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Background Indications and outcomes in lumbar spinal fusion for degenerative disease are notoriously heterogenous. Selected subsets of patients show remarkable benefit. However, their objective identification is often difficult. Decision-making may be improved with reliable prediction of long-term outcomes for each individual patient, improving patient selection and avoiding ineffective procedures. Methods Clinical prediction models for long-term functional impairment [Oswestry Disability Index (ODI) or Core Outcome Measures Index (COMI)], back pain, and leg pain after lumbar fusion for degenerative disease were developed. Achievement of the minimum clinically important difference at 12 months postoperatively was defined as a reduction from baseline of at least 15 points for ODI, 2.2 points for COMI, or 2 points for pain severity. Results Models were developed and integrated into a web-app (https://neurosurgery.shinyapps.io/fuseml/) based on a multinational cohort [N = 817; 42.7% male; mean (SD) age: 61.19 (12.36) years]. At external validation [N = 298; 35.6% male; mean (SD) age: 59.73 (12.64) years], areas under the curves for functional impairment [0.67, 95% confidence interval (CI): 0.59–0.74], back pain (0.72, 95%CI: 0.64–0.79), and leg pain (0.64, 95%CI: 0.54–0.73) demonstrated moderate ability to identify patients who are likely to benefit from surgery. Models demonstrated fair calibration of the predicted probabilities. Conclusions Outcomes after lumbar spinal fusion for degenerative disease remain difficult to predict. Although assistive clinical prediction models can help in quantifying potential benefits of surgery and the externally validated FUSE-ML tool may aid in individualized risk–benefit estimation, truly impacting clinical practice in the era of “personalized medicine” necessitates more robust tools in this patient population.

Purpose Adolescent idiopathic scoliosis (AIS) affects up to 3% of otherwise healthy adolescents. The extreme long-term outcomes of nonoperative treatment are underreported. This study aimed to investigate the long-term outcome of nonoperative-treated AIS patients. Comparison between a bracing and an observation approach were performed. Methods In a retrospective cohort study, 20 nonoperatively treated AIS patients were observed concerning patient-related outcome measures (PROM) (visual analog scale (VAS), Short Form Health Survey 36 item (SF 36), Scoliosis Research Society (SRS 24), Oswestry Low Back Pain Disability Index (ODI), Psychological General Well-Being Index (PGWBI)), radiological curve progression and health-related quality of life (HRQoL). Baseline characteristics and radiological imaging were collected. At follow-up, anteroposterior and lateral X-rays as well as questionnaires were analyzed. Results Twenty patients (16 females, mean age: 14.6 ± 3.2 years) with a follow-up time of 42 ± 9 years were included. Nine patients (initial Cobb 35° ± 19°) were treated with bracing for a mean time of 26 ± 9 months, while the other 11 patients (initial Cobb 29° ± 11°) were observed. The primary curve progressed from 32° ± 15° to 52° ± 25° in average with no significant difference between the cohorts (p = 0.371). At final follow-up, a mean ODI score of 7 ± 7.9 points with no difference depending on the treatment (p = 0.668) was seen. No significant differences were observed for PROMs. Curve magnitude correlated neither at diagnosis (p = 0.617) nor at follow-up (p = 0.535) with the ODI score at final follow-up. Conclusion After a mean of 42 years, patients with nonoperative treatment of moderate AIS demonstrated a good clinical outcome despite progression of the deformity. Level of evidence Level IV, therapeutic study.

Objectives This article presents the findings of a pilot study situated in a tertiary care cancer centre and examines the impact of an art therapy group on the experiences of women living through breast cancer. Study design The study design used in this study is a qualitative cross-case comparative case. Methods Ten women were interviewed about their experiences making art, many for the first time. Interviews were transcribed and analysed, along with the participants’ artist statements. Results Categories include the following: the significant benefits of art therapy on their sense of self-efficacy; the emotionally enhancing nature of making art for the first time; the power of their artwork to trigger insights about themselves (including subcategories of self-actualization, existential growth, and post-traumatic growth) or in communicating their experiences to loved ones; and how making art changed their worldview and life philosophies, creating doorways of possibilities. Conclusion This study suggests that art therapy provides a safe context to reflect on profound personal changes and to re-story losses following adversity through creative practices as a dimension of care.

Demonstrate how self-reported health (SRH) percentile ranks can be used in public health and clinical practice for better interpretable data.Secondary analysis was completed to standardize Health Status Questionnaire-12 Version 2.0 (HSQ-12) scores. The HSQ-12 is a multi-item measure of SRH, with a Total Health Status Scale (THSS) and two subscales, Physical Health Status Scale (PHSS) and Mental Health Status Scale (MHSS). The sample included adult (19 and older) participants in Medicaid, including a normed sample (n=7,110) and population cohorts of midlife women (n=417) and pregnant women (n=1,888).Normed percentile data for HSQ-12 using the Medicaid sample were calculated and populations of midlife and pregnant women were compared with the normed percentile ranks. Results illustrate differences in percentile rank scores for the various population cohorts.This innovative strategy has the potential to lead to decisions that may positively influence health policies, outcomes, and lower health costs.

