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Background and purpose: Functional neurological disorders (FNDs) have attracted much attention from the neurological medical community over the last decades as new developments in neurosciences have reduced stigma around these by showing brain network dysfunctions. An overlap with other neurological conditions such as multiple sclerosis (MS) is well known by clinicians but there is a lack of clinical and fundamental research in this field to better define diagnosis and therapeutic decisions, as well as a lack of deep understanding of the underlying pathophysiology. Aim: We aimed to provide a critical commentary on the state of knowledge about the borderland between FNDs and MS. Methods: We based our commentary on a joint point of view between an FND specialist and an MS expert. Results: A brief review of the previous literature and relevant new studies covering the overlap between FNDs and MS is presented, along with suggestions for future research directions. Conclusion: There are clear diagnostic criteria for both FNDs and MS and a strict application of these will help better diagnosis and prevent unnecessary treatment escalation in MS or absence of referral to multimodal therapy in FND. Better teaching of younger neurologists is needed as well as prospective research focusing on pathophysiology. [ABSTRACT FROM AUTHOR]

Inhibition of the lectin pathway of complement ameliorates hypocomplementemia and restores serum bactericidal activity in patients with severe COVID-19 In a separate study of secondary infection in hospitalised COVID-19 patients,10 we demonstrated that serum bactericidal activity (SBA) against I Klebsiella pneumoniae i is compromised in plasma from acute COVID-19 patients. On admission, all 18 COVID-19 patients showed hypocomplementemia, that is low CH SB 50 sb values (Figure 1A), and elevated plasma C5a (Figure 1B), with no significant differences between the treated and untreated groups, despite the untreated patients having less severe disease than those chosen for narsoplimab treatment (Table 1). [Extracted from the article]

Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid‐β. This is a joint statement of the European Association of Neurology and the European Psychiatric Association. After numerous unsuccessful endeavors to create a disease‐modifying therapy for Alzheimer's disease, substantial and consistent evidence supporting the clinical effectiveness of monoclonal antibodies aimed at amyloid‐β is finally emerging. The latest trials not only achieved their primary objective of slowing the progression of the disease over several months but also demonstrated positive secondary clinical outcomes and a decrease in amyloid‐β levels as observed through positron emission tomography scans. Taken as a whole, these findings mark a significant breakthrough by substantiating that reducing amyloid‐β yields tangible clinical benefits, beyond mere changes in biomarkers. Concurrently, the regular utilization of the new generation of drugs will determine whether statistical efficacy translates into clinically meaningful improvements. This may well signify the dawning of a new era in the development of drugs for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Even in families with a high prevalence of multiple sclerosis (MS), we are as yet unable to predict the development of MS with adequate accuracy at the individual level. To predict or not to predict: Multiple sclerosis and B-cell subset-specific genetic risk scores Although this work does show that the genetic susceptibility factors of MS correlate with the composition of the B-cell compartment early in life even of healthy children, it also highlights some current limitations and unmet needs in improving MS prediction. [Extracted from the article]

The ability to categorize stimuli - predator or prey, friend or foe - is an essential feature of the decision-making process. Underlying that ability is the development of an internally generated category boundary to generate decision outcomes. While classic temporal difference reinforcement models assume midbrain dopaminergic neurons underlie the prediction error required to learn boundary location, these neurons also demonstrate a robust response to nonreward incentive stimuli. More recent models suggest that this may reflect a motivational aspect to performing a task which should be accounted for when modeling dopaminergic neuronal behavior. To clarify the role of substantia nigra dopamine neurons in uncertain perceptual decision making, we investigated their behavior using single neuron extracellular recordings in patients with Parkinson's disease undergoing deep brain stimulation. Subjects underwent a simple auditory categorical decision-making task in which they had to classify a tone as either low- or high-pitched relative to an explicit threshold tone and received feedback but no reward. We demonstrate that the activity of human SN dopaminergic neurons is predictive of perceptual categorical decision outcome and is modulated by uncertainty. Neuronal activity was highest during difficult (uncertain) decisions that resulted in correct responses and lowest during easy decisions that resulted in incorrect responses. This pattern of results is more consistent with a 'motivational' role with regards to perceptual categorization and suggests that dopamine neurons are most active when critical information - as represented by uncertainty - is available for learning decision boundaries. [ABSTRACT FROM AUTHOR]

BACKGROUND Individuals with a history of colorectal cancer (CRC) have an increased risk of subsequent cancer. In this study, the authors used cancer registry data to evaluate whether this increased risk of cancer after CRC differed by anatomic subsite of a first CRC. METHODS Individuals diagnosed with a first primary CRC between 1992 and 2009 were identified from 12 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the incidence of subsequent cancers in these patients who had an index CRC versus the cancer incidence rates in the general population. SIRs were calculated for cancers at anatomic sites within and outside the colorectum in analyses stratified by subsite of the index CRC. RESULTS Cancer incidence rates were significantly higher in individuals who had a previous CRC than in the general population (SIR, 1.15; 95% CI, 1.13-1.16). Individuals with an index CRC located between the transverse and descending colon experienced the greatest increased risk both overall (SIR, 1.29-1.33) and particularly with respect to the risk of a second CRC (SIR, 2.53-3.35). The incidence of small intestinal cancer was elevated significantly regardless of the index CRC subsite (SIR, 4.31; 95% CI, 3.70-4.77), and the incidence of endometrial cancer was elevated in those who had an index CRC in the proximal colon (SIR, 1.37-1.79). CONCLUSIONS The risk of second cancer after CRC differs by anatomic site of the first tumor and is particularly pronounced for those with prior CRC located in the transverse to descending colon. The mechanisms underlying this pattern of second cancer risk remain unknown. Cancer 2013;119:3140-3147. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

In neurology, as in any other clinical specialty, there is a need to develop treatment strategies that allow stratification of therapies to optimize efficacy and minimize toxicity. Pharmacogenomics is one such method for therapy optimization: it aims to elucidate the relationship between human genome sequence variation and differential drug responses. Approaches have focused on candidate approaches investigating absorption-, distribution-, metabolism, and elimination (ADME)-related genes (pharmacokinetic pathways), and potential drug targets (pharmacodynamic pathways). To date, however, only few genetic variants have been incorporated into clinical algorithms. Unfortunately, a large number of studies have thrown up contradictory results due to a number of deficiencies, including small sample sizes, inadequate phenotyping, and genotyping strategies. Thus, there still exists an urgent need to establish biomarkers that could help to select for patients with an optimal benefit to risk relationship. Here we review recent advances, and limitations, in pharmacogenomics for agents used in neuroimmunology, neurodegenerative diseases, ischemic stroke, epilepsy, and primary headaches. Further work is still required in all of these areas, which really needs to progress on several fronts, including better standardized phenotyping, appropriate sample sizes through multicenter collaborations and judicious use of new technological advances such as genome-wide approaches, next generation sequencing and systems biology. In time, this is likely to lead to improvements in the benefit-harm balance of neurological therapies, cost efficiency, and identification of new drugs. Ann Neurol 2011 [ABSTRACT FROM AUTHOR]

