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We develop an efficient and robust iterative framework suitable for solving the linear system of equations resulting from the spectral element discretisation of the curl-curl equation of the total electric field encountered in geophysical controlled-source electromagnetic applications. We use the real-valued equivalent form of the original complex-valued system and solve this arising real-valued two-by-two block system (outer system) using the generalised conjugate residual method preconditioned with a highly efficient block-based PREconditioner for Square Blocks (PRESB). Applying this preconditioner equates to solving two smaller inner symmetric systems which are either solved using a direct solver or iterative methods, namely the generalised conjugate residual or the flexible generalised minimal residual methods preconditioned with the multigrid-based auxiliary-space preconditioner AMS. Our numerical experiments demonstrate the robustness of the outer solver with respect to spatially variable material parameters, for a wide frequency range of five orders of magnitude (0.1-10’000 Hz), with respect to the number of degrees of freedom, and for stretched structured and unstructured as well as locally refined meshes. For all the models considered, the outer solver reaches convergence in a small (typically < 20) number of iterations. Further, our numerical tests clearly show that solving the two inner systems iteratively using the indicated preconditioned iterative methods is computationally beneficial in terms of memory requirement and time spent as compared to a direct solver. On top of that, our iterative framework works for large-scale problems where direct solvers applied to the original complex-valued systems succumb due to their excessive memory consumption, thus making the iterative framework better suited for large-scale 3D problems. Comparison to a similar iterative framework based on a block-diagonal and the auxiliary-space preconditioners reveals that the PRESB preconditioner requires slightly fewer iterations to converge yielding a certain gain in time spent to obtain the solution of the two-by-two block system.

SUMMARYFor forward modelling of realistic 3-D land-based controlled-source electromagnetic (EM) problems, we develop a parallel spectral element approach, blending the flexibility and versatility of the finite element method in using unstructured grids with the accuracy of the spectral method. Complex-shaped structures and topography are accommodated by using unstructured hexahedral meshes, in which the elements can have curved edges and non-planar faces. Our code is the first spectral element algorithm in EM geophysics that uses the total field formulation (here that of the electric field). Combining unstructured grids and a total field formulation provides advantages in dealing with topography, in particular, when the transmitter is located on rough surface topography. As a further improvement over existing spectral element methods, our approach does not only allow for arbitrary distributions of conductivity, but also of magnetic permeability and dielectric permittivity. The total electric field on the elements is expanded in terms of high-order Lagrangian interpolants, and element-wise integration in the weak form of the boundary value problem is accomplished by Gauss–Legendre–Lobatto quadrature. The resulting complex-valued linear system of equations is solved using the direct solver MUMPS, and, subsequently, the magnetic field is computed at the points of interest by Faraday’s law. Five numerical examples comprehensively study the benefits of this algorithm. Comparisons to semi-analytical and finite element results confirm accurate representation of the EM responses and indicate low dependency on mesh discretization for the spectral element method. A convergence study illuminates the relation between high order polynomial approximation and mesh size and their effects on accuracy and computational cost revealing that high-order approximation yields accurate modelling results for very coarse meshes but is accompanied by high computational cost. The presented numerical experiments give evidence that 2nd and 3rd degree polynomials in combination with moderately discretized meshes provide better trade-offs in terms of computational resources and accuracy than lowest and higher order spectral element methods. To our knowledge, our final example that includes pronounced surface topography and two geometrically complicated conductive anomalies represents the first successful attempt at using 2nd order hexahedral elements supporting curved edges and non-planar faces in controlled-source EM geophysics.

Since the inception of the COVID-19 pandemic, over 60 cases of acute disseminated encephalomyelitis (ADEM) or ADEM-like clinically isolated syndromes have been linked to COVID-19 infection. However, cases linked to COVID-19 vaccination remain exceptionally rare. To the author’s knowledge, eight published cases of ADEM or ADEM-like clinically isolated syndrome have been described after patients received COVID-19 vaccinations, all of which occurred in adults. This report details the first documented case of an ADEM-like illness in a pediatric patient, which developed shortly after receiving the Pfizer (Pfizer-BioNTech, Germany) COVID-19 vaccination. The patient made a near complete clinical recovery over 10 days after receiving a 5-day course of intravenous immunoglobulin therapy.