Introduction The assessment of energy expenditure (EE) at workplaces maintains a central topic in occupational health due to increasing work-related issues. Today 80% of employees in the healthcare system are women. Limited research concerning their physical activity at work is available. The purpose of the study was the investigation of body composition, maximum physical capacity and quantification of physical work activity for female healthcare workers under real-time conditions. Methods Occupational physical activity (PA) of 33 female healthcare workers in a university hospital was quantified. Health associate professionals (HAP), health professionals (HP), and females working from cleaners and helpers (CH) department participated. All underwent cardio pulmonary exercise test. For every working task VO2, VCO2 and RER were measured and EE was calculated individually for each task. Results Forty-two different working tasks were identified and grouped in seven categories to compare physical activity (PA): ‘office and laboratory work’, ‘bedside patient care’, ‘instrument reprocessing, packing boxes’, ‘walking with patient, or alone’, ‘pushing carts or wheelchairs’, ‘strenuous cleaning in bent posture’ and ‘lifting heavy boxes, weights or items’. By comparing groups of healthcare workers, CH and HAP spent significant (p < 0.01) more EE (in kcal/min) 3.9 resp. 3.2 than HP 2.5. Light PA e.g. office and laboratory work (2.7 ± 0.6) and bedside patient care (2.9 ± 0.7) were accomplished by HP and HAP while HAP and CH performed moderate PA such as ‘packing boxes’ (3.6 ± 0.8), ‘pushing carts’ and ‘strenuous cleaning’ (4.7 ± 0.9). Work performed by CH and HAP, i.e. ‘strenuous cleaning’ and ‘lifting heavy items’ showed highest kcal per kg Fat Free Mass (FFM) per hour with 5.80 [4.05–7.81] and 6.94 [5.18–9.03] kcal/kgFFM/h. Conclusion Our findings lend preliminary support to the hypothesis that the majority of activities in female healthcare workers were of low and moderate PA and can be accomplished by middle aged and even older female workers. CH performed tasks with heavy physical activities (PA) like cleaning and lifting heavy weights. HAP performed light/moderate PA below their maximum physical capacity.

Background Mobility is important for daily life functioning, with particular challenges regarding road safety under pharmacological treatment in patients with a psychiatric disease. Methods According to PRISMA guidelines, a systematic literature search on PubMed database (January 1970 to December 2020) was performed. Primary endpoints were driving performance in on-road tests, driving simulator performance, or psychomotor and visual perception functions assessed to estimate fitness to drive according to legal regulations in patient studies. Results Forty studies were identified (1533 patients, 38% female, median age 45 years), of which more than 60% were cross-sectional and open-label trials. Under steady-state medication, 31% (range 27%–42.5%) of schizophrenic or schizoaffective patients under antipsychotics and 18% (range 16%–20%) of unipolar and bipolar patients under antidepressants showed severe impairment in skills relevant for driving. Data point to an advantage of second-generation antipsychotics compared with first-generation antipsychotics as well as modern antidepressants over tricyclic antidepressants with respect to driving. Most patients significantly improved or stabilized in driving skills within 2–4 weeks of treatment with non-sedative or sedative antidepressants. Diazepam significantly worsened driving the first 3 weeks after treatment initiation, whereas medazepam (low dose), temazepam, and zolpidem did not impair driving. In long-term users of sedating antidepressants or benzodiazepines, impairments in on-road tests were not evident. Conclusion The available evidence suggests that psychopharmacologic medicines improve or at least stabilize driving performance of patients under long-term treatment when given on clinical considerations. To enhance treatment compliance, existing classification systems of medicinal drugs concerning impact on driving performance should also incorporate information about effects of long-term-treatment.

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

Supplemental Digital Content is Available in the Text., Endometriosis (ENDO) and interstitial cystitis/bladder pain syndrome (IC/BPS) are chronic pain conditions for which better treatments are urgently needed. Development of new therapies with proven clinical benefit has been slow. We have conducted a review of existing preclinical in vivo models for ENDO and IC/BPS in rodents, discussed to what extent they replicate the phenotype and pain experience of patients, as well as their relevance for translational research. In 1009 publications detailing ENDO models, 41% used autologous, 26% syngeneic, 18% xenograft, and 11% allogeneic tissue in transplantation models. Intraperitoneal injection of endometrial tissue was the subcategory with the highest construct validity score for translational research. From 1055 IC/BPS publications, most interventions were bladder centric (85%), followed by complex mechanisms (8%) and stress-induced models (7%). Within these categories, the most frequently used models were instillation of irritants (92%), autoimmune (43%), and water avoidance stress (39%), respectively. Notably, although pelvic pain is a hallmark of both conditions and a key endpoint for development of novel therapies, only a small proportion of the studies (models of ENDO: 0.5%-12% and models of IC/BPS: 20%-44%) examined endpoints associated with pain. Moreover, only 2% and 3% of publications using models of ENDO and IC/BPS investigated nonevoked pain endpoints. This analysis highlights the wide variety of models used, limiting reproducibility and translation of results. We recommend refining models so that they better reflect clinical reality, sharing protocols, and using standardized endpoints to improve reproducibility. We are addressing this in our project Innovative Medicines Initiative-PainCare/Translational Research in Pelvic Pain.

