modifiable factors among TNB youth are not fully known. The current paper details the protocol for a systematic review aimed at (1) identifying substance use and misuse prevalence among TNB youth (ages

Background Due to their high biodiversity, small water bodies play an important role for freshwater ecosystems. Nonetheless, systematic pesticide monitoring in small creeks with a catchment

Abstract Cannabis use characteristics, such as earlier initiation and frequent use, have been associated with an increased risk for developing psychotic experiences and psychotic disorders. However, little is known how these characteristics relate to specific aspects of sub-clinical psychopathology in the general population. Here, we explore the relationships between cannabis use characteristics and psychopathology in a large general population sample (N = 2,544, mean age 29.2 years, 47% women) by employing a network approach. This allows for the identification of unique associations between two cannabis use characteristics (lifetime cumulative frequency of cannabis use, age of cannabis use initiation), and specific psychotic experiences and affective symptoms, while controlling for early risk factors (childhood trauma, urban upbringing). We found particularly pronounced unique positive associations between frequency of cannabis use and specific delusional experiences (persecutory delusions and thought broadcasting). Age of cannabis use initiation was negatively related to visual hallucinatory experiences and irritability, implying that these experiences become more likely the earlier use is initiated. Earlier initiation, but not lifetime frequency of cannabis use, was related to early risk factors. These findings suggest that cannabis use characteristics may contribute differentially to risk for specific psychotic experiences and affective symptoms in the general population.

Objective To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs).Methods Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients’ vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression.Results In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14–347) days in patients being double-vaccinated, and after 88 (range 14–270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p

Online maps showing locations for voluntary, temporary firearm storage are a novel approach in suicide and injury prevention. A study team from two states with maps (Colorado and Washington) interviewed leaders from six additional states with maps and six without. Key considerations for map creation were: trust and partnerships; legal issues; funding; and map maintenance. Addressing these considerations – through stronger networks, liability protection, or sustainable programming – may enhance dissemination and use of out-of-home firearm storage options.

Background: Ageing of skeletal muscle is characterized in some by muscle fiber type grouping due to denervation-reinnervation cycles, but the severity of fiber type grouping varies widely across individuals of the same chronological age. It remains unknown whether fiber type grouping is associated with lower muscle mass and/or reduced physical function in elderly. Therefore, we assessed the relationship between fiber type grouping and indices of muscle mass and physical function in older adults. In addition, we assessed whether fiber type grouping is affected by prolonged resistance training in older adults. Methods: Twenty young (21 ± 2 y) and twenty older (70 ± 4 y) healthy men participated in the present study. Body composition (DXA-scan), quadriceps cross-sectional area (CT-scan) and muscle strength (1RM) were assessed at baseline (young and old) and following 12 weeks of resistance training (old only). Percutaneous skeletal muscle biopsies from the vastus lateralis were collected at baseline (young and old) and following exercise training (old only). Immunohistochemical analyses were performed to evaluate type I and type II muscle fiber distribution, size, myonuclear content and grouping. Results: At baseline, type II fibers were significantly (P

BackgroundFirearm safety among individuals with Alzheimer disease and related dementias (ADRD) is an underdiscussed and underresearched concern in the United States, especially given the growing population of community-dwelling adults with ADRD. The “Safety in Dementia” (SiD) web-based decision aid was developed to support caregivers in addressing firearm access; the efficacy of SiD is unknown. ObjectiveThrough the SiD decision aid, the Safe at Home (S@H) study aims to support caregivers in making decisions about home safety that align with their goals and values, and behaviors regarding firearm access for persons with ADRD and firearm access. MethodsThe S@H study is a 2-armed randomized controlled trial to test the effect of the SiD decision aid on caregivers of community-dwelling adults with ADRD who have firearm access. S@H aims to recruit 500 ADRD caregivers (age ≥18 years, fluent in English or Spanish, and in the United States) through online or social media advertisements and through relevant organizations. Participants are randomized to view SiD or a control website at their own pace; all participants complete web-based questionnaires at baseline, 2 weeks, 2 months, and 6 months. The primary outcome is immediate preparation for decision-making; secondary outcomes include longitudinal decision outcomes and self-reported modifications to firearm access. The relative reach and effectiveness of each recruitment method (online/social media and through relevant organizations) will be assessed by examining differences in caregiver participation, retention rates, and relative cost. ResultsThe study enrollment began in May 2022. As of December 2022, a total of 117 participants had enrolled. ConclusionsThe S@H study is the first randomized trial of a firearm safety decision aid for ADRD caregivers. The results from this study will inform how best to support caregivers in decision-making regarding firearm safety. Further, results may guide approaches for recruiting caregivers and for dissemination of resources. Trial RegistrationClinicalTrials.gov NCT05173922; https://clinicaltrials.gov/ct2/show/NCT05173922 International Registered Report Identifier (IRRID)DERR1-10.2196/43702

