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ABSTRACTAutoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

ABSTRACT:Background:Early and effective treatment of central nervous system (CNS) inflammatory disorders is vital to reduce neurologic morbidity and improve long-term outcomes in affected children. Rituximab is a B-cell-depleting monoclonal antibody whose off-label use for these disorders is funded in the province of Alberta, Canada, by the Short-Term Exceptional Drug Therapy (STEDT) program. This study describes the use of rituximab for pediatric CNS inflammatory disorders in Alberta.Methods:Rituximab applications for CNS inflammatory indications in patients <18 years of age were identified from the STEDT database between January 1, 2012, and December 31, 2019. Patient information was linked to other provincial datasets including the Discharge Abstract Database, Pharmaceutical Information Network, and Provincial Laboratory data. Analysis was descriptive.Results:Fifty-one unique rituximab applications were identified, of which 50 were approved. New applications increased from one in 2012 to a high of 12 in 2018. The most common indication was autoimmune encephalitis without a specified antibody (n= 16, 31%). Most children were approved for a two-dose (n= 33, 66%) or four-dose (n= 16, 32%) induction regimen. Physician-reported outcomes were available for 24 patients, of whom 14 (58%) were felt to have fully met outcome targets.Conclusion:The use of rituximab for pediatric CNS inflammatory disorders has increased, particularly for the indication of autoimmune encephalitis. This study identified significant heterogeneity in dosing practices and laboratory monitoring. Standardized protocols for the use of rituximab in these disorders and more robust outcome reporting will help better define the safety and efficacy of rituximab in this population

BackgroundIt remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course.MethodsThis large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis.ResultsIn total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015).ConclusionsIn RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

AbstractObjectives:Considerable literature has examined the COVID-19 pandemic’s negative mental health sequelae. It is recognised that most people experiencing mental health problems present to primary care and the development of interventions to support GPs in the care of patients with mental health problems is a priority. This review examines interventions to enhance GP care of mental health disorders, with a view to reviewing how mental health needs might be addressed in the post-COVID-19 era.Methods:Five electronic databases (PubMed, PsycINFO, Cochrane Library, Google Scholar and WHO ‘Global Research on COVID-19’) were searched from May – July 2021 for papers published in English following Arksey and O’Malley’s six-stage scoping review process.Results:The initial search identified 148 articles and a total of 29 were included in the review. These studies adopted a range of methodologies, most commonly randomised control trials, qualitative interviews and surveys. Results from included studies were divided into themes: Interventions to improve identification of mental health disorders, Interventions to support GPs, Therapeutic interventions, Telemedicine Interventions and Barriers and Facilitators to Intervention Implementation. Outcome measures reported included the Seven-item Generalised Anxiety Disorder Scale (GAD-7), the Nine-item Patient Health Questionnaire (PHQ-9) and the ‘The Patient Global Impression of Change Scale’.Conclusion:With increasing recognition of the mental health sequelae of COVID-19, there is a lack of large scale trials researching the acceptability or effectiveness of general practice interventions. Furthermore there is a lack of research regarding possible biological interventions (psychiatric medications) for mental health problems arising from the pandemic.

IMPORTANCE: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). OBJECTIVE: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. DESIGN, SETTING, AND PARTICIPANTS: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. EXPOSURE: AHSCT vs fingolimod, natalizumab, or ocrelizumab. MAIN OUTCOMES: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. RESULTS: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). CONCLUSION: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

BackgroundSome studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS.MethodsWe compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS.ResultsIncluded patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2–47.3) vs 43.9 (43.3–44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78–0.94); p<0.001) and similar age at wheelchair dependence.ConclusionsWe demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

BackgroundSimultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years.MethodsData from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement.Results23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability.ConclusionsThe effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

BackgroundOver the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time.MethodsAll patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3–4.ResultsA total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria.ConclusionsContrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