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. Key points: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex.In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord.Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord.Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain‐ or spinal‐only conditions, especially at latencies that produced the strongest effects of paired stimulation.Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system. [ABSTRACT FROM AUTHOR]

Background: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. Methods: Among 2424 patients with stage I–III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow‐up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all‐cause and CRC‐specific mortality according to post‐diagnostic use and dose of multivitamin supplements. Results: During a median follow‐up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non‐users, post‐diagnostic users of multivitamin supplements at a dose of 3–5 tablets/week had lower CRC‐specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36–0.83, p =.005), and post‐diagnostic users at doses of 3–5 and 6–9 tablets/week had lower all‐cause mortality (HR, 0.81; 95% CI, 0.67–0.99, p =.04; HR, 0.79; 95% CI, 0.70–0.88), p <.001). The dose–response analysis showed a curvilinear relationship for both CRC‐specific (pnonlinearity <.001) and all‐cause mortality (pnonlinearity =.004), with the maximum risk reduction observed at 3–5 tablets/week and no further reduction at higher doses. Compared to non‐users in both pre‐ and post‐diagnosis periods, new post‐diagnostic users at dose of <10 tablets/week had a lower all‐cause mortality (HR, 0.81; 95% CI, 0.71–0.94, p =.005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07–2.33) and discontinued users (HR, 1.35; 95% CI, 1.14–1.59) had a higher risk of mortality. Conclusions: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC‐specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC‐specific mortality. In this prospective study of 2424 patients with stage I–III colorectal cancer (CRC), the authors observed a curvilinear relationship in the use of multivitamin supplements: compared to non‐users, users at a dose of 3–9 tablets/week had a lower risk of CRC‐specific and all‐cause mortality, whereas users at a dose higher than 10 tablets/week had a higher CRC‐specific mortality. [ABSTRACT FROM AUTHOR]

Mono-l-aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT).This open label phase I clinical trial at the University of California, Davis Medical Center examined the pharmacokinetic properties of Npe6 and clinical response to PDT with this photosensitizer. A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (basal cell carcinoma=22 lesions, squamous cell cancer=13 lesions, papillary carcinoma=14 lesions). Patients received one of five ascending doses (0.5 mg/kg (n=4), 1.0 mg/kg (n=3), 1.65 mg/kg (n=3), 2.5 mg/kg (n=3), or 3.5 mg/kg (n=1)) 4–8 h prior to light activation. The total light dose (range 25–200 J/cm2) depended on the tumor shape and size. Light was delivered using an argon-pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed.Four weeks post-PDT, 20 of 22 basal cell carcinoma tumors (91%) showed a complete response. Eighteen of 27 other malignant cutaneous tumors showed a complete (n=15/27, 56%) or partial (n=3/27, 11%) response. Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration. Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11 individual patients indicated that a two-compartment model with a residual phase best fits the data. The meanα,β, and terminal half-lives were 8.63±2.92, 105.90±37.59 and 168.11±53.40 h (±1 SD), respectively. The observed mean volume of distribution was 5.94±2.55 l, and the mean clearance was 0.0394±0.0132 l/h. These values were independent of the dose administered.The photosensitizer, NPe6, was well tolerated with minimal phototoxic side effects, and demonstrated preliminary efficacy against cutaneous malignancies. [ABSTRACT FROM AUTHOR]

Background: Anterior chamber configuration can be assessed via optical or ultrasonic techniques. Scheimpfiug photography is a non-invasive method measuring the anterior segment. The Anterior Eye Segment analysis system, EAS-1000, utilizes the Scheimpfiug principle and was found to have good repeatability. Previous repeatability studies, however, have had limitations in their design. The current study investigated the intra-observer and interobserver repeatability of the EAS-1000. Methods: Twenty-five healthy young subjects were recruited. The anterior chamber angles in different quadrants were measured by two examiners for interobserver analysis. The first examiner repeated the measurement at another session for intra-observer analysis. The 95% limits of agreement and intra-class correlation coefficient (ICC) were calculated. The anterior chamber depth was also measured and compared with ultrasound biometry. Results: The anterior chamber angle assessment demonstrated good intra-observer (ICC ranging from 0.77 to 0.90 for different quadrants) and interobserver (ICC ranging from 0.68 to 0.81 for different quadrants) repeatability. The 95% intra-observer limits of agreement were within ±5°. The 95% interobserver limits of agreement were within ±6°. There was no significant difference between male and female subjects or among angles at different quadrants. The anterior chamber depth was found to be repeatable (ICC > 0.90) with 95% limits of agreement ±0.1 mm. The anterior chamber depth was shallower than that obtained from ultrasound biometry. Conclusions: The EAS-100 is a non-invasive instrument which is repeatable for measuring the anterior chamber angle and depth. It provides quick results and is good for screening purposes. There is an under-estimation of anterior chamber depth, as previously reported. [ABSTRACT FROM AUTHOR]

This design improves the authors' previous work by including losses in the nonlinear medium. Unlike other all-optical switches, the nonlinear region for soliton interaction in this design is much shorter, This provides greater flexibility on the choices of nonlinear material as well as reduction of the threshold soliton power. The coupling between the signal and control beams is included in our numerical experiments. [ABSTRACT FROM AUTHOR]

A tri-state all-optical switch is designed based on tile repulsive effect of two propagating spatial solitons in a nonlinear medium. The solitons are launched from linear optical waveguides connected to the nonlinear medium. The coupling loss is minimized by choosing the appropriate values of the refractive indexes of the waveguide material and the substrate. Radiation loss is minimized by using single-mode optical waveguides. [ABSTRACT FROM AUTHOR]

The nonlinear effect and the diffraction effect on a spatial soliton are isolated by rewriting the nonlinear Schrödinger equation into a form of the linear Schrödinger equation with a nonlinear potential. Numerical results on these effects are obtained for a fundamental spatial soliton, a second-order spatial soliton, and two coupled solitons in a parallel-plate waveguide. The effects of waveguide loss are also included. [ABSTRACT FROM AUTHOR]