It is argued that suitably trained neural language models exhibit key properties of epistemic agency: they hold probabilistically coherent and logically consistent degrees of belief, which they can rationally revise in the face of novel evidence. To this purpose, we conduct computational experiments with rankers: T5 models [Raffel et al. 2020] that are pretrained on carefully designed synthetic corpora. Moreover, we introduce a procedure for eliciting a model's degrees of belief, and define numerical metrics that measure the extent to which given degrees of belief violate (probabilistic, logical, and Bayesian) rationality constraints. While pretrained rankers are found to suffer from global inconsistency (in agreement with, e.g., [Jang et al. 2021]), we observe that subsequent self-training on auto-generated texts allows rankers to gradually obtain a probabilistically coherent belief system that is aligned with logical constraints. In addition, such self-training is found to have a pivotal role in rational evidential learning, too, for it seems to enable rankers to propagate a novel evidence item through their belief systems, successively re-adjusting individual degrees of belief. All this, we conclude, confirms the Rationality Hypothesis, i.e., the claim that suitable trained NLMs may exhibit advanced rational skills. We suggest that this hypothesis has empirical, yet also normative and conceptual ramifications far beyond the practical linguistic problems NLMs have originally been designed to solve.

Abstract Spinal metastases often occur in the advanced stages of breast, lung or prostate cancer, resulting in a significant impact on the patient’s quality of life. Current treatment modalities for spinal metastases include both systemic and localized treatments that aim to decrease pain, improve mobility and structural stability, and control tumour growth. With the development of non-toxic photosensitizer drugs, photodynamic therapy (PDT) has shown promise as a minimally invasive non-thermal alternative in oncology, including for spinal metastases. To apply PDT to spinal metastases, predictive algorithms that optimize tumour treatment and minimize the risk of spinal cord damage are needed to assess the feasibility of the treatment and encourage a broad acceptance of PDT in clinical trials. This work presents a framework for PDT modelling and planning, and simulates the feasibility of using a BPD-MA mediated PDT to treat bone metastases at two different wavelengths (690 nm and 565 nm). An open-source software for PDT planning, PDT-SPACE, is used to evaluate different configurations of light diffusers (cut-end and cylindrical) fibres with optimized power allocation in order to minimize the damage to spinal cord or maximize tumour destruction. The work is simulated on three CT images of metastatically involved vertebrae acquired from three patients with spinal metastases secondary to colorectal or lung cancer. Simulation results show that PDT at a 565 nm wavelength has the ability to treat 90% of the metastatic lesion with less than 17% damage to the spinal cord. However, the energy required, and hence treatment time, to achieve this outcome with the 565 nm is infeasible. The energy required and treatment time for the longer wavelength of 690 nm is feasible ( $${\sim }\,40$$ ∼ 40 min), but treatment aimed at 90% of the metastatic lesion would severely damage the proximal spinal cord. PDT-SPACE provides a simulation platform that can be used to optimize PDT delivery in the metastatic spine. While this work serves as a prospective methodology to analyze the feasibility of PDT for tumour ablation in the spine, preclinical studies in an animal model are ongoing to elucidate the spinal cord damage extent as a function of PDT dose, and the resulting short and long term functional impairments. These will be required before there can be any consideration of clinical trials.