Background Exact knowledge of the sacral anatomy is crucial for the percutaneous insertion of iliosacral screws. However, dysplastic anatomical patterns are common. In addition to a preoperative computed tomography (CT) analysis, conventional radiographic measures may help to identify upper sacral dysplasia and to avoid damage to surrounding structures. Aiming to further increase safety in percutaneous iliosacral screw placement in the presence of sacral dysmorphism, this study examined the prevalence of previously established radiographic signs and, in addition, defined the “critical SI angle” as a new radiographic criterion. Methods Pelvic CT scans of 98 consecutive trauma patients were analysed. Next to assessment of established signs indicating upper sacral dysplasia, the critical sacroiliac (SI) angle was defined in standardized pelvic outlet views. Results The critical SI angle significantly correlates with the presence of mammillary bodies and an intraarticular vacuum phenomenon. With a cut-off value of − 14.2°, the critical SI angle detects the feasibility of a safe iliosacral screw insertion in pelvic outlet views with a sensitivity of 85.9% and a specificity of 85.7%. Conclusions The critical SI angle can support the decision-making when planning iliosacral screw fixation. The clinical value of the established signs of upper sacral dysplasia remains uncertain.

Background High continuity of care is a key feature of strong general practice. This study aimed to assess the effect of a programme for enhancing strong general practice care on the continuity of care in Germany. The second aim was to assess the effect of continuity of care on hospitalization patterns. Methods We performed an observational study in Germany, involving patients who received a strong general practice care programme (n=1.037.075) and patients who did not receive this programme (n=723.127) in the year 2017. We extracted data from a health insurance database. The cohorts were compared with respect to three measures of continuity of care (Usual Provider Index, Herfindahl Index, and the Sequential Continuity Index), adjusted for patient characteristics. The effects of continuity in general practice on the rates of hospitalization, rehospitalization, and avoidable hospitalization were examined in multiple regression analyses. Results Compared to the control cohort, continuity in general practice was higher in patients who received the programme (continuity measures were 12.47 to 23.76% higher, PP Conclusion Higher continuity of care may be one of the mechanisms underlying lower hospitalization rates in patients who received strong general practice care, but further research is needed to examine the causality underlying the associations.

A study of in vitro refolding and isotope effects on protein structure, activity and stability shows that different folding dynamics can lead to important changes in protein properties., The biological function of a protein is intimately related to its structure and dynamics, which in turn are determined by the way in which it has been folded. In vitro refolding is commonly used for the recovery of recombinant proteins that are expressed in the form of inclusion bodies and is of central interest in terms of the folding pathways that occur in vivo. Here, biophysical data are reported for in vitro-refolded hydrogenated hen egg-white lysozyme, in combination with atomic resolution X-ray diffraction analyses, which allowed detailed comparisons with native hydrogenated and refolded perdeuterated lysozyme. Distinct folding modes are observed for the hydrogenated and perdeuterated refolded variants, which are determined by conformational changes to the backbone structure of the Lys97–Gly104 flexible loop. Surprisingly, the structure of the refolded perdeuterated protein is closer to that of native lysozyme than that of the refolded hydrogenated protein. These structural differences suggest that the observed decreases in thermal stability and enzymatic activity in the refolded perdeuterated and hydrogenated proteins are consequences of the macromolecular deuteration effect and of distinct folding dynamics, respectively. These results are discussed in the context of both in vitro and in vivo folding, as well as of lysozyme amyloidogenesis.

Physical effort of workload of female employees in the healthcare system is perceived to rise. Research focused mainly on physical activity levels of registered nurses (RN). Therefore, we investigated physical strain during daily routine of other hospital workers next to RN. O

We report on outcomes of surgically versus (vs) non-surgically treated patients with moderate adolescent idiopathic scoliosis (AIS) after minimum of 29 years. AIS patients with a follow-up of ≥ 41 years in the surgical group and ≥ 29 years in the non-surgical group were included. Patients were treated surgically for primary curves ≥ 45° vs non-surgically for curves

Background A secondary care hospital in rural India serving a highly tuberculosis (TB) and malnutrition endemic region. Objective In this study conducted on patients with chronic protein energy malnutrition (PEM) and TB, we sought to compare nurse-estimated vs. smartphone photograph analytic methods for assessing caloric intake and determine the incidence of refeeding hypophosphatemia (RH) and refeeding syndrome (RFS) in patients with TB. Methods Inpatients were prospectively enrolled. Baseline demographic, comorbidity and preadmission caloric data were collected. Nurse estimated caloric intake was compared with digital “before and after” meal images. Serum phosphorus was measured on days 1, 3 and 7 post admission. Patients with RH underwent further evaluation for RFS-associated findings. Results 27 patients were enrolled. 85% were at risk of RFS by National Institute for Health and Care Excellence (NICE) criteria. Significant discrepancy (>700 calories) was noted between nurse-estimated caloric intake compared to digital images. RH was found in 37% (10/27). None developed clinical RFS. Conclusions Our study suggests more standardized methods of caloric intake are needed in resource-limited settings with high co-prevalence of PEM and TB. We noted that despite RH being common in inpatients with PEM+TB given high caloric diets, RFS was not detected.