An efficient wavelet-packet-based time–frequency technique is proposed in this paper. This technique has found applications in inverse synthetic aperture radar (ISAR). It combines the Wigner–Ville distribution (WVD) of each sub-band signal partitioned from an input signal by the wavelet-packet transform (WPT). These distributions are used to estimate the parameters in Doppler processing. Similar parametric compensation is carried out in range processing so that a specific scatterer is focused in both range and cross-range. The end result uses the Fourier imaging method to obtain a high-resolution radar image. This technique is primarily based on estimation and compensation of the Doppler scattering parameters of the dominant scatterers for improved focus. It can be of great value to the scattering-oriented ISAR imaging. © 1998 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Using the coupled amplitude-phase formulation, an alternate approach to the inverse scattering transform (IST) for solving the coupled nonlinear Schrödinger equation is presented. The solution method to the nonlinear Schrödinger equation (NSE) for a single soliton described in a previous article is extended to the coupled NSE. The solutions reveal certain criteria for decoupling two copropagating solitons in an XPM system. The dynamics of soliton propagation are confirmed by numerical simulations with the use of the local interpolatary cardinal spline (LICS) method. The results agree well with theoretical prediction. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is commonly diagnosed and managed in primary care but there is evidence that this has been suboptimal, with low confidence expressed in providing interventions requiring behaviour change. The aim of this study was to determine the acceptability of a general practitioner (GP)–physiotherapist partnership in the diagnosis and management of COPD in primary care and to explore the experiences of participants during the implementation of the model. Methods: Semi‐structured interviews were conducted with physiotherapists (n = 3), GPs (n = 2), practice nurses (PNs) (n = 2) and patients (n = 12) who had participated in the InNovaTivE Gp‐physiotheRapist pArTnErship for copD (INTEGRATED) trial. We sought to explore participants' views about their experiences and perceived benefits, barriers and facilitators to the implementation of this model of care. Interviews were transcribed, coded and thematically analysed. Synthesis of the data was guided by the Theoretical Domains Framework for clinician interviews and the health belief model for patient interviews. Results: All clinicians felt that this integrated model helped to optimise care for patients with COPD by facilitating evidence‐based practice. GPs and PNs valued the physiotherapist's knowledge and skills relating to diagnosis and management, which was reported to complement their own management and improve patient outcomes. Patients reported a sense of empowerment following their appointments and acknowledged improved self‐management skills. However, physiotherapists reported many patients were already engaging in positive health behaviours. Responses were mixed on the effectiveness of the model in facilitating teamwork between clinicians with different perspectives concerning management, communication pathways and logistical issues, such as time and room availability, being cited as barriers. Conclusions: An experienced cardiorespiratory physiotherapist embedded into a small number of primary care practices to work in partnership with GPs for COPD diagnosis and management was acceptable and viewed as beneficial for patients. Barriers relating to logistics and resources remain, which must be addressed to optimise implementation. Patient or Public Contribution: Patient input was obtained from qualitative feedback from a prior study conducted by two authors and was used to refine the model of care to determine the added value of a physiotherapist integrated into the primary care team. This feedback was also used to refine the interview guides utilised in this study determine the acceptability of this model of care. We had health service involvement from the rehabilitation service of the local health district who were directly involved in determining study aims and establishing the project around the priorities for their chronic disease integration service. For example, this project aimed to engage with a less severe patient population in primary care who would benefit from pulmonary rehabilitation. The findings from this study will be used to further tailor the model of care to the needs of the public and patients. Trial Registration: ACTRN12619001127190 [ABSTRACT FROM AUTHOR]

Aims: Treatment of multiple sclerosis (MS) relapses consists of short‐term administration of high‐dose glucocorticoids (GCs). However, over 40% of patients show an insufficient response to GC treatment. We aimed to develop a predictive model for such GC resistance. Methods: We performed a receiver operating characteristic (ROC) curve analysis following the transcriptomic assay of whole blood samples from stable, relapsing GC‐sensitive and relapsing GC‐resistant patients with MS in two different European centers. Results: We identified 12 genes being regulated during a relapse and differentially expressed between GC‐sensitive and GC‐resistant patients with MS. Using these genes, we defined a statistical model to predict GC resistance with an area under the curve (AUC) of the ROC analysis of 0.913. Furthermore, we observed that relapsing GC‐resistant patients with MS have decreased GR, DUSP1, and TSC22D3 mRNA levels compared with relapsing GC‐sensitive patients with MS. Finally, we showed that the transcriptome of relapsing GC‐resistant patients with MS resembles those of stable patients with MS. Conclusion: Predicting GC resistance would allow patients to benefit from prompt initiation of an alternative relapse treatment leading to increased treatment efficacy. Thus, we think our model could contribute to reducing disability development in people with MS. [ABSTRACT FROM AUTHOR]

Summary: Aim: To examine the relationship between periodontal disease and tooth loss and risk of inflammatory bowel disease (IBD). Methods: We conducted a prospective cohort study of 86,602 women from the Nurses' Health Study (1992–2016) and 50,349 men from the Health Professionals Follow‐up Study (1986–2016) with available data on periodontal disease and tooth loss. Cases of IBD were initially reported by participants and then confirmed by medical record review. We used Cox proportional hazards modelling to estimate multivariable‐adjusted hazard ratios (aHRs) and 95% CIs. Results: Through the end of follow‐up, we documented 175 cases of Crohn's disease (CD) and 209 cases of ulcerative colitis (UC). After adjustment for potential risk factors, there was no association between periodontal disease and risk of CD (pooled aHR: 0.99, 95% CI: 0.65–1.52, p = 0.970) or UC (aHR: 0.99, 95% CI: 0.68–1.45, p = 0.971). Similarly, we did not observe an association between tooth loss and risk of CD (aHR: 0.72, 95% CI: 0.43–1.21, p = 0.218) or UC (aHR: 0.89, 95% CI: 0.58–1.36, p = 0.581) in the pooled analysis. The associations were not modified by sex, age, body mass index (BMI), smoking status or NSAID use (all pinteraction > 0.87). Conclusion: In two large prospective cohort studies, we did not observe an association between periodontal disease and tooth loss and risk of CD or UC. [ABSTRACT FROM AUTHOR]

Objectives: The CD274 (programmed cell death 1 ligand 1, PD‐L1)/PDCD1 (programmed cell death 1, PD‐1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of Fusobacterium nucleatum. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of F. nucleatum in colorectal carcinoma. Methods: We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE‐1 methylation level and KRAS, BRAF and PIK3CA mutations. Results: Fusobacterium nucleatum DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue (P = 0.0077). For one category‐unit increase in three ordinal F. nucleatum categories (negative vs. low vs. high), multivariable‐adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41–1.51), 0.64 (0.32–1.28) and 0.50 (0.25–0.99), respectively (Ptrend = 0.032). Conclusions: Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor F. nucleatum enrichment) tend to be used by different tumor subgroups. [ABSTRACT FROM AUTHOR]