ObjectiveFew patients with suicide risk are counseled on lethal means safety by health providers. This study tested the feasibility of different delivery methods for Lock to Live (L2L), a web-based decision aid of safe storage options for firearms and medications.MethodsPatients reporting suicide ideation on the PHQ9 depression screener during outpatient health visits were included. Invitation messages to visit L2L were sent via combinations of email, text, Electronic Health Record (EHR) message, mailed letter, or provider referral, followed by a survey about storage behavior and acceptability. Provider interviews evaluated logistical considerations and acceptability.ResultsThe population-based method reached 2,729 patients and the best method (EHR message plus 2 email reminders) had 11% uptake (L2L visitation rate). Provider referral had small reach (14 patients) and 100% uptake (all visited). Provider interviews identified several strategies to promote uptake including: EHR reminders, provider training, quality metrics with accountability, a clearly communicated lethal means screening/counseling policy, and strong organizational leadership support.ConclusionDespite the low uptake for population-based (11%), far more patients with suicide risk were engaged in the L2L tool through population-based outreach than provider-referral over the same time frame.

BackgroundPrevention in psychiatry provides a promising way to address the burden of mental illness. However, established approaches focus on specific diagnoses and do not address the heterogeneity and manifold potential outcomes of help-seeking populations that present at early recognition services. Conceptualizing the psychopathology manifested in help-seeking populations from a network perspective of interacting symptoms allows transdiagnostic investigations beyond binary disease categories. Furthermore, modern technologies such as smartphones facilitate the application of the Experience Sampling Method (ESM). ObjectiveThis study is a combination of ESM with network analyses to provide valid insights beyond the established assessment instruments in a help-seeking population. MethodsWe will examine 75 individuals (aged 18-40 years) of the help-seeking population of the Cologne early recognition center. For a maximally naturalistic sample, only minimal exclusion criteria will be applied. We will collect data for 14 days using a mobile app to assess 10 transdiagnostic symptoms (ie, depressive, anxious, and psychotic symptoms) as well as distress level 5 times a day. With these data, we will generate average group-level symptom networks and personalized symptom networks using a 2-step multilevel vector autoregressive model. Additionally, we will explore associations between symptom networks and sociodemographic, risk, and resilience factors, as well as psychosocial functioning. ResultsThe protocol was designed in February 2020 and approved by the Ethics Committee of the University Hospital Cologne in October 2020. The protocol was reviewed and funded by the Köln Fortune program in September 2020. Data collection began in November 2020 and was completed in November 2021. Of the 258 participants who were screened, 93 (36%) fulfilled the inclusion criteria and were willing to participate in the study. Of these 93 participants, 86 (92%) completed the study. The first results are expected to be published in 2022. ConclusionsThis study will provide insights about the feasibility and utility of the ESM in a help-seeking population of an early recognition center. Providing the first explorative phenotyping of transdiagnostic psychopathology in this population, our study will contribute to the innovation of early recognition in psychiatry. The results will help pave the way for prevention and targeted early intervention in a broader patient group, and thus, enable greater intended effects in alleviating the burden of psychiatric disorders. International Registered Report Identifier (IRRID)DERR1-10.2196/35206

Abstract Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. The thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein that is released from secretory organelles and relocalized on the sporozoite plasma membrane. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors. Here, we identified the human platelet-derived growth factor receptor β (hPDGFRβ) as one such protein receptor. Deletion constructs showed that the von Willebrand factor type A and thrombospondin repeat domains of TRAP are both required for optimal binding to hPDGFRβ-expressing cells. We also demonstrate that this interaction is conserved in the human-infective parasite Plasmodium vivax, but not the rodent-infective parasite Plasmodium yoelii. We observed expression of hPDGFRβ mainly in cells associated with the vasculature suggesting that TRAP:hPDGFRβ interaction may play a role in the recognition of blood vessels by invading sporozoites.

Abstract Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44–66), 26% were female and median BMI was 37 kg/m2 (IQR 34–39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by − 200 pg/mL (95%CI − 334 to − 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: − 8.8 pg/mL (95%CI − 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI − 236 to − 113; p