Deep Neural Networks (DNN) are increasingly used as components of larger software systems that need to process complex data, such as images, written texts, audio/video signals. DNN predictions cannot be assumed to be always correct for several reasons, among which the huge input space that is dealt with, the ambiguity of some inputs data, as well as the intrinsic properties of learning algorithms, which can provide only statistical warranties. Hence, developers have to cope with some residual error probability. An architectural pattern commonly adopted to manage failure-prone components is the supervisor, an additional component that can estimate the reliability of the predictions made by untrusted (e.g., DNN) components and can activate an automated healing procedure when these are likely to fail, ensuring that the Deep Learning based System (DLS) does not cause damages, despite its main functionality being suspended. In this paper, we consider DLS that implement a supervisor by means of uncertainty estimation. After overviewing the main approaches to uncertainty estimation and discussing their pros and cons, we motivate the need for a specific empirical assessment method that can deal with the experimental setting in which supervisors are used, where the accuracy of the DNN matters only as long as the supervisor lets the DLS continue to operate. Then we present a large empirical study conducted to compare the alternative approaches to uncertainty estimation. We distilled a set of guidelines for developers that are useful to incorporate a supervisor based on uncertainty monitoring into a DLS., Accepted for publication at the Journal of Software: Testing, Verification and Reliability. arXiv admin note: substantial text overlap with arXiv:2102.00902

To describe the process of developing, and evaluating the feasibility and acceptability of, an EMR-based transition readiness assessment.A Cerner-based version of the UNC TRAll clinics met form completion goals (N = 10/clinic). The assessment rate ranged from 66 to 100% across clinics. No families refused completion of the form. Most staff (70%) reported completing the form in10 min. Staff reported on challenges experienced and provided recommendations to streamline administration and enhance clinical care. All staff reported the form helped them identify knowledge gaps in their patients. Two clinics continued using the form following completion of the pilot study.Implementation was most feasible in clinics that were well-staffed and had lengthier patient visits, however, time and staff resources were the biggest challenges to implementation across clinics. Based on staff feedback to improve efficiency and developmentally-tailor assessment, the form will be divided into Beginner Skills and Advanced Skills.Integrating transition readiness assessment into the EMR has the potential to improve clinical care by facilitating staff's ability to efficiently identify knowledge gaps in their transition-aged patients and intervene.

On complex problems, state of the art prediction accuracy of Deep Neural Networks (DNN) can be achieved using very large-scale models, consisting of billions of parameters. Such models can only be run on dedicated servers, typically provided by a 3rd party service, which leads to a substantial monetary cost for every prediction. We propose a new software architecture for client-side applications, where a small local DNN is used alongside a remote large-scale model, aiming to make easy predictions locally at negligible monetary cost, while still leveraging the benefits of a large model for challenging inputs. In a proof of concept we reduce prediction cost by up to 50% without negatively impacting system accuracy., Comment: Research Abstract. Contact me for a pre-print of the full paper (currently not yet published)