Background and purpose: Kelchlike protein 11 antibodies (KLHL11‐IgGs) were first described in 2019 as a marker of paraneoplastic neurological syndromes (PNSs). They have mostly been associated with testicular germ cell tumors (tGCTs). Methods: Two patients with KLHL11‐IgG encephalitis are reported, and the literature is comprehensively reviewed. Results: Patient 1 had been in remission from a tGCT 10 years prior. He developed episodic vertigo and diplopia progressing over a few days. Treatment with corticosteroids (CSs) was started a few days after symptom onset. Patient 2 had transient diplopia, which resolved spontaneously. Visual problems persisted for 7 months, when he additionally developed a progressive cerebellar syndrome. One year after onset, CS treatment was started. Initial magnetic resonance imaging was unremarkable in both patients, but analysis of cerebrospinal fluid (CSF) revealed chronic inflammation. KLHL11‐IgG was positive in both patients (Patient 1 only in CSF, Patient 2 in serum). Neoplastic screening has so far not revealed any signs of active underlying malignancy. We found 15 publications of 112 patients in total with KLHL11‐IgG encephalitis. Most patients (n = 82) had a cerebellar syndrome with or without signs of rhombencephalitis. The most common symptoms were ataxia (n = 82) and vertigo (n = 47), followed by oculomotor disturbances (n = 35) and hearing disorders (n = 31). Eighty of 84 patients had a GCT as an underlying tumor. Conclusions: Our cases demonstrate classical symptoms of KLHL11‐IgG encephalitis. Early diagnosis and therapy are imperative. As with other PNSs, clinical awareness is needed and further studies are required especially in regard to therapeutic management. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerotic vascular disease is the leading cause of mortality and morbidity worldwide. Our previous study uncovered that endothelium‐specific knockdown of YAP suppresses atherogenesis, suggesting that YAP is a promising therapeutic target against atherosclerotic vascular disease. We established a drug screening platform, which aimed to identify new YAP inhibitors for anti‐atherosclerotic treatment. Experimental Approach: Drug screening was performed by a luciferase reporter gene assay. RNA sequencing was performed to acquire the transcriptomic profile of CBL0137‐treated endothelial cells. We assessed and validated the inhibitory effect of CBL0137 on YAP activity and inflammatory response in HUVECs and HAECs. We evaluated the vasoprotective effect of CBL0137 in vivo against plaque formation in ApoE−/− mice, using both disturbed flow‐induced and chronic western diet‐induced atherosclerotic models. Key Results: We identified CBL0137 as a novel YAP inhibitor from an FDA drug library. CBL0137 inhibited YAP activity by restraining its phosphorylation at Y357. CBL0137 inhibited YAP activity to repress endothelial inflammation. Mechanistically, CBL0137 suppressed YAP phosphorylation at Y357 via the tyrosine‐protein kinase Src. Furthermore, administration of CBL0137 ameliorated endothelial inflammation and the atherogenesis induced by disturbed flow and consumption of an atherogenic diet in ApoE−/− mice. Conclusion and Implications: To our knowledge, this is the first study to identify CBL0137 as a novel YAP inhibitor. We have demonstrated that pharmacologically targeting YAP by CBL0137 inhibits atherogenesis. The present results suggest that CBL0137 holds promise as a new drug for the treatment of atherosclerotic vascular disease. [ABSTRACT FROM AUTHOR]

Background and purpose: Neuronal autoantibodies can support the diagnosis of primary autoimmune cerebellar ataxia (PACA). Knowledge of PACA is still sparce. This article aims to highlight the relevance of anti‐neurochondrin antibodies and possible therapeutical consequences in people with PACA. Methods: This is a case presentation and literature review of PACA associated with anti‐neurochondrin antibodies. Results: A 33‐year‐old man noticed reduced control of the right leg in May 2020. During his first clinic appointment at our institution in September 2021, he complained about gait imbalance, fine motor disorders, tremor, intermittent diplopia and slurred speech. He presented a pancerebellar syndrome with stance, gait and limb ataxia, scanning speech and oculomotor dysfunction. Within 3 months the symptoms progressed. An initial cerebral magnetic resonance imaging, June 2020, was normal, but follow‐up imaging in October 2021 and July 2022 revealed marked cerebellar atrophy (29% volume loss). Cerebrospinal fluid analysis showed lymphocytic pleocytosis of 11 x 103/L (normal range 0–4) and oligoclonal bands type II. Anti‐neurochondrin antibodies (immunoglobulin G) were detected in serum (1:10,000) and cerebrospinal fluid (1:320, by cell‐based indirect immunofluorescence assay and immunoblot, analysed by the EUROIMMUN laboratory). After ruling out alternative causes and neoplasia, diagnosis of PACA was given and immunotherapy (steroids and cyclophosphamide) was started in January 2022. In March 2022 a stabilization of disease was observed. Conclusion: Cerebellar ataxia associated with anti‐neurochondrin antibodies has only been described in 19 cases; however, the number of unrecognized PACAs may be higher. As anti‐neurochondrin antibodies target an intracellular antigen and exhibit a mainly cytotoxic T‐cell‐mediated pathogenesis, important therapeutic implications may result. Because of the severe and rapid clinical progression, aggressive immunotherapy was warranted. This case highlights the need for rapid diagnosis and therapy in PACA, as stabilization and even improvement of symptoms are attainable. [ABSTRACT FROM AUTHOR]

The article introduces this issue on drug discovery targets ranging from clinically validated to more speculative, but promising, pathways in human disease.

Brain morphometry is usually based on non‐enhanced (pre‐contrast) T1‐weighted MRI. However, such dedicated protocols are sometimes missing in clinical examinations. Instead, an image with a contrast agent is often available. Existing tools such as FreeSurfer yield unreliable results when applied to contrast‐enhanced (CE) images. Consequently, these acquisitions are excluded from retrospective morphometry studies, which reduces the sample size. We hypothesize that deep learning (DL)‐based morphometry methods can extract morphometric measures also from contrast‐enhanced MRI. We have extended DL+DiReCT to cope with contrast‐enhanced MRI. Training data for our DL‐based model were enriched with non‐enhanced and CE image pairs from the same session. The segmentations were derived with FreeSurfer from the non‐enhanced image and used as ground truth for the coregistered CE image. A longitudinal dataset of patients with multiple sclerosis (MS), comprising relapsing remitting (RRMS) and primary progressive (PPMS) subgroups, was used for the evaluation. Global and regional cortical thickness derived from non‐enhanced and CE images were contrasted to results from FreeSurfer. Correlation coefficients of global mean cortical thickness between non‐enhanced and CE images were significantly larger with DL+DiReCT (r = 0.92) than with FreeSurfer (r = 0.75). When comparing the longitudinal atrophy rates between the two MS subgroups, the effect sizes between PPMS and RRMS were higher with DL+DiReCT both for non‐enhanced (d = −0.304) and CE images (d = −0.169) than for FreeSurfer (non‐enhanced d = −0.111, CE d = 0.085). In conclusion, brain morphometry can be derived reliably from contrast‐enhanced MRI using DL‐based morphometry tools, making additional cases available for analysis and potential future diagnostic morphometry tools. [ABSTRACT FROM AUTHOR]