Introduction Increasingly, older adults are turning to emergency departments (EDs) to address healthcare needs. To achieve these research demands, infrastructure is needed to both generate evidence of intervention impact and advance the development of implementation science, pragmatic trials evaluation and dissemination of findings from studies addressing the emergency care needs of older adults. The Geriatric Emergency Care Applied Research Network (https://gearnetwork.org) has been created in response to these scientific needs—to build a transdisciplinary infrastructure to support the research that will optimise emergency care for older adults and persons living with dementia.Methods and analysis In this paper, we describe our approach to developing the GEAR Network infrastructure, the scoping reviews to identify research and clinical gaps and its use of consensus-driven research priorities with a transdisciplinary taskforce of stakeholders that includes patients and care partners. We describe how priority topic areas are ascertained, the process of conducting scoping reviews with integrated academic librarians performing standardised searches and providing quality control on reviews, input and support from the taskforce and conducting a large-scale consensus workshop to prioritise future research topics. The GEAR Network approach provides a framework and systematic approach to develop a research agenda and support research in geriatric emergency care.Ethics and dissemination This is a systematic review of previously conducted research; accordingly, it does not constitute human subjects research needing ethics review. These reviews will be prepared as manuscripts and submitted for publication to peer-reviewed journals, and the results will be presented at conferences.Open Science Framework registered DOI: 10.17605/OSF.IO/6QRYX, 10.17605/OSF.IO/AKVZ8, 10.17605/OSF.IO/EPVR5, 10.17605/OSF.IO/VXPRS.

Fighting has been part of the fabric of the NHL for nearly a century. Recent sharp declines in the frequency of fighting and increased understanding of the long-term consequences of traumatic brain injuries have led many to question whether fighting still has a place in the modern NHL. League commissioner Gary Bettman as recently as 2019 testified before Canadian Parliament that fighting has a deterrent effect, reducing the overall level of violent and dangerous plays within the game. This study empirically examines this claim and tests whether fighting indeed serves as a deterrent to undesirable behaviors in the NHL. I examine data on all regular season penalties from 2010-2019 to determine whether fighting and the threat of fighting is empirically related the level of violence in NHL games. Using a mix of descriptive and quasi-experimental approaches, I find no quantifiable evidence that fighting serves as a deterrent to undesirable violent behaviors in the NHL. To the contrary, I find that teams and players who fight are responsible for a disproportionate amount of the violent penalties that happen across the league. These results have implications for player safety in the many professional-and especially junior-hockey leagues around the world that sanction in-game fighting.

Endothelial cells form the inner layer of blood vessels, making them the first barrier between the blood and interstitial tissues; thus endothelial cells play a crucial role in inflammation. In the inflammatory response, one important element is the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). While other pro-inflammatory agents like thrombin and histamine induce acute but transient changes in endothelial cells, which have been well studied biologically as well as mechanically, TNF-α is primarily known for its sustained effects on permeability and leukocyte recruitment. These functions are associated with transcriptional changes that take place on the timescale of hours and days. Here, we investigated the early mechanical action of TNF-α and show that even just 4 min after TNF-α was added onto human umbilical vein endothelial cell monolayers, there was a striking rise in mechanical substrate traction force and internal monolayer tension. These traction forces act primarily at the boundary of the monolayer, as was to be expected. This increased internal monolayer tension may, in addition to TNF-α's other well-studied biochemical responses, provide a mechanical signal for the cells to prepare to recruit leukocytes.

Background: The purpose of this study is to assess the efficacy of a suture-mediated closure device during percutaneous endovascular aortic repair. Methods: A single-center, retrospective analysis of patients undergoing endovascular repair for infrarenal, thoracic and thoracoabdominal aortic aneurysms and aortic dissections via percutaneous femoral access between April 2017 and June 2021 was performed. The primary endpoint of the study was the efficacy and technical success of the Perclose ProGlide closure device during percutaneous endovascular procedures. The secondary endpoints were intraoperative and postoperative inguinal and vascular complications during and after device use. Results: A total of 376 punctures were performed in 263 patients with the deployment of the ProGlide vascular closure system. Twenty-two cases involved percutaneous re-puncture as part of a staged procedure. The primary and secondary technical success rates were 93.1% (350/376) and 94.7% (356/376), respectively. In 20 patients (5.3%), intraoperative femoral exposure due to complications was required. Postoperative complications occurred in 13 cases (3.5%), 2 of which required surgical reintervention. There was no statistical significance between the type of endovascular procedure and primary technical success (p = 0.56). The introduction of larger-diameter sheaths was not associated with increased intraoperative and postoperative complication rates (p = 0.75 and p = 0.78, respectively). Percutaneous re-puncture of the vascular access site did not result in a lower overall technical success rate (20/22, 90.9% primary technical success rate, p = 0.67; 21/22, 95.5% secondary technical success rate, p = 0.86) or an increased number of perioperative complications (1/22, 4.5% intraoperative complications, p = 0.86; 2/22, 9.1% postoperative complications, p = 0.13). Conclusion: The application of the ProGlide closure system is a safe and efficient method to achieve hemostasis during percutaneous endovascular aortic repair. Complex aortic pathologies, which often require a staged approach with re-puncture, can also be successfully treated with this closure system.