Introduction and objectives: The ability to adapt to new task demands flexibly and to stabilise performance in the presence of distractors is termed cognitive control and is mediated by dopaminergic and cholinergic neurotransmission. We aimed to test the hypothesis that the effect of the cholinergic agonist nicotine on cognitive control depends on baseline dopamine levels. Methods: Thirty-eight healthy non-smokers (16 males; Mage=24.05 years) performed a cognitive control task including distractor and switch trials twice. Subjects were split into two parallel groups. One group received 2 g of L-tyrosine two hours prior to testing to manipulate dopamine availability experimentally, while the other group received placebo on both days. One hour later, both groups received in a within-subject design: on one day, a 7 mg nicotine patch; on the other day, a matched placebo. Response time costs for distractor and switch trials served as measures of cognitive stability and flexibility. Results: Nicotinic modulation reduced response time costs in switch trials and increased costs in distractor trials (nicotine×condition, p=0.027) with a trend-wise interaction between nicotine, L-tyrosine and trial type (nicotine×L-tyrosine×condition, p=0.068), which was due to stronger nicotine effects under L-tyrosine. Conclusions: Our data provide preliminary evidence that nicotine has opponent effects on cognitive stability and flexibility. Subjects who received the dopamine precursor L-tyrosine were more prone to nicotine effects on behaviours, which are improvements in cognitive flexibility at the cost of decreased cognitive stability.

To quantify joint degeneration and the clinical outcome after curettage and cementation in subchondral giant cell tumors of the bone (GCTB) at the knee.We conducted a retrospective analysis of 14 consecutive patients (seven female, seven male) with a mean age of 34 years (range 19-51) who underwent curettage and subchondral cementation for a biopsy-confirmed GCTB at the distal femur or the proximal tibia between August 2001 and August 2017, with a mean follow-up period of 54.6 months (range 16.1-156 months). The Whole-Organ Magnetic Resonance Imaging Score (WORMS), Kellgren-Lawrence (KL) classification, and Musculo-Skeletal Tumor Society (MSTS) score were assessed.Radiological degeneration progressed from preoperative to the latest follow-up, with a median WORMS from 2.0 to 4.0 (p = 0.006); meanwhile, the median KL score remained at 0 (p = 0.102). Progressive degeneration (WORMS) tended to be associated with the proximity of the tumor to the articular cartilage (mean 1.57 mm; range 0-12 mm) (p = 0.085). The most common degenerative findings were cartilage lesions (n = 11), synovitis (n = 5), and osteophytes (n = 4). Mean MSTS score increased from 23.1 (preoperatively) to 28.3 at the latest follow-up (p 0.01). Seven patients (50%) were treated for a local recurrence, with six revision surgeries performed. Removal of the cement spacer and filling of the cavity with a cancellous autograft was performed in seven patients. Conversion to a total knee arthroplasty was performed in one patient for local tumor control.Cementation following the curettage of GCTB around the knee is associated with slight degeneration at medium-term follow-up and leads to a significant reduction in pain. Removal of the cement and reconstruction with an autograft may be beneficial in the long term.

Pedicle fractures are a rare but potentially devastating complication of posterior instrumented spinal fusion (PSF). Preoperative awareness of the possible risk factors may help prevent these fractures by modifying the surgical plan. However, the risk factors have not yet been identified.To determine the preoperative parameters associated with postoperative L5 pedicle fracture after L4/5 PSF.Case control study.Patients undergoing L4/5 PSF at a single academic institution between 2014 and 2020.Occurrence of postoperative L5 pedicle fracture.Of 253 patients (female:male, 145:108) undergoing L4/5 PSF from 2014 to 2020, patients with postoperative L5 pedicle fractures were identified retrospectively as "cases" (n = 8, all female, age: 70 ± 10.7 years). As a control group all remaining patients with a follow-up of more than 12 months were allocated (n = 184, 104 females, age: 64.27 ± 13.00 years). In all but 16 cases, anterior support with transforaminal or posterior interbody fusion was performed. Demographic and clinical data (body mass index (BMI)), surgical factors, and comorbidities) were compared. Radiological assessment of spinopelvic parameters was performed using pre- and postoperative standing lateral radiographs.The overall incidence of L5 pedicle fractures after L4/5 spinal fusion was 3.16%, with a median time from index surgery to diagnosis of 25 days (range, 6-199 days) (75% within the first 32 days postoperatively). Patients with L5 pedicle fractures had higher pelvic incidence (PI) (71° ± 9° vs. 56° ± 11°; p=.001), sacral slope (SS) (45° ± 7° vs. 35° ± 8°; p=.002), L5 slope (30° ± 11° vs. 15° ± 10°, p=.001), L5 incidence (42° ± 14° vs. 26° ± 11°; p= .003), L1-S1 lumbar lordosis (LL) postop (57° ± 10° vs. 45° ± 11°; p=.006), and L4 -S1 LL postop (33° ± 7° vs. 28° ± 7°; p=.049) compared with the control group. Pelvic tilt and PI- LL mismatch were not significantly different. Female gender was a significant risk factor for L5 pedicle fractures (p=.015). BMI (kg/mL5 pedicle fractures occurred in 3% of the patients after single level L4/5 PSF. Risk factors are female gender, higher PI, SS, L5 slope, L5 incidence, and LL postop but not high BMI. These findings can be used for surgical planning and decision of fusion levels.