Introduction: Data on structural brain changes after infection with SARS‐CoV‐2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS‐CoV‐2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. Methods: Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre‐SARS‐CoV‐2 images with age as an explanatory variable. The residuals were used to determine whether the post‐SARS‐CoV‐2 volumes differed significantly from the baseline. Results: Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS‐CoV‐2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. Conclusions: Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS‐CoV‐2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results. [ABSTRACT FROM AUTHOR]

Objective: Using a strength-based framework, we aimed to describe and compare First Nations patients who completed care in an ED to those who took their own leave. Methods: Routinely collected adult patient data from a metropolitan ED collected over a 5-year period were analysed. Results: A total of 6446 presentations of First Nations patients occurred from 2016 to 2020, constituting 3% of ED presentations. Of these, 5589 (87%) patients waited to be seen and 857 (13%) took their own leave. Among patients who took their own leave, 624 (73%) left not seen and 233 (27%) left at own risk after starting treatment. Patients who were assigned a triage category of 4-5 were significantly more likely to take their own leave (adjusted odds ratio [OR] 3.17, 95% confidence interval [CI] 2.67-3.77, P < 0.001). Patients were significantly less likely to take their own leave if they were >60 years (adjusted OR 0.69, 95% CI 1.01-1.36, P = 0.014) and had private health insurance (adjusted OR 0.61, 95% CI 0.45-0.84, P < 0.001). Patients were more likely to leave if they were women (adjusted OR 1.17, 95% CI 1.01-1.36, P = 0.04), had an unknown housing status (adjusted OR 1.76, 95% CI 1.44-2.15, P < 0.001), were homeless (adjusted OR 1.50, 95% CI 1.22-1.93, P < 0.001) or had a safety alert (adjusted OR 1.60, 95% CI 1.35-1.90, P < 0.001). Conclusion: A lower triage category is a strong predictor of First Nations patients taking their own leave. It has been documented that First Nations patients are under-triaged. One proposed intervention in the metropolitan setting is to introduce practices which expediate the care of First Nations patients. Further qualitative studies with First Nations patients should be undertaken to determine successful approaches to create equitable access to emergency healthcare for this population. [ABSTRACT FROM AUTHOR]

Introduction: Post‐COVID‐19 syndrome affects approximately 10–25% of people after a COVID‐19 infection, irrespective of initial COVID‐19 severity. The aim of this project was to assess the clinical characteristics, course, and prognosis of post‐COVID‐19 syndrome using a systematic multidimensional approach. Patients and Methods: An online survey of people with suspected and confirmed COVID‐19 and post‐COVID‐19 syndrome, distributed via Swiss COVID‐19 support groups, social media, and our post‐COVID‐19 consultation, was performed. A total of 8 post‐infectious domains were assessed with 120 questions. Data were collected from October 15 to December 12, 2021, and 309 participants were included. Analysis of clinical phenomenology of post‐COVID‐19 syndrome was performed using comparative statistics. Results: The three most prevalent post‐COVID‐19 symptoms in our survey cohort were fatigue (288/309, 93.2%), pain including headache (218/309, 70.6%), and sleep–wake disturbances (mainly insomnia and excessive daytime sleepiness, 145/309, 46.9%). Post‐COVID‐19 syndrome had an impact on work ability, as more than half of the respondents (168/268, 62.7%) reported an inability to work, which lasted on average 26.6 weeks (95% CI 23.5–29.6, range 1–94, n = 168). Quality of life measured by WHO‐5 Well‐being Index was overall low in respondents with post‐COVID‐19 syndrome (mean, 95% CI 9.1 [8.5–9.8], range 1–25, n = 239). Conclusion: Fatigue, pain, and sleep–wake disturbances were the main symptoms of the post‐COVID‐19 syndrome in our cohort and had an impact on the quality of life and ability to work in a majority of patients. However, survey respondents reported a significant reduction in symptoms over 12 months. Post‐COVID‐19 syndrome remains a significant challenge. Further studies to characterize this syndrome and to explore therapeutic options are therefore urgently needed. [ABSTRACT FROM AUTHOR]

Background: Certain dietary patterns can elicit systemic and intestinal inflammatory responses, which may influence adaptive anti‐tumor immune responses and tumor behavior. We hypothesized that pro‐inflammatory diets might be associated with higher colorectal cancer mortality and that the association might be stronger for tumors with lower immune responses. Methods: We calculated an empirical dietary inflammatory pattern (EDIP) score in 2829 patients among 3988 incident rectal and colon carcinoma cases in the Nurses' Health Study and Health Professionals Follow‐up Study. Using Cox proportional hazards regression analyses, we examined the prognostic association of EDIP scores and whether it might be modified by histopathologic immune reaction (in 1192 patients with available data). Results: Higher EDIP scores after colorectal cancer diagnosis were associated with worse survival, with multivariable‐adjusted hazard ratios (HRs) for the highest versus lowest tertile of 1.41 (95% confidence interval [CI]: 1.13–1.77; Ptrend = 0.003) for 5‐year colorectal cancer‐specific mortality and 1.44 (95% CI, 1.19‐1.74; Ptrend = 0.0004) for 5‐year all‐cause mortality. The association of post‐diagnosis EDIP scores with 5‐year colorectal cancer‐specific mortality differed by degrees of tumor‐infiltrating lymphocytes (TIL; Pinteraction =.002) but not by three other lymphocytic reaction patterns. The multivariable‐adjusted, 5‐year colorectal cancer‐specific mortality HRs for the highest versus lowest EDIP tertile were 1.59 (95% CI: 1.01–2.53) in TIL‐absent/low cases and 0.48 (95% CI: 0.16–1.48) in TIL‐intermediate/high cases. Conclusions: Pro‐inflammatory diets after colorectal cancer diagnosis were associated with increased mortality, particularly in patients with absent or low TIL. [ABSTRACT FROM AUTHOR]