BackgroundFirearms are common in the households of persons with Alzheimer disease and related dementias (ADRD). Safety in Dementia (SiD) is a free web-based decision aid that was developed to support ADRD caregivers in addressing firearm access. ObjectiveWe aimed to evaluate the feasibility and acceptability of SiD among a web-based sample of ADRD caregivers. MethodsSiD was tested in 2 phases by using participants who were recruited from a web-based convenience sample (Amazon Mechanical Turk participants). In phase 1, caregivers were randomized to view either the intervention (SiD) or the control (Alzheimer’s Association materials), and the blinding of participants to the study arms was conducted. In phase 2, caregivers of individuals with ADRD and firearm access were recruited; all of these participants viewed the firearm section of SiD. In both phases, participants viewed SiD independently for as long as they wanted. Measures for evaluating decision-making and SiD acceptability were used, and these were assessed via a self-administered web-based questionnaire. ResultsParticipants were recruited for phases 1 (n=203) and 2 (n=54). Although it was feasible to collect the study outcome data in a web-based format, in phase 1, there were no significant differences between SiD and the control in terms of decision-making and self-efficacy. The majority (137/203, 67.5%) of phase 1 participants spent between 5 and 10 minutes reviewing the resources. In phase 2, 61% (33/54) of participants spent 5 to 10 minutes viewing the firearm section, and 31% (17/54) spent 10 to 20 minutes viewing this section. Usability and acceptability were high across the phases. ConclusionsSiD represents a new resource for promoting safety among people with dementia, and high acceptability was achieved in a pilot trial. In this sample, SiD performed similarly to Alzheimer’s Association materials in supporting decision-making and self-efficacy.

Objectives The main study objective was to identify challenges and barriers experienced by dermatologists and rheumatologists when engaging women of reproductive age in shared decision-making (SDM) related to treatment and management of chronic inflammatory disease (CID) before, during and after pregnancy.Design A mixed-methods study was conducted, employing (1) semistructured interviews, (2) an online survey and (3) triangulation of findings.Participants 524 dermatologists and rheumatologists entered the study; 495 completed it; 388 met inclusion criteria for analysis. Participants were included if actively practising in Germany (GER), the UK or the USA; had a minimum 5% caseload of female patients of reproductive age with either axial spondyloarthritis, psoriasis, psoriatic arthritis or rheumatoid arthritis; and had experience prescribing biologics.Results 48 interviews and 340 surveys were analysed. Interviews underscored dermatologists and rheumatologists’ suboptimal integration of SDM in clinical practice. In the survey, 90% (n=305) did not know about SDM models. A perceived lack of competency counselling patients on pregnancy and family planning was also identified during interviews. Among the survey sample, 44% (n=150) of specialists agreed they preferred leaving pregnancy-related discussions to obstetricians and/or gynaecologists and 57% (n=189) reported having suboptimal skills discussing contraceptive methods with patients. Another finding that emerged from interviews was the perception that all biologics are strictly contraindicated during pregnancy. Suboptimal knowledge was noted among 57% (n=95) of dermatologists and 48% (n=83) of rheumatologists surveyed in that regard, with a statistically significant difference by country among dermatologists (GER: 42% vs UK: 71% vs USA: 57%, p=0.015).Conclusions This study identified low levels of knowledge, skill and confidence, as well as attitudinal issues, that explain why SDM is not fully integrated in dermatology and rheumatology clinical practice. Blended-learning interventions are recommended to assist CID specialists in developing effective communication and patient engagement competencies.

Introduction: Lethal means counseling (to reduce access to firearms or other suicide methods) is a recommended critical yet challenging component of care of suicidal patients. Questions remain about communication strategies for those in acute crisis. Methods: This qualitative study was an analysis of semi-structured interviews with English-speaking, community-dwelling adults with a history of lived-experience of suicidal ideation or attempts in themselves or a family member. We used a mixed inductive and deductive approach to identify descriptive themes related to communication and decision-making. Results: Among 27 participants, 14 (52%) had personal and 23 (85%) had family experience with suicide ideation or attempts. Emergent themes fell into two domains: (1) communication in a state of high emotionality; and (2) specific challenges in communication: initiating, maintaining engagement, considering context. Conclusion: Engaging suicidal individuals in lethal means counseling may be more effective when messaging and approaches consider their emotional state and communication challenges.