Background The optimal positioning of anterior cruciate ligament graft is still controversially discussed. We therefore wanted to determine the tunnel-to-joint (TJA), tunnel-to-shaft (TSA), and graft-tunnel divergence angles which would provide the best outcome, determined by the KOOS (Knee Injury and Osteoarthritis Outcome Score). This study evaluated the clinical influence of graft orientation as measured with the KOOS questionnaire in patients with anterior cruciate ligament reconstruction with bone-patellar tendon-bone autografts. Methods We designed a prospective cohort study, with a 1 ¼ year recruitment phase from March 2011 to July 2012 and a minimal follow-up period of 1 year. Inclusion criteria were patients ≥ 18 years of age receiving an ACL reconstruction with bone-patellar tendon-bone autografts at our institution after having suffered an acute ACL rupture. The primary outcome was the KOOS. Independent variables were patient age, gender, laterality of rupture, mechanism of trauma, and type of femoral and tibial fixation, as well as sagittal graft-tunnel divergence, TJA, and TSA, the latter two being assessed on coronal slices of magnetic resonance imaging. Equations modeling the relationship between TJA, TSA, and graft-tunnel divergence with the KOOS overall score were fitted, and the optimum angles were mathematically determined. Results In total, 31 patients were included in our study. Our cohort with a median age of 28 years was predominantly male. The mathematically determined optimal placement of the implant in the coronal plane was a TJA of 74.8°, a TSA of 80.1°, and a graft-tunnel divergence angle of 8.5°. Conclusion With regard to patient-reported outcome, the optimal graft orientation is provided by a coronal tunnel-to-shaft angle of 80° and tunnel-to-joint angle of 75°, respectively. Interestingly, in our series, patients reported best clinical outcomes with a sagittal graft-tunnel divergence. These results should be validated in larger studies. Electronic supplementary material The online version of this article (10.1186/s13018-018-0954-3) contains supplementary material, which is available to authorized users.

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Aim and objective Peri-implantitis is a key concern for dental implants and the main common reason for implant failure. This investigation evaluated the risk factors and their implications on peri-implantitis. Materials and methods A retrospective search of the patients' clinical notes was performed to identify the documented cases of peri-implantitis. The inclusion criteria encompassed patients who were 18 years and older and were seen at the School of Dental Medicine, University of Nevada, Las Vegas, from January 2014 through September 2018. The search revealed that the number of peri-implantitis cases was 28, with an overall 45 implants. Data were collected and analyzed using the Chi-square test. Results Total 28 patients presented with peri-implantitis. The distribution of males to females with peri-implantitis was 60.7 and 39.3%, respectively. The highest number of patients (21.4%) presenting with peri-implantitis fell within the age range of 65-69 years; 53.3% of peri-implantitis cases were in the maxillary arch. The predilection area for peri-implantitis was the mandibular first molar (24.4%). Periodontitis was the most significant cause (60.7%); respiratory diseases (42.9%) followed by hypertension (28.6%) were the most prevalent medical conditions in the studied population. Peri-implantitis occurred most frequently among Caucasians (62.7%), followed by Hispanics (29%). Conclusion Within the limitations of the current evaluation, findings support previous claims that periodontitis remains the strongest predictor of peri-implantitis. A correlation may exist between peri-implantitis and the location of the implant and respiratory disease. Clinical significance The implant location, the presence of periodontitis, and respiratory diseases are considered to be risk factors for peri-implantitis.

Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0.2 mg/kg per day, or fenfluramine 0.7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0.7 mg/kg per day group versus placebo; 0.2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9.0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0.2 mg/kg per day (39), fenfluramine 0.7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74.9% in the fenfluramine 0.7 mg/kg group (from median 20.7 seizures per 28 days to 4.7 seizures per 28 days), 42.3% in the fenfluramine 0.2 mg/kg group ( from median 17.5 seizures per 28 days to 12.6 per 28 days), and 19.2% in the placebo group ( from median 27.3 per 28 days to 22.0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0.7 mg/kg per day showing a 62.3% greater reduction in mean MCSF compared with placebo (95% CI 47.7-72.8, p

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Several clinical, genetic and acquired risk factors for venous thromboembolism (VTE) have been identified. However, the molecular pathophysiology and mechanisms of disease progression remain poorly understood. This is reflected by uncertainties regarding the primary and secondary prevention of VTE and the optimal duration of antithrombotic therapy. A growing body of literature points to clinically relevant differences between VTE phenotypes (e.g. deep vein thrombosis (DVT) versus pulmonary embolism (PE), unprovoked versus provoked VTE). Extensive links to cardiovascular, inflammatory and immune-related morbidities are testament to the complexity of the disease. The GMP-VTE project is a prospective, multi-center cohort study on individuals with objectively confirmed VTE. Sequential data sampling was performed at the time of the acute event and during serial follow-up investigations. Various data levels (e.g. clinical, genetic, proteomic and platelet data) are available for multi-dimensional data analyses by means of advanced statistical, bioinformatic and machine learning methods. The GMP-VTE project comprises n = 663 individuals with acute VTE (mean age: 60.3 ± 15.9 years; female sex: 42.8%). In detail, 28.4% individuals (n = 188) had acute isolated DVT, whereas 71.6% subjects (n = 475) had PE with or without concomitant DVT. In the study sample, 28.9% (n = 129) of individuals with PE and 30.1% (n = 55) of individuals with isolated DVT had a recurrent VTE event at the time of study enrolment. The systems-oriented approach for the comprehensive dataset of the GMP-VTE project may generate new biological insights into the pathophysiology of VTE and refine our current understanding and management of VTE.