Background: Plant‐based foods have been recommended for health. However, not all plant foods are healthy, and little is known about the association between plant‐based diets and specific molecular subtypes of colorectal cancer (CRC). We examined the associations of healthy and unhealthy plant‐based diets with the incidence of CRC and its molecular subtypes. Methods: While 123 773 participants of the Nurses' Health Study and the Health Professionals Follow‐up Study had been followed up (3 143 158 person‐years), 3077 of them had developed CRC. Healthy and unhealthy plant‐based diet indices (hPDI and uPDI, respectively) were calculated using repeated food frequency questionnaire data. We determined the tumoural status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations. Results: Higher hPDI was associated with lower CRC incidence (multivariable hazard ratio [HR] comparing extreme quartiles, 0.86, 95% confidence interval [CI]: 0.77, 0.96; P‐trend =.04), whereas higher uPDI was associated with higher CRC incidence (multivariable HR comparing extreme quartiles, 1.16, 95% CI: 1.04, 1.29; P‐trend =.005). The association of hPDI significantly differed by KRAS status (P‐heterogeneity =.003) but not by other tumour markers. The hPDI was associated with lower incidence of KRAS‐wildtype CRC (multivariable HR comparing extreme quartiles, 0.74, 95% CI: 0.57, 0.96; P‐trend =.004) but not KRAS‐mutant CRC (P‐trend =.22). Conclusions: While unhealthy plant‐based diet enriched with refined grains and sugar is associated with higher CRC incidence, healthy plant‐based diet rich in whole grains, fruits and vegetables is associated with lower incidence of CRC, especially KRAS‐wildtype CRC. [ABSTRACT FROM AUTHOR]

Background and Purpose: The "venous hypothesis" of multiple sclerosis (MS) postulates that intracranial venous congestion disintegrates the blood-brain barrier, resulting in iron accumulation in brain parenchyma triggering the inflammatory process of MS. Transcranial sonography (TCS) reveals brain parenchyma hyperechogenic alterations (BPHA) that are thought to reflect iron accumulation. We sought to investigate potential association of BPHA with chronic cerebrospinal venous insufficiency (CCSVI) in MS. Methods: MS patients were evaluated according to established TCS protocol for extrapyramidal disorders examining the presence of hyperechogenicities in different basal ganglia regions. Cerebral and cervical venous system was assessed according to proposed ultrasound protocol for CCSVI detection. Results: In a total of 32 MS patients (age = 40 ± 14 years; male = 41%; EDSS-score = 3.1 ± 2.2) brain parenchyma hyperechogenic alterations were detected in twelve (38%) patients. The two sonographers agreed independently in 28 (87.5%) of the 32 examinations, resulting in a substantial to almost perfect agreement (Cohen's weighted kappa: substantia nigra = 0.904, Lentiform nucleus = 0.871, Thalamus = 0.784, caudate nucleus = 0.651). Two (6%) patients fulfilled the neurosonology criteria of CCSVI, while in 7 patients (22%) one positive criterion was detected. No BPHA were observed in any MS patient fulfilling CCSVI criteria. The prevalence of one positive CCSVI feature did not differ (P = .999) among patients with present (25%) or absent (20%) BPHA. Conclusion: There was no association of BPHA with CCSVI findings. Our findings do not support the "venous hypothesis" resulting in iron accumulation even in the few MS patients fulfilling CCSVI-criteria. [ABSTRACT FROM AUTHOR]

Summary: Background and aims: There are limited data on alcohol dose and types and risk of Crohn's Disease (CD) and Ulcerative Colitis (UC). We therefore sought to comprehensively examine the association between alcohol consumption and risk of CD and UC. Methods: We conducted a prospective cohort study of 237,835 participants from the Nurses' Health Study, Nurses' Health Study II, and Health Professional Follow‐Up Study. Alcohol consumption was obtained through questionnaires submitted every four years; additional covariates were obtained at two or four‐year intervals. Cases were confirmed independently by two physicians through medical record review. We used Cox proportional hazards regression to estimate age and multivariable‐adjusted hazards ratios and 95% confidence intervals. Results: Across 5,170,474 person‐years of follow‐up, 370 cases of CD and 486 cases of UC were documented. Increased consumption of alcohol intake was not associated with CD (Ptrend = 0.455) or UC (Ptrend = 0.745). Compared to non‐users, the MV‐adjusted HRs for 15.0 + g/day of alcohol intake group were 0.84 (95% CI 0.56, 1.24) for CD and 1.08 (95% CI 0.77, 1.51) for UC. In analyses of alcohol subtypes, we observed that only moderate consumption of beer (>1‐4 servings/week) was marginally associated with reduced risk of CD, while consumption of >4 servings/week of liquor was associated with an increased risk of UC. Conclusion: This prospective study did not identify a relationship between overall alcohol consumption and risk of CD or UC. Our suggestive associations between alcohol types and risk of CD and UC deserve additional investigation. [ABSTRACT FROM AUTHOR]

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow‐up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF). Relationships with the time to first relapse, sNfL concentrations, T2‐weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high‐efficacy therapy were analyzed in covariate‐adjusted statistical models. Results: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF. Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high‐efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose‐dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging‐defined disease activity and sNfL. Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477–489 [ABSTRACT FROM AUTHOR]

The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjögren’s syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies. [ABSTRACT FROM AUTHOR]

The syndrome of chronic obstructive pulmonary disease (COPD) consists of chronic bronchitis (CB), bronchiectasis, emphysema, and reversible airway disease that combine uniquely in an individual patient. Older patients are at risk for COPD and its components—emphysema, CB, and bronchiectasis. Bacterial and viral infections play a role in acute exacerbations of COPD (AECOPD) and in acute exacerbations of CB (AECB) without features of COPD. Older patients are at risk for resistant bacterial organisms during their episodes of AECOPD and AECB. Organisms include the more-common bacteria implicated in AECOPD/AECB such as Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Less-common nonenteric, gram-negative organisms including Pseudomonas aeruginosa, gram-positive organisms including Staphylococcus aureus, and strains of nontuberculosis Mycobacteria are more often seen in AECOPD/AECB episodes involving elderly patients with frequent episodes of CB or those with bronchiectasis. Risk-stratified antibiotic treatment guidelines appear useful for purulent episodes of AECOPD and episodes of AECB. These guidelines have not been prospectively validated for the general population and especially not for the elderly population. Using a risk-stratification approach for elderly patients, first-line antibiotics (e.g., amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole, and doxycycline), with a more-limited spectrum of antibacterial coverage, are used in patients who are likely to have a low probability of resistant organisms during AECOPD/AECB. Second-line antibiotics (e.g., amoxicillin/clavulanic acid, second- or third-generation cephalosporins, and respiratory fluoroquinolones) with a broader spectrum of coverage are reserved for patients with significant risk factors for resistant organisms and those who have failed initial antibiotic treatment. [ABSTRACT FROM AUTHOR]

Fas-associated protein with death domain (FADD) is an essential adaptor protein in death receptor-mediated signal transduction. During apoptotic signaling, FADD functions in the cytoplasm, where it couples activated receptors with initiator caspase-8. However, in resting cells, FADD is predominantly stored in the nucleus. In this study, we examined the modalities of FADD intracellular trafficking. We demonstrate that, upon CD95 activation, FADD redistributes from the nucleus to the cytoplasm. This inducible nuclear–cytoplasmic translocation of FADD is independent of CD95 internalization, formation of the death-inducing signaling complex, and caspase-8 activation. In contrast to nuclear export of FADD, its subsequent recruitment and accumulation at endosomes containing internalized CD95 requires a caspase-8-dependent feedback loop. These data indicate the existence of differential pathways directing FADD nuclear export and cytoplasmic trafficking, and identify subcellular compartmentalization of FADD as a novel regulatory mechanism in death receptor signaling. [ABSTRACT FROM AUTHOR]