Abstract Introduction The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis. Case presentation We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (

Objectives: To present our experience with various therapeutic approaches for the treatment of secondary aortoenteric fistulas following open and endovascular aortic aneurysm repair. Methods and Materials: A retrospective data analysis of patients treated for secondary aortoenteric fistulas in a single vascular institution between January 2005 and December 2018 was performed. Analyzed parameters included patients’ demographics, clinical presentation, diagnostic work-up, perioperative data and repair durability during follow-up. Results: Twenty-three patients with aortoenteric fistulas were treated in the target period. The fistulous connection was located in 21 cases (91.3%) in the duodenum and in two cases (8.7%) in the small intestine. Average time between the initial procedure and detection of the aortoenteric fistula was 69.4 ± 72.5 months. The most common presenting symptom was gastrointestinal bleeding (n = 12, 52.2%), followed by symptoms suggestive of chronic infection (n = 11, 47.8%). Open surgical repair was performed in 19 patients (bridging in 3 patients), and endovascular repair was carried out in two cases and one patient underwent a hybrid operation. One patient underwent abscess drainage due to significant comorbidities. Mean follow-up was 35.1 ± 35.5 months. In-hospital mortality and overall mortality were 43.5% (10/23) and 65.2% (15/23), respectively. Patients presenting with bleeding had a significantly higher perioperative mortality rate in comparison to patients presenting with chronic infection (66.7% (8/12) and 18.2% (2/11), respectively, p = 0.019). Patients who underwent stent-graft implantation for control of acute life-threatening bleeding showed significantly better perioperative survival in comparison to patients that were acutely treated with an open procedure (66.6%, (4/6) and 0% (0/6), respectively, p = 0.014). Perioperative mortality was also higher for ASA IV patients (71.4%, 5/7), when compared to ASA III Patients (31.2%, 5/16), although this did not reach statistical significance (p = 0.074). Conclusion: Treatment of secondary aortoenteric fistulas is associated with a high perioperative mortality rate. Patients who survive the perioperative period following open surgical repair in the absence of hemorrhagic shock show acceptable midterm results during follow-up. Stent-graft implantation for bleeding control in patients presenting with life-threatening bleeding seems to be associated with lower perioperative mortality rates.

More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.

Tension and mechanical properties of muscle tissue are tightly related to proper skeletal muscle function, which makes experimental access to the biomechanics of muscle tissue formation a key requirement to advance our understanding of muscle function and development. Recently developed elastic in vitro culture chambers allow for raising 3D muscle tissue under controlled conditions and to measure global tissue force generation. However, these chambers are inherently incompatible with high-resolution microscopy limiting their usability to global force measurements, and preventing the exploitation of modern fluorescence based investigation methods for live and dynamic measurements. Here, we present a new chamber design pairing global force measurements, quantified from post-deflection, with local tension measurements obtained from elastic hydrogel beads embedded in muscle tissue. High-resolution 3D video microscopy of engineered muscle formation, enabled by the new chamber, shows an early mechanical tissue homeostasis that remains stable in spite of continued myotube maturation.

The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.

Introduction Degenerative cervical myelopathy (DCM) is a disabling spinal disorder characterised by sensorimotor deficits of upper and lower limbs, neurogenic bladder dysfunction and neuropathic pain. When suspected, cervical MRI helps to reveal spinal cord compression and rules out alternative diagnoses. However, the correlation between radiological findings and symptoms is weak. Cerebrospinal fluid pressure (CSFP) analysis may complement the appreciation of cord compression and be used for intraoperative and postoperative monitorings in patients undergoing surgical decompression.Methods and analysis Twenty patients diagnosed with DCM undergoing surgical decompression will receive standardised lumbar CSFP monitoring immediately before, during and 24 hours after operation. Rest (ie, opening pressure, CSF pulsation) and stimulated (ie, Valsalva, Queckenstedt’s) CSFP—findings in DCM will be compared with 20 controls and results from CSFP monitoring will be related to clinical and neurophysiological findings. Arterial blood pressure will be recorded perioperatively and postoperatively to calculate spinal cord perfusion pressure and spinal vascular reactivity index. Furthermore, measures of CSFP will be compared with markers of spinal cord compression by means of MR imaging.Ethics and dissemination The study protocol conformed to the latest revision of the Declaration of Helsinki and was approved by the local Ethics Committee of the University Hospital of Zurich (KEK-ZH number PB-2016-00623). The main publications from this study will cover the CSFP fluid dynamics and pressure analysis preoperative, perioperative and postoperative correlated with imaging, clinical scores and neurophysiology. Other publications will deal with preoperative and postoperative spinal perfusion. Furthermore, we will disseminate an analysis on waveform morphology and the correlation with blood pressure and ECG. Parts of the data will be used for computational modelling of cervical stenosis.Trial registration number ClinicalTrials.gov Registry (NCT02170155).