Background High-dose cisplatin (Cis) is a preferred systemic agent for concurrent chemoradiation (CRT) in locally advanced head and neck squamous cell cancer (LAHNSCC) patients. As some patients are unable to tolerate Cis, this study compares the toxicity and efficacy of weekly cisplatin-paclitaxel (CP) regimen with Cis. Methods Patients with LAHNSCC receiving definitive chemoradiation either with Cis (Cisplatin-100 mg/m2 q3w x 3) or CP (Cisplatin-20 mg/m2 ; Paclitaxel-30 mg/m2 qw x7) were included. Results Cis and CP groups were comprised of 114 and 111 subjects, respectively. Complete response for Cis versus CP groups was 88% versus 88%, respectively. Median follow-up for the study was 58.5 months. After adjusting for potential treatment selection bias, no significant differences were evident between Cis and CP groups for overall survival (hazard ratios [HR] 0.85, 95% CI 0.59-1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62-1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52-1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61-1.23, P = 0.42). Patients in the CP group had less acute and chronic toxicities. Conclusions Weekly CP regimen can serve as an alternative systemic therapy with radiation in patients with LAHNSCC who are not fit for Cis.

The ketogenic diet (KD) is an effective treatment option for intractable epilepsy. Here, we reviewed the last 10 years of our experience with the KD and characterized its use in patients under 3 years of age. Medical records of all patients under the age of 3 years who were treated with the ketogenic diet from April 2004 to June 2014 were retrospectively reviewed. One hundred and nine patients with drug-resistant epilepsy were included. The mean age at the initiation of the KD was 1.4 ± 0.8 years old. The youngest patient was 3 weeks old. After 3 months, 39% (42/109) of patients responded to the KD and experienced more than 50% seizure reduction. Of those 42 patients, 20 (18%) achieved complete seizure control. Patients with a genetic etiology showed a better response to the KD in seizure reduction than the other patients (p = 0.03). Age at initiation of the KD was not related to eventual seizure outcome (p = 0.6). The KD continues to be an effective, safe, and well tolerated treatment option for infants with intractable epilepsy.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Objective: The MAST family of microtubule-associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at

OBJECTIVES: Evidence-based care of extremely preterm infants ( METHODS: Using data from the Extremely Low Gestational Age Newborn Study cohort, we classified 2-year NDI using definitions developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. We classified 10-year NDI using definitions developed by an expert panel, which added epilepsy and ASD at 10 years. RESULTS: Of 1506 infants, 80% survived. Data sufficient to classify severity of NDI at both 2 and 10 years were available for 67% of survivors (n = 802). Among children classified as having moderate to severe NDI at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. Cohen’s κ statistic indicated minimal to fair agreement between NDI at 2 and 10 years (0.34, P < .001). CONCLUSIONS: NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.

The emergence of e-cigarettes on the consumer market led to a tremendous rise in e-cigarette consumption among adolescents in the United States. The success of JUUL and other pod systems was linked to its high nicotine delivery capacity. In compliance with the European Tobacco Product directive, liquid nicotine contents in the European JUUL variants are limited to 20 mg/mL or below. A short time after launching the initial version in Europe, JUUL pods have been modified in terms of the wick material used. This modification has been demonstrated previously to lead to an elevated aerosol generation, consequently, to a larger amount of nicotine per puff generated. The present study was designed to assess whether the mentioned differences between the “initial” and “modified” JUUL versions may cause a significant difference during consumption, and how nicotine delivery compares with tobacco cigarettes. In this single-center three-arm study, nicotine pharmacokinetics and influence on urge to smoke/vape were compared for tobacco cigarettes, the “initial” version of the European JUUL, and the “modified” version of the European JUUL. Participants, 15 active smokers and 17 active e-cigarette users, were instructed to consume their study product according to a pre-directed puffing protocol. Venous blood was sampled for nicotine analysis to cover the acute phase and the first 30 min after starting. Nicotine delivery and the reduction of urge to smoke/vape upon usage of both European JUUL variants were lower in comparison to tobacco cigarettes. This suggests a lower addictive potential. Modification of the pod design did not result in significant differences at the first ten puffs, as confirmed by a vaping machine experiment. Apparently, the limitations by the initially used wick material only come into effect after longer usage time.

Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment. Objective: The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for cognitive impairment. Methods: Data of 2,426 individuals from the OOA aged 54–99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified into three education categories: 8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Results: Our results showed that individuals who attained lowest levels of education (8 years (OR = 2.96 and 1.85). Conclusion: Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.

Introduction: Door-to-CT scan time (DCT) and door-to-needle time (DNT) are important process measures in acute ischemic stroke (AIS) patients undergoing intravenous thrombolysis (IVT). We examined the impact of a telemedical prenotification by emergency medical service (EMS) (called the “Stroke Angel” program) on DCT and DNT and IVT rate compared to standard of care. Patients and Methods: Two prospective observational studies including AIS patients admitted via EMS from 2011 to 2013 (cohort I; n = 496) and from January 1, 2015 to May 31, 2018 (cohort II; n = 349) were conducted. After cohort I, the 4-Item Stroke Scale and a digital thrombolysis protocol were added. Multivariable logistic and linear regression analysis was performed. Results: In cohort I, DCT was lower in the intervention group (13 vs. 26 min using standard of care; p < 0.001), but no significant difference in median DNT (35 vs. 39 min; p = 0.24) was observed. In cohort II, a reduction of DCT (8 vs. 15 min; p < 0.001) and DNT (25 vs. 29 min p = 0.003) was observed in the intervention group. Compared to standard of care, the likelihood of DCT ≤10 min or DNT ≤20 min in the intervention group was 2.7 (adjusted odds ratio [aOR] 2.7; 95% CI: 2.1–3.5) and 1.8 (aOR 1.8; 95% CI: 1.1–2.9), respectively. In cohort II, IVT rate was higher (aOR 1.4; 95% CI: 1.1–1.9) in the intervention group. Conclusion: Although the positive effects of Stroke Angel in AIS provided a rationale for implementation in routine care, larger studies of practice implementation will be needed. Using Stroke Angel in the prehospital management of AIS impacts on important process measures of IVT delivery.