Increased COVID-19 severity was also demonstrated by an analysis of a more homogenous cohort of MS patients treated in France and Italy8 demonstrating an odds ratio (OR) of 2.05 (95%CI 1.39-3.02). Despite the majority of patients (35/51) having a mild-to-moderate disease course, 16/51 were hospitalized, 10/51 had a severe disease course, and 3/51 died.5 Despite small patient numbers, 3/51 exceeds the worldwide COVID-19 fatality rates (1.5%6; MS specific 3.3% (95%-confidence interval (95%CI), 2.5%-4.3%7). Is COVID-19 severity associated with reduction in T lymphocytes in anti-CD20-treated people with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder?. [Extracted from the article]

Aims: Myelin oligodendrocyte glycoprotein antibodies (MOG‐IgG) have been proposed to define "MOG encephalomyelitis" (MOG‐EM), with published diagnostic and "red flag" criteria. We aimed to evaluate these criteria in a routine clinical setting. Methods: We retrospectively analyzed patients with borderline/positive MOG‐IgG and applied the diagnostic and red flag criteria to determine likelihood of MOG‐EM diagnosis. Para‐/clinical parameters were described and analyzed with chi‐square test. Results: In total, 37 patients fulfilled MOG‐EM diagnostic criteria (female‐to‐male ratio: 1.6:1, median onset age: 28.0 years [IQR 18.5‐40.5], n = 8 with pediatric onset). In 24/37, red flags were present, predominantly MOG‐IgG at assay cutoff and/or MRI lesions suggestive of multiple sclerosis (MS). As proposed in the consensus criteria, these patients should rather be described as "possible" MOG‐EM. Of these, we classified 13 patients as "unlikely" MOG‐EM in the presence of the red flag "borderline MOG‐IgG" with negative MOG‐IgG retest or coincidence of ≥1 additional red flag. This group mainly consisted of patients diagnosed with MS (n = 11). Frequency of cerebrospinal fluid (CSF‐)—specific oligoclonal bands (OCB) is significantly lower in definite vs possible and unlikely MOG‐EM (P =.0005). Conclusion: Evaluation of diagnostic and red flag criteria, MOG‐IgG retesting (incl. change of assay), and CSF‐specific OCB are relevant in clinical routine cohorts to differentiate MOG‐EM from MS. [ABSTRACT FROM AUTHOR]

Summary: Background: Although immune‐mediated diseases (IMDs) including inflammatory bowel diseases (IBDs) are known to cluster, to what extent this is due to common environmental influences is unknown. Aim: To examine the incidence of IBD in individuals with another IMD. Methods: We used data from the prospective Nurses' Health Study II cohort (1995‐2017) to examine the effect of diagnoses of several common IMDs on subsequent risk of Crohn's disease (CD) or ulcerative colitis (UC) using Cox proportional hazards models, adjusting for detailed diet and lifestyle confounders. Results: We documented 132 cases of CD and 186 cases of UC over 2 016 163 person‐years of follow‐up (median age at IBD diagnosis 50 years). Compared to participants with no history of IMD, the HRs of CD for those with 1 and ≥ 2 IMDs were 2.57 (95% CI 1.77‐3.74) and 2.74 (95% CI 1.36 to 5.49), respectively (Ptrend < 0.0001). This association was only modestly attenuated by adjustment for environmental risk factors (HR 2.35 and 2.46, respectively). The risk of UC was not increased, with multivariable‐adjusted HRs of 1.22 (95% CI 0.85‐1.76) and 1.33 (95% CI 0.67‐2.65) for those with 1 and ≥ 2 IMDs, respectively, compared to those with none (Ptrend 0.16) (Pheterogeneity comparing CD and UC 0.037). Asthma, atopic dermatitis, psoriasis and rosacea were individually associated with higher risk of CD (HR ranging from 2.15 to 3.39) but not UC. Conclusions: Individuals with one or more IMDs are at an increased risk for CD but not UC. [ABSTRACT FROM AUTHOR]

Germline mutation in the PTEN gene is the genetic basis of PTEN hamartoma tumor syndrome with the affected individuals harboring features of autism spectrum disorders. Characterizing a panel of 14 autism‐associated PTEN missense mutations revealed reduced protein stability, catalytic activity, and subcellular distribution. Nine out of 14 (64%) PTEN missense mutants had reduced protein expression with most mutations confined to the C2 domain. Selected mutants displayed enhanced polyubiquitination and shortened protein half‐life, but that did not appear to involve the polyubiquitination sites at lysine residues at codon 13 or 289. Analyzing their intrinsic lipid phosphatase activities revealed that 78% (11 out of 14) of these mutants had twofold to 10‐fold reduction in catalytic activity toward phosphatidylinositol phosphate substrates. Analyzing the subcellular localization of the PTEN missense mutants showed that 64% (nine out of 14) had altered nuclear‐to‐cytosol ratios with four mutants (G44D, H123Q, E157G, and D326N) showing greater nuclear localization. The E157G mutant was knocked‐in to an induced pluripotent stem cell line and recapitulated a similar nuclear targeting preference. Furthermore, iPSCs expressing the E157G mutant were more proliferative at the neural progenitor cell stage but exhibited more extensive dendritic outgrowth. In summary, the combination of biological changes in PTEN is expected to contribute to the behavioral and cellular features of this neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

International statements have suggested the pulmonary rehabilitation (PR) model as an appropriate rehabilitation option for people recovering from coronavirus disease 2019 (COVID-19). In this case series, we present our COVID-19 telehealth rehabilitation programme, delivered within a PR setting, and discuss the management of our first three cases. All patients were male, with a median age of 73 years. Following hospital discharge, the patients presented with persistent limitations and/or symptoms (e.g. breathlessness, fatigue, and reduced exercise capacity) which warranted community-based rehabilitation. Patients were assessed and provided with an initial six-week rehabilitation programme supported via telehealth using a treatable traits approach. Patients demonstrated improvements in exercise capacity and breathlessness; however, fatigue levels worsened in two cases and this was attributed to the difficulties of managing returning to work and/or carer responsibilities whilst trying to recover from a severe illness. We found that PR clinicians were well prepared and able to provide an individualized rehabilitation programme for people recovering from COVID-19. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk. [ABSTRACT FROM AUTHOR]