BackgroundCancer patients often suffer from the physical and psychological burden of their disease and its treatment. This is frequently insufficiently identified and addressed in clinical practice. In the context of improving patient-centered care in oncological patients, patient-reported outcomes (PROs) represent an important addition to current routine care. So far, available PRO questionnaires for cancer patients are unsuitable for routine procedures due to their length and complexity. ObjectiveThis study aimed to develop and psychometrically test a short questionnaire to measure health-related quality of life (HrQoL) in cancer patients for use in routine care. MethodsThis observational study consists of two parts: (1) a qualitative study to develop a short questionnaire measuring HrQoL and (2) a quantitative study to psychometrically test this questionnaire in five oncological departments of a comprehensive cancer center. In part 1 of the study, semistructured interviews with 28 cancer patients, as well as five focus groups with 22 clinicians and nurses, were conducted to identify clinically relevant dimensions of HrQoL. The identified dimensions were complemented with related dimensions from empirical studies and reviewed via expert discussion. Based on this, a short instrument was developed. In part 2 of the study, the developed questionnaire was tested in cancer in- and outpatients at five participating oncological clinics using additional standardized questionnaires assessing HrQoL and other important PROs. The questionnaire was presented to more than 770 patients twice during treatment. ResultsThe project started in May 2017 with recruitment for study phase I beginning in December 2017. Recruitment for study phases I and II ended in April 2018 and February 2019, respectively. After study phase II and psychometrical analyses, the newly developed questionnaire measuring the HrQoL of all cancer entities in routine care was finalized. ConclusionsWith five to six dimensions and one item per dimension, the developed questionnaire is short enough to not disrupt routine procedures during treatment and is profound enough to inform clinicians about the patient’s HrQoL impairments and status. Trial RegistrationOpen Science Framework Registries 10.17605/OSF.IO/Y7XCE; https://osf.io/y7xce/ International Registered Report Identifier (IRRID)RR1-10.2196/17854

BackgroundDental professionals are subjected to higher risks for musculoskeletal disorders (MSDs) than other professional groups, especially the hand region. This study aims to investigate the prevalence of hand complaints among dentists (Ds) and dental assistants (DAs) and examines applied therapies.MethodsFor this purpose, an online questionnaire analysed 389 Ds (240female/149male) and 406 DAs (401female/5male) working in Germany. The self-reported data of the two occupational groups were compared with regard to the topics examined. The questionnaire was based on the Nordic Questionnaire (self-reported lifetime, 12-month and 7-day MSDs prevalence of the hand, the conducted therapy and its success), additional occupational and sociodemographic questions as well as questions about specific medical conditions.Results30.8% of Ds affirmed MSDs in the hand at any time in their lives, 20.3% in the last twelve months and 9.5% in the last seven days. Among DAs, 42.6% reported a prevalence of MSDs in the hand at any time in their lives, 31.8% in the last 12 months and 15.3% in the last seven days. 37.5% of the Ds and 28.3% of the DAs stated that they had certain treatments. For both, Ds and DAs, physiotherapy was the most frequently chosen form of therapy. 89.7% of Ds and 63.3% of DAs who received therapy reported an improvement of MSDs.ConclusionAlthough the prevalence of MSDs on the hand is higher among DAs than among Ds, the use of therapeutic options and the success of therapy is lower for DAs compared to Ds.

Abstract Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes – to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254–649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254–649T > G CLRN1 represents a founder allele that may significantly contribute to deafblindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes.