This study investigated the potential role of quantitative ultrasound (QUS) to assess low bone mass in anorexia nervosa patients (AN). Bone parameters from QUS and DXA were positively correlated and significantly reduced in AN compared with controls, suggesting that QUS is a pertinent technique to assess low bone mass in these patients.The aim of this study was to investigate the potential role of an alternative technique, quantitative ultrasound (QUS), to assess low bone mass in patients with anorexia nervosa (AN).Two hundred seven young women (134 patients with AN and 73 healthy controls) with ages ranging from 14.4 to 38.4 years participated in this observational cross-sectional study. Bone mass was concomitantly evaluated by DXA to determine areal bone mineral density (aBMD; g/cmBUA (66.5 ± 4.6 dB/MHz vs 61.0 ± 5.0 dB/MHz) and aBMD at the hip (0.916 ± 0.013 g/cmBUA measurement at the heel by QUS appears to be a pertinent nonionizing technique to assess low bone mass in patients with AN.

OBJECTIVES: To determine whether missing the HepB birth dose vaccine is a risk factor for incomplete vaccination later in childhood. METHODS: This was a retrospective cohort study of infants born over one year at an academic medical center. The “not vaccinated at birth” group consisted of all infants who did not receive the HepB birth dose vaccine by seven days of life, while the “vaccinated at birth” group included infants who did receive the birth dose. The primary outcome was vaccination status at 18 months of age, determined from the state vaccination registry. RESULTS: Infants “not vaccinated at birth” had lower vaccination rates. At 18 months, 44% of the “vaccinated at birth” group received all recommended vaccines, compared with 23% of the “not vaccinated at birth” group ( p < 0.001); at 24 months, rates were 65% and 45%, respectively ( p < 0.001). Over 80% of the variability in vaccination completions were related to a single latent variable, which is most likely vaccine hesitancy/refusal. CONCLUSIONS: Infants who miss the HepB birth dose vaccine are at risk for under-immunization by 18 and 24 months of age. This suggests that parents likely form opinions about vaccines long before the birth of their child; therefore, efforts to influence attitudes must begin earlier.

Assess impact of multimodality weight gain prevention intervention.Randomized clinical trial among 39 overweight young Puerto Rico college students using 10 weekly peer-support sessions promoting dietary, physical activity, and other lifestyle changes enhanced by stress-reduction and mindfulness approaches. Body mass index (BMI) and self-reported behaviors were measured at baseline and at 10 weeks and 6 months after baseline.At the completion of the intervention, BMIs in the experimental arm were 0.8 units lower than at baseline (z = -3.0; P = .008) and 1.2 lower at 6 months after baseline (z = -4.1; P.001); BMIs in the control arm were 0.7 higher (z = 2.7; P = .02) at 10 weeks and 0.8 higher at 6 months (z = 3.1; P = .005). Group × time interaction confirmed that BMI differed significantly over time between arms (χBody mass index in the experimental arm decreased at the end of intervention and was maintained at 6 months' follow-up.

Background Conventional stented valves (CV) remain gold standard for aortic valve disease. Bovine prostheses have been improved and rapid deployment valves (RDV) have arrived in the recent decade. We compare clinical and hemodynamic short-term outcome of six bovine valves. Methods We retrospectively evaluated 829 consecutive patients (all-comers) receiving bovine aortic valve replacement (AVR). Four CV from different manufacturers (Mitroflow, Crown, Perimount, Trifecta) and two RDV (Perceval, Intuity) were compared in terms of pre-, intra-, and postprocedural data. A risk model for mortality was created. Results All valves reduced gradients. From 23 mm, all CV showed acceptable gradients. Twenty-one millimeter Mitroflow/Perceval and 19 mm Crown showed above-average gradients. As baseline data differed, we performed propensity matching between aggregated isolated CV and RDV groups. Cardiopulmonary bypass (CPB), clamp, and surgery times were shorter with RDV (87.4 ± 34.0 min vs 111.0 ± 34.2, 54.3 ± 21.1 vs 74.9 ± 20.4, 155.2 ± 42.9 vs 178.0 ± 46.8, p Conclusion Isolated bovine AVR has low mortality. Valves ≥ 23 mm show comparable gradients while the valve model matters

The Pre-Conception and Pre-Natal Diagnostic Techniques Act was written to prevent societally unacceptable harms including intentional sex selection. The pragmatism required to enforce this law has profound effects on the ability of rural Indians to access diagnostic ultrasonography. In so doing, it may have inadvertently placed a heavier burden on the poorest and worsened health inequity in India, creating serious ethical and justice concerns. It is time to re-examine and update the law such that diagnostic ultrasonography is widely available in even the most peripheral primary health and community health centres. Shorter, more accessible ultrasonography training courses should be offered; collaboration between radiologists and rural practitioners and facilities should be encouraged. Finally, modern ultrasound machines can carefully record all images via a "silent observer" modality. With some modifications to previously used silent observer modalities, this technology allows both greater access and better policing of potential misuse of ultrasound technology.