Infants born extremely preterm (28 weeks' gestation) are at high risk of neurodevelopmental impairment (NDI) with 50% of survivors showing moderate or severe NDI when at 2 years of age. We sought to develop novel models by which to predict neurodevelopmental outcomes, hypothesizing that combining baseline characteristics at birth with medical care and environmental exposures would produce the most accurate model.Using a prospective database of 692 infants from the Preterm Epo Neuroprotection (PENUT) Trial, which was carried out between December 2013 and September 2016, we developed three predictive algorithms of increasing complexity using a Bayesian Additive Regression Trees (BART) machine learning approach to predict both NDI and continuous Bayley Scales of Infant and Toddler Development 3rd ed subscales at 2 year follow-up using: 1) the 5 variables used in the National Institute of Child Health and Human Development (NICHD) Extremely Preterm Birth Outcomes Tool, 2) 21 variables associated with outcomes in extremely preterm (EP) infants, and 3) a hypothesis-free approach using 133 potential variables available for infants in the PENUT database.The NICHD 5-variable model predicted 3-4% of the variance in the Bayley subscale scores, and predicted NDI with an area under the receiver operator curve (AUROC, 95% CI) of 0.62 (0.56-0.69). Accuracy increased to 12-20% of variance explained and an AUROC of 0.77 (0.72-0.83) when using the 21 pre-selected clinical variables. Hypothesis-free variable selection using BART resulted in models that explained 20-31% of Bayley subscale scores and AUROC of 0.87 (0.83-0.91) for severe NDI, with good calibration across the range of outcome predictions. However, even with the most accurate models, the average prediction error for the Bayley subscale predictions was around 14-15 points, leading to wide prediction intervals. Higher total transfusion volume was the most important predictor of severe NDI and lower Bayley scores across all subscales.While the machine learning BART approach meaningfully improved predictive accuracy above a widely used prediction tool (NICHD) as well as a model utilizing NDI-associated clinical characteristics, the average error remained approximately 1 standard deviation on either side of the true value. Although dichotomous NDI prediction using BART was more accurate than has been previously reported, and certain clinical variables such as transfusion exposure were meaningfully predictive of outcomes, our results emphasize the fact that the field is still not able to accurately predict the results of complex long-term assessments such as Bayley subscales in infants born EP even when using rich datasets and advanced analytic methods. This highlights the ongoing need for long-term follow-up of all EP infants.Supported by the National Institute of Neurological Disorders and StrokeU01NS077953 and U01NS077955.

Purpose To identify barriers that transcend multiple adult care specialties and identify potential solutions. Design and methods Twenty-one adult care providers practicing in the specialty areas of internal medicine, family medicine, gastroenterology, endocrinology, and neurology participated in one of six semi-structured focus group interviews. Data were coded and analyzed according to the Socio-ecological Model of Adolescent/Young Adult Readiness for Transition (SMART). Results Three themes and one subtheme emerged from the data. These fell within the beliefs/expectations, knowledge, access/insurance, and relationships (subtheme) domains of the SMART model. Family beliefs/expectations regarding the provider role, difficulty accessing reliable information, and limited access to mental health and behavioral providers reportedly affect providers' ability to provide optimal health care. Conclusions Adult providers identified several barriers affecting their ability to care for newly transferred patients. Increased education of families and improved methods of communication between providers were recommended. Barriers related to access and insurance are common and require larger systems-level collaborations between health care systems and payor sources. Practical implications Some recommendations (e.g., educating families on the distinct roles of the PCP vs. specialist, highlighting new treatment opportunities in adult care, conveying trust and endorsing the new provider), represent concrete steps pediatric providers can immediately take to improve transfer. Other steps will require forging bridges across the pediatric and adult care world to expand patient access to medical, mental health, and behavioral services.

Background The technical feasibility of transumbilical single-incision surgery (SIL) for pancreatic resections has been demonstrated. However, this technique is hampered by the limited degrees of freedom for instrument handling. Dual-incision laparoscopy (DIL) with an additional trocar may simplify dissection and allow drainage. Material and methods Between December 2009 and May 2017, 21 patients were treated with SIL (12/2009 to 01/2014) or DIL (02/2014 to 05/2017) pancreatic resection. All data were collected in a database and retrospectively analysed. Results Demographic parameters of the patients did not differ significantly in the DIL or the SIL group. No conversion to open surgery was required. No intraoperative complication occurred in either group. The surgical difficulty score was significantly higher in the SIL group (4.4 ± 1.56 vs 2.18 ± 1.95; p = .006). Postoperative serum amylase levels were higher (101.9 U/l ± 50.11 vs 48.91 U/l ± 35.20; p = .01) and return to normal levels (6.4 ± 9.66 days vs 2.09 ± 1.98 days; p = .045) was later in the SIL group. Three complications requiring radiological or surgical intervention were witnessed in the SIL group and one complication in the DIL group (p = .42). Conclusion DIL surgery is a safe and feasible alternative to SIL surgery, facilitating key steps of distal pancreatic tail resection.