Use of electronic media is widespread among adolescents. Many male adolescents spend a major part of their evenings playing video games. The increased exposure to artificial light as well as the exciting nature of this pastime is under suspicion to impair sleep. Sleep is considered to be important for memory consolidation, so there is also a potential risk for memory impairment due to video gaming. As learning and gaining knowledge is a very important part of adolescence, we decided to study the effects of prolonged video gaming on sleep and memory. The study was structured in a repeated measures design. Eighteen male participants played either the violent video game "Counter Strike: Global Offensive" or the board game "Monopoly" for five hours each on two Saturday nights. The game evenings were followed by sleep studies. Memory testing and vigilance evaluation was performed the next morning. During the course of the study, saliva samples were taken to determine melatonin and cortisol levels. The results of this crossover study showed slightly reduced sleep efficiency after "Counter Strike: Global Offensive" (-3.5%, p = .017) and impaired declarative memory recall (p = .005) compared to "Monopoly". Melatonin levels at bedtime were lower after "Counter Strike: Global Offensive" (p = .005), cortisol levels were elevated while playing the video game (p = .031). Negative effects on sleep were not strong but consistent with more wake after sleep onset (+12 min) and a higher arousal index after "Counter Strike: Global Offensive". We conclude that excessive video gaming in the evening can contribute to worsened sleep and impaired memory in male adolescents.

Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.

BackgroundPharmacodynamic biomarkers are becoming increasingly valuable for assessing drug activity and target modulation in clinical trials. However, identifying quality biomarkers is challenging due to the increasing volume and heterogeneity of relevant data describing the biological networks that underlie disease mechanisms. A biological pathway network typically includes entities (e.g. genes, proteins and chemicals/drugs) as well as the relationships between these and is typically curated or mined from structured databases and textual co-occurrence data. We propose a hybrid Natural Language Processing and directed relationships-based network analysis approach using IBM Watson for Drug Discovery to rank all human genes and identify potential candidate biomarkers, requiring only an initial determination of a specific target-disease relationship.MethodsThrough natural language processing of scientific literature, Watson for Drug Discovery creates a network of semantic relationships between biological concepts such as genes, drugs, and diseases. Using Bruton's tyrosine kinase as a case study, Watson for Drug Discovery's automatically extracted relationship network was compared with a prominent manually curated physical interaction network. Additionally, potential biomarkers for Bruton's tyrosine kinase inhibition were predicted using a matrix factorization approach and subsequently compared with expert-generated biomarkers.ResultsWatson's natural language processing generated a relationship network matching 55 (86%) genes upstream of BTK and 98 (95%) genes downstream of Bruton's tyrosine kinase in a prominent manually curated physical interaction network. Matrix factorization analysis predicted 11 of 13 genes identified by Merck subject matter experts in the top 20% of Watson for Drug Discovery's 13,595 ranked genes, with 7 in the top 5%.ConclusionTaken together, these results suggest that Watson for Drug Discovery's automatic relationship network identifies the majority of upstream and downstream genes in biological pathway networks and can be used to help with the identification and prioritization of pharmacodynamic biomarker evaluation, accelerating the early phases of disease hypothesis generation.

ObjectivesThe aim of this study was to examine the natural history of brain involvement in adult-onset myotonic dystrophies type 1 and 2 (DM1, DM2).MethodsWe conducted a longitudinal observational study to examine functional and structural cerebral changes in myotonic dystrophies. We enrolled 16 adult-onset DM1 patients, 16 DM2 patients, and 17 controls. At baseline and after 5.5 ± 0.4 years participants underwent neurological, neuropsychological, and 3T-brain MRI examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps (baseline-follow-up in each participant) to focus on disease-related effects over time.ResultsWe found minor neuropsychological deficits with mild progression in DM1 more than DM2. Daytime sleepiness was restricted to DM1, whereas fatigue was present in both disease entities and stable over time. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up. In DM2, white matter reduction was of lesser extent, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Intriguingly, longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls.ConclusionThe lack of significant disease-related progression of gray and white matter involvement over a period of five years in our cohort of DM1 and DM2 patients suggests either a rather slowly progressive process or even a stable course of cerebral changes in middle-aged adult-onset patients. Being the first longitudinal neuroimaging trial in DM1 and DM2, this study provides useful additional information regarding the natural history of brain involvement.

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.