Summary Objective Add‐on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double‐blind, placebo‐controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo‐controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long‐term open‐label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient‐reported outcomes from GWPCARE5. Methods Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. Results By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open‐label extension. Median treatment duration was 274 days (range 1‐512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty‐two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance This trial shows that long‐term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment‐resistant DS.

Summary Objective Since 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. Methods Twenty‐five US‐based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4‐week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2‐10 mg/kg/d, titrated to a maximum dose of 25‐50 mg/kg/d. Patient visits were every 2‐4 weeks through 16 weeks and every 2‐12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last‐observation‐carried‐forward method to account for missing data. Adverse events (AEs) were documented at each visit. Results Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4‐62). Median number of concomitant AEDs was 3 (range, 0‐10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add‐on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). Significance Results from this ongoing EAP support previous observational and clinical trial data showing that add‐on CBD may be an efficacious long‐term treatment option for TRE.

ObjectiveTo validate an amended protocol for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) including real-time quaking-induced conversion (RT-QuIC) and to observe its use in CJD surveillance.MethodsIn the framework of a prospective epidemiologic study, all neuropathologically confirmed cases with sCJD who received CSF RT-QuIC analysis during diagnostic workup (n = 65) and a control group of individuals without CJD (n = 118) were selected to investigate the accuracy of an amended diagnostic protocol. The patients had been referred to the German National Reference Center for Transmissible Spongiform Encephalopathies. The influence of the amended protocol on incidence figures was evaluated in the context of 3 years of surveillance activity (screened cases using 14-3-3 test n = 18,789, highly suspicious cases of CJD n = 704). Annual incidences were calculated with current criteria and the amended protocol.ResultsThe amended protocol showed a sensitivity of 97% and a specificity of 99%. When it was applied to all suspected cases who were referred to the reference center, the assessed incidence of CJD increased from 1.7 to 2.2 per million in 2016.ConclusionCJD surveillance remains challenging because information from external health care institutions can be limited. RT-QuIC shows excellent diagnostic accuracy when applied in the clinical setting to symptomatic patients. Data for RT-QuIC alone when applied as a general screening test are not available yet. We propose an amended research protocol that improves early and accurate clinical diagnosis of sCJD during surveillance activities. The use of this protocol will probably lead to a significant increase of the incidence rate.Classification of evidenceThis study provides Class III evidence that for patients with suspected sCJD, criteria for clinical diagnosis plus the CSF RT-QuIC accurately identifies patients with sCJD (sensitivity 97%, specificity 99%).

In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study.Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome.266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 ± 6 065 €; TAU: 10 033 ± 7 696 €; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 ± 8 329 €; TAU: 14 244 ± 8 419 €; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 ± 10 476 €) than TAU (20 066 ± 15 391 €) for the study period (p0.001) and for time in hospital (ALGO: 17 582 ± 9 939 €; TAU: 21 516 ± 12 718 €; p = 0.036).Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation.Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample.

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.

Background Using sweat chloride as a biomarker for CFTR modifying drugs requires knowledge of analytical and biological variation. Methods 979 sweat chloride concentrations from 128 subjects enrolled in the placebo arm of 2 multicenter, investigational drug trials were analyzed to determine coefficients of variation (CV) as well as reference change value (RCV) and index of individuality (II). Results For these populations, calculated values for the two studies were: analytical variation (3.9, 4.1%); within-subject variation (4.4, 6.0%); between-subject variation (8.9, 7.0%); RCV (13.7, 17.0%) and II (0.7, 1.0). Sweat chloride variation was not affected by sex, collection site or sample weight; but was slightly affected by age in one of the two studies. Conclusion Through determination of analytical as well as between- and within-subject variation, and with a larger sample size, our data allows improved estimates of the RCV and II, and can contribute to future trials of CFTR modulators and inform the design and interpretation of n of 1 trials in both research and clinical settings.

The aim of this study was to evaluate antidepressant add-on treatment within the acute treatment of schizophrenia spectrum disorder patients. Antidepressant add-on was evaluated in 365 patients within a naturalistic multicenter study. Patients with/without antidepressant add-on were compared regarding clinical and treatment-related variables, response and remission, and remission of depressive and negative symptoms. The efficacy of antidepressant add-on treatment was furthermore analyzed applying marginal structure models. Twenty-three percent of the patients received antidepressant add-on for a mean duration of 50.28 (33.42) days. Patients with the diagnosis of a schizoaffective disorder, multiple illness episodes, and a longer duration of their illness as well as those with significantly fewer baseline positive symptoms, more negative and depressive symptoms, more side effects, and less subjective well-being were augmented with antidepressants. At discharge no significant effect of antidepressant add-on treatment was observed in terms of a 25% improvement (p=0.2623), a 50% improvement (p=0.3946), remission (p=0.0552), or remission of depressive (p=0.6336) and negative symptoms (p=0.8756). Also, when analyzing marginal structure models considering the diagnostic subgroups, no significant effect was found. Add-on with antidepressants is common. A final recommendation in terms of this strategy’s efficacy cannot be given.