Much of the current data on nonalcoholic fatty liver disease (NAFLD) are derived from biopsy‐based studies that may introduce ascertainment and selection bias. Selection of patients for liver biopsy has implications for clinical practice and the reported epidemiology of NAFLD. The aim of this study was to determine patient factors predictive of histologic versus empiric clinical diagnosis of NAFLD in real‐world practice. Adults from TARGET‐NASH were included in this study. Descriptive statistics are provided for the cohort and compare the characteristics of histologic NAFLD versus patients with clinically diagnosed NAFLD, followed by logistic regression and machine‐learning models to describe predictors of liver biopsy. The records of 3,474 subjects were analyzed; median age was 59 years, 59% were female, 75% were White, and median body mass index was 32 kg/m2. Using histologic and/or clinical criteria, a diagnosis of nonalcoholic steatohepatitis was made in 37%, and cirrhosis in 33%. Comorbid conditions included cardiovascular disease (19%), mental health diagnoses (49%), and osteoarthritis (10%). Predictors of a biopsy diagnosis included White race, female sex, diabetes, and elevated alanine aminotransferase (ALT). ALT increased the odds of liver biopsy by 14% per 10‐point rise. Machine‐learning analyses showed non‐White patients with ALT, The aim of this study was to determine patient factors predictive of histologic versus empiric clinical diagnosis of NAFLD in real world practice in adults enrolled in the TARGET‐NASH study. The records of 3,474 subjects were analyzed; median age was 59 years, 59% were female, 75% were white, and median BMI was 32 kg/m2. In this real‐world cohort of patients with NAFLD, two thirds of patients did not have a liver biopsy; these patients were more likely to be non‐white, older, with a normal ALT.

Background During the Syrian civil war, patients were initially treated on-site in Syria and later transferred to medical centers in Israel. Relevant details concerning the exact nature of injury and medical/surgical care received in Syria were unavailable to clinicians in Israel. Many of these patients required abdominal re-exploration for obvious or suspected problems related to their injury. Our aim is to present our approach to abdominal trauma patients who survived initial on-site surgery and needed subsequent abdominal re-exploration abroad, in our medical center. Methods Clinical data from all medical records were retrospectively analyzed. Each patient underwent total body computerized tomography on arrival, revealing diverse multi-organ trauma. We divided the patient population who had abdominal trauma into 4 sub-groups according to the location in which abdominal surgical intervention was performed (abdominal surgery performed only in Syria, surgery in Syria and subsequent re-laparotomy in Israel, abdominal surgery only in Israel, and management of patients without abdominal surgical intervention). We focused on missed injuries and post-operative complications in the re-laparotomy sub-group. Results By July 2018, 1331 trauma patients had been admitted to our hospital, of whom 236 had suffered abdominal trauma. Life-saving abdominal intervention was performed in 138 patients in Syria before arrival to our medical center. A total of 79 patients underwent abdominal surgery in Israel, of whom 46 (33%) required re-laparotomy. The absence of any communication between the surgical teams across the border markedly affected our medical approach. Indications for re-exploration included severe peritoneal inflammation, neglected or overlooked abdominal foreign bodies, hemodynamic instability and intestinal fistula. Mortality occurred in 37/236 patients, with severe abdominal trauma as the main cause of fatality in 10 of them (4.2%), usually following urgent re-laparotomy. Conclusions Lack of information about the circumstances of injury in an environment of catastrophe in Syria at the time and the absence of professional communication between the surgical teams across the border markedly dictated our medical approach. Our concerns were that some patients looked deceptively stable while others had potentially hidden injuries. We had no information on who had had definitive versus damage control surgery in Syria. The fact that re-operation was not performed by the same team responsible for initial abdominal intervention also posed major diagnostic challenges and warranted increased clinical suspicion and a change in our standard medical approach.

Purpose In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects. Methods A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation. Results The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment. Conclusions Rifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol.