Summary: The hybrid finite‐discrete element method (FDEM) is widely used for engineering applications, which, however, is computationally expensive and needs further development, especially when rock fracture process is modeled. This study aims to further develop a sequential hybrid FDEM code formerly proposed by the authors and parallelize it using compute unified device architecture (CUDA) C/C++ on the basis of a general‐purpose graphics processing unit (GPGPU) for rock engineering applications. Because the contact detection algorithm in the sequential code is not suitable for GPGPU parallelization, a different contact detection algorithm is implemented in the GPGPU‐parallelized hybrid FDEM. Moreover, a number of new features are implemented in the hybrid FDEM code, including the local damping technique for efficient geostatic stress analysis, contact damping, contact friction, and the absorbing boundary. Then, a number of simulations with both quasi‐static and dynamic loading conditions are conducted using the GPGPU‐parallelized hybrid FDEM, and the obtained results are compared both quantitatively and qualitatively with those from either theoretical analysis or the literature to calibrate the implementations. Finally, the speed‐up performance of the hybrid FDEM is discussed in terms of its performance on various GPGPU accelerators and a comparison with the sequential code, which reveals that the GPGPU‐parallelized hybrid FDEM can run more than 128 times faster than the sequential code if it is run on appropriate GPGPU accelerators, such as the Quadro GP100. It is concluded that the GPGPU‐parallelized hybrid FDEM developed in this study is a valuable and powerful numerical tool for rock engineering applications. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Multiple sclerosis (MS) is an autoimmune disease of the CNS, which predominantly affects women. Studies investigating the sex distribution in MS are sparse. We aim to analyze the female‐to‐male ratio (F/M ratio) in different MS phenotypes in association with age at diagnosis and year of birth. Methods: We performed a retrospective cross‐sectional analysis by cumulating data (sex, year of birth, age at diagnosis, and MS phenotypes) from unpublished and published studies of the participating centers. Results: Datasets of 945 patients were collected. The overall F/M ratio was 1.9:1.0 and female preponderance was present in all phenotypes except for primary progressive MS (PPMS), in which men were predominantly affected (F/M ratio: 0.5:1.0). Female preponderance declined with increasing age at diagnosis and was no longer present in relapsing‐remitting MS (RRMS) patients > 58 years of age. Conclusion: Our data demonstrate an age dependency of female preponderance in MS except for PPMS. This could be influenced by the lifecycle of sex hormone secretion in women. In PPMS, a male preponderance was observed in all age‐groups, which might point to pathophysiological mechanisms being less influenced by sex hormones. [ABSTRACT FROM AUTHOR]

Abstract: A family history of colorectal cancer (CRC) in first‐degree relatives (FDRs) increases the risk of CRC. However, the influence of family history on survival among CRC patients remains unclear. We conducted a pooled analysis of survival in 5010 incident CRC cases. Cox proportional hazards models were used to estimate the association of family history with overall survival (OS) and CRC‐specific survival (CSS). We also assessed the impact of the number of affected FDRs and age at CRC diagnosis in the affected FDRs on survival. Among CRC cases, 819 (16%) patients reported a family history of CRC. There were 1580 total deaths over a median follow‐up of 4.6 years, of which 1046 (66%) deaths were due to CRC. Having a family history of CRC was not associated with OS [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.89–1.19] or CSS (HR, 1.13; 95% CI, 0.95–1.36)]. There were no associations between the number of affected relatives or age at CRC diagnosis of the affected relative with survival (all Ptrend > 0.05). However, a family history of CRC did confer worse CSS in patients diagnosed with distal colon cancer (HR, 1.45, 95% CI, 1.03–2.04). A family history of CRC was generally not associated with survival after CRC diagnosis. However, having a family history of CRC was associated with worse CRC prognosis in individuals with distal colon cancer, suggesting a possible genetic predisposition with distinct pathogenic mechanism that may lead to worse survival in this group. [ABSTRACT FROM AUTHOR]

Objectives Low ultraviolet-B ( UVB) radiation causes hypovitaminosis D, which is a known risk factor for multiple sclerosis ( MS) and associated with MS disease activity. Our objective is to test whether vitamin D supplementation is most effective in lowering disease activity during the period of the year with low UVB radiation and consequently low serum 25-hydroxyvitamin D3 (25( OH)D3) concentration. Methods Retrospective analysis of medical records from our outpatient department identified 40 MS patients with available data of at least 6 months before and during oral vitamin D supplementation. Serum 25( OH)D3 concentration was analyzed using immunoassay. UVB radiation data were provided by the local government. Annualized and quarterly relapse rates before and during vitamin D supplementation served as outcome parameters. Results During vitamin D supplementation (18,950 international units/week (mean, SD 3,397)), serum 25( OH)D3 concentration increased by 51 nmol/L and the UVB-related seasonal variability in 25( OH)D3 levels ceased (rho = −0.13, p > .05). Furthermore, the annualized relapse rate decreased by approximately 50%. This was almost solely driven by the prominent reduction in the quarterly relapse rate in late winter/early spring, when 25( OH)D3 levels of nonsupplemented patients were the lowest. Conclusions Our study demonstrated the modulation of seasonal MS disease activity through vitamin D supplementation. Given the prominent reduction in the quarterly relapse rate in late winter/early spring, our data indicate a beneficial effect of supplementing MS patients with vitamin D, especially during this period of the year. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective The aim of the Pulmonary Rehabilitation Guidelines (Guidelines) is to provide evidence-based recommendations for the practice of pulmonary rehabilitation ( PR) specific to Australian and New Zealand healthcare contexts. Methods The Guideline methodology adhered to the Appraisal of Guidelines for Research and Evaluation ( AGREE) II criteria. Nine key questions were constructed in accordance with the PICO (Population, Intervention, Comparator, Outcome) format and reviewed by a COPD consumer group for appropriateness. Systematic reviews were undertaken for each question and recommendations made with the strength of each recommendation based on the GRADE (Gradings of Recommendations, Assessment, Development and Evaluation) criteria. The Guidelines were externally reviewed by a panel of experts. Results The Guideline panel recommended that patients with mild-to-severe COPD should undergo PR to improve quality of life and exercise capacity and to reduce hospital admissions; that PR could be offered in hospital gyms, community centres or at home and could be provided irrespective of the availability of a structured education programme; that PR should be offered to patients with bronchiectasis, interstitial lung disease and pulmonary hypertension, with the latter in specialized centres. The Guideline panel was unable to make recommendations relating to PR programme length beyond 8 weeks, the optimal model for maintenance after PR, or the use of supplemental oxygen during exercise training. The strength of each recommendation and the quality of the evidence are presented in the summary. Conclusion The Australian and New Zealand Pulmonary Rehabilitation Guidelines present an evaluation of the evidence for nine PICO questions, with recommendations to provide guidance for clinicians and policymakers. [ABSTRACT FROM AUTHOR]