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

BACKGROUND: This study examined the association between race/ethnicity and health insurance payer type with pediatric opioid and non-opioid ordering in an inpatient hospital setting. METHODS: Cross-sectional inpatient encounter data from June 2013 to June 2018 was retrieved from a pediatric children’s hospital in Southern California (N = 55,944), and statistical analyses were performed to determine associations with opioid ordering. RESULTS: There was a significant main effect of race/ethnicity on opioid and non-opioid orders. Physicians ordered significantly fewer opioid medications, but a greater number of non-opioid medications, for non-Hispanic African American children than non-Hispanic Asian, Hispanic/Latinx, and non-Hispanic White pediatric patients. There was also a main effect of health insurance payer type on non-opioid orders. Patients with government-sponsored plans (e.g., Medi-Cal, Medicare) received fewer non-opioid prescriptions compared with patients with both HMO and PPO coverage. Additionally, there was a significant race/ethnicity by insurance interaction on opioid orders. Non-Hispanic White patients with “other” insurance coverage received the greatest number of opioid orders. In non-Hispanic African American patients, children with PPO coverage received fewer opioids than those with government-sponsored and HMO insurance. For non-Hispanic Asian patients, children with PPO were prescribed more opioids than those with government-sponsored and HMO coverage. CONCLUSION: Findings suggest that the relationship between race/ethnicity, insurance type, and physician decisions opioid prescribing is complex and multifaceted. Given that consistency in opioid prescribing should be seen regardless of patient background characteristics, future studies should continue to assess and monitor unequitable differences in care.

Purpose Progressive loss (sarcopenia) and fatty infiltration of muscle mass (myosteatosis) are well-established risk factors for an adverse clinical outcome in obese patients. Data concerning non-obese sarcopenic patients in oncologic surgery are scarce and heterogeneous. The aim of this study was to determine the impact of sarcopenia and myosteatosis in non-obese patients with cancer of the right colon on clinical outcome. Methods This study comprised 85 patients with a BMI 2, who underwent surgery for right colon cancer in a single center. Skeletal muscle area (SMA), visceral fat area (VFA), and myosteatosis were retrospectively assessed using preoperative abdominal CT images. Univariate und multivariate analysis was performed to evaluate the association between body composition, complications, and oncologic follow-up. Results Traditional risk factors such as visceral fat (p = 0.8653), BMI (p = 0.8033), myosteatosis (p = 0.7705), and sarcopenia (p = 0.3359) failed to show any impact on postoperative complications or early recurrence. In our cohort, the skeletal muscle index (SMI) was the only significant predictor for early cancer recurrence (p = 0.0467). Conclusion SMI is a significant prognostic factor for early cancer recurrence in non-obese colon cancer patients. Our study shows that conventional thresholds for sarcopenia and BMI do not seem to be reliable across various cohorts. Target prehabilitation programs could be useful to improve outcome after colorectal surgery. Trial Registration DRKS00014655, www.apps.who.int/trialsearch

Nontuberculous mycobacteria (NTM) are an emerging cause of infections, including chronic lymphadenitis in children. To identify risk factors for NTM lymphadenitis, particularly complicated disease, we collected epidemiologic, clinical, and microbiological data on 138 cases of NTM lymphadenitis in children across 13 centers in Germany and Austria. We assessed lifestyle factors but did not identify specific risk behaviors. We noted that more cases of NTM lymphadenitis occurred during cold months than during warm months. Moreover, we noted female sex and age

Nina Schaller,1 Helge Krusemark,1 Esther Mende,1 Michael Weiß,1 Bianca Spanier,1 Otto Zelger,1 Jan Bischof,1 Bernhard Haller,2 Martin Halle,1,3,&ast; Monika Siegrist1,&ast; 1Department of Prevention and Sports Medicine, School of Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Munich, Germany; 2Institute of AI and Informatics in Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Munich, Germany; 3DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany&ast;These authors contributed equally to this workCorrespondence: Nina Schaller, Department of Prevention and Sports Medicine, School of Medicine, University Hospital ‘rechts der Isar’, Technical University of Munich, Georg-Brauchle-Ring 56, Munich, 80992, Germany, Tel +49 89 289 24441, Fax +49 89 289 24451, Email nina.schaller@mri.tum.dePurpose: Mobility is a crucial factor for independence and quality of life in old age. Nevertheless, many old people in retirement homes do not meet the physical activity recommendations. The aim of the Bestform-F – Best Function of Range of Motion feasibility study (bestform-F) was to evaluate the feasibility of implementing a machine-based multimodal exercise training program in older residents in retirement homes.Materials and Methods: The participants (n = 77) were recruited from two retirement homes and took part in a six-month multimodal exercise training program (2x/week, 45 minutes) on pneumatic strength training machines, a balance platform and bicycle ergometers. Feasibility criteria were recruitment number ≥ 35 participants within six months, dropout rate < 40% of participants within six months of exercise, and training adherence ≥ 50% of participants taking part in at least 50% of offered training sessions. Additionally, physical performance, fear of falling, cognitive function, and quality of life were assessed at baseline and after six months.Results: For the bestform-F study, 77 (85.6 ± 6.6 years; 78% women) out of 215 eligible residents from two senior residences were recruited. The dropout rate over six months was 10% (8/77 participants). The training adherence rate for the finishing participants was 77% (53/69 participants). In addition to the achieved feasibility criteria, significant improvements were recorded in the Chair Stand Test, Six-Minute Walk Test, and fear of falling after six months.Conclusion: All feasibility criteria have been fulfilled. The high number of recruited participants, the low dropout rate, and high adherence to the training program confirm the feasibility of a multimodal machine-based exercise training program offered to residents in retirement homes. The results provide a basis for a cluster-randomized controlled trial aimed at further investigating the efficacy of the bestform-F program.Keywords: machine-based exercise, seniors, sarcopenia, mobility, resistance training, balance

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

Test Input Prioritizers (TIP) for Deep Neural Networks (DNN) are an important technique to handle the typically very large test datasets efficiently, saving computation and labeling costs. This is particularly true for large-scale, deployed systems, where inputs observed in production are recorded to serve as potential test or training data for the next versions of the system. Feng et. al. propose DeepGini, a very fast and simple TIP, and show that it outperforms more elaborate techniques such as neuron- and surprise coverage. In a large-scale study (4 case studies, 8 test datasets, 32'200 trained models) we verify their findings. However, we also find that other comparable or even simpler baselines from the field of uncertainty quantification, such as the predicted softmax likelihood or the entropy of the predicted softmax likelihoods perform equally well as DeepGini., Comment: Accepted at ISSTA 2022

Patients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort.TARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal-Wallis tests were used to compare differences in symptoms between groups.A total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%).The prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Mycoplasma spp. are important pathogens in poultry and cause high economic losses for poultry industry worldwide. In other bird species (e.g. white storks, birds of prey, and several waterfowl species), Mycoplasma spp. are regularly found in healthy individuals, hence, considered apathogenic or part of the microbiota of the upper respiratory tract. However, as Mycoplasma spp. are absent in healthy individuals of some wild bird species, they might play a role as respiratory pathogen in these bird species, e.g. Mycoplasma gallisepticum in house finches. The knowledge on the occurrence of Mycoplasma spp. in wild birds is limited. To evaluate the relevance of Mycoplasma spp. in free-ranging nightingales and tits, 172 wild caught birds were screened for the presence of mycoplasmas. The birds were sampled via choanal swabs and examined via molecular methods (n = 172) and, when possible, via culture (n = 142). The Mycoplasma sp. was determined by sequencing the 16S rRNA gene and 16S-23S Intergenic Transcribed Spacer Region. All birds were tested negative for mycoplasmas via PCR and/or mycoplasmal culture. Hence, free-ranging nightingales and tits do not show any mycoplasma in their microbial flora of the respiratory tract. Therefore, these songbird species may suffer from clinical mycoplasmosis when being infected. We hypothesize that birds relying on their vocal ability for reproduction have excluded mycoplasmas from their respiratory flora compared to other bird species.