Objective. Immunity is increasingly implicated in the aetiology of certain types of epilepsy, however, the clinical and EEG features in such cases remain poorly defined. We present stereo‐electroencephalography (SEEG) findings in patients who were thought to have autoantibody‐mediated epilepsy on the basis of clinical improvement after administration of immunotherapy (IT). Methods. All patients undergoing SEEG implantation in our service were reviewed and those receiving immunotherapy, either before, during, or after SEEG evaluation, were identified. Response to immunotherapy was defined as greater than 50% seizure reduction. We compared the clinical features and SEEG findings between those who responded to immunotherapy and those who did not. Results. Sixty‐two cases underwent SEEG evaluation. Of these, 11 received immunotherapy and three cases demonstrated a positive clinical benefit. The three responsive patients had multifocal seizure onset, repetitive spiking interictally and ictally, perisylvian semiology, seizure onset in the posterior perisylvian regions, and normal neuroimaging. Significance. Seronegative immunotherapy responders exist in epilepsy populations, therefore the diagnosis of autoimmune‐associated epilepsy should be considered before proceeding to epilepsy surgery. Possible features of an electroclinical syndrome associated with autoimmunity may include multifocal seizure onset, perisylvian involvement, and normal neuroimaging.

Pathogenic fungi use diverse infection strategies to obtain nutrients from plants. Biotrophic fungi feed only on living plant tissue, whereas necrotrophic fungi kill host cells to extract nutrients. To prevent disease, plants need to distinguish between pathogens with different life cycles, as a successful defense against a biotroph, which often involves programmed cell-death around the site of infection, is not an appropriate response to some necrotrophs. Plants utilize a vast collection of extracellular and intracellular receptors to detect the signatures of pathogen attack. In turn, pathogens are under strong selection to mask or avoid certain receptor responses while enhancing or manipulating other receptor responses to promote virulence. In this review, we focus on the plant receptors involved in resistance responses to fungal pathogens and highlight, with examples, how the infection strategy of fungal pathogens can determine if recognition responses are effective at preventing disease.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R2) of the case–control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R2) of 0.027 (Pvalue = 4.6 × 10−8), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96–5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

A 58-year-old man presented to the ED with a 1-week history of progressive weight loss, generalized weakness, unsteadiness, and dizziness. In hospital, he experienced a witnessed episode of loss of consciousness with no observable respirations that lasted for 15 minutes. His arterial blood gas demonstrated hypercapnic respiratory failure, and he required mask ventilation and vasoactive medications. Similar episodes occurred several more times over the course of the night that required the patient to be intubated. The paroxysmal episodes persisted necessitating continued invasive ventilatory support and admission to the ICU. The episodes occurred in both awake and asleep states and required the ventilator settings to dictate a minimum rate, but minimal ventilatory support otherwise. Further history revealed other symptomatic complaints of vertigo, dysphagia, and hypophonia that had progressed over a 2-month period. The patient’s medical history was pertinent for a diagnosis of prostatic carcinoma 3 years previously that was found to be castrate resistant. He had metastases to his hip, ribs, and thoracic spine. Previous treatments had included bicalutamide, docetaxel, and abiraterone; he was receiving leuprolide therapy on presentation.

This primer summarizes the diagnosis, treatment, complications, and prognosis of anti-N-methyl-d-aspartate receptor encephalitis for healthcare professionals, especially those in acute care specialities. Anti-N-methyl-d-aspartate receptor encephalitis is an immune-mediated encephalitis that is classically paraneoplastic and associated with ovarian teratomas in young women. Other less common neoplastic triggers include testicular cancers, Hodgkin lymphoma, lung and breast cancers. It may also be triggered by infection, occurring as a para-infectious phenomenon, seen most commonly after herpes simplex-1 encephalitis. Presentation varies but typically consists of behavioural and cognitive manifestations, seizures, dysautonomia, movement disorders, central hypoventilation, and coma, necessitating intensive care unit admission. Diagnosis of anti-N-methyl-d-aspartate receptor encephalitis requires high clinical suspicion plus ancillary testing, the most sensitive being cerebrospinal fluid analysis for anti-N-methyl-d-aspartate receptor antibodies. Imaging in search of an ovarian teratoma should be exhaustive and tumours need to be surgically treated. Treatment should be expeditious with pulsed steroids and either plasma exchange or intravenous immunoglobulin. Second-line treatments include intravenous rituximab, cyclophosphamide, azathioprine, and intrathecal methotrexate. Most patients recover to be functionally independent, but the in-hospital course can be months long followed by extensive rehabilitation. Given the lengthy course of illness, we explain why education and debriefing are important for staff, and where families can obtain additional help.

Introduction:Mental disorders are increasingly common among adults in both the developed and developing world and are predicted by the WHO to be the leading cause of disease burden by 2030. Many common physical conditions are more common among people who also have a common mental disorder. This scoping review aims to examine the current literature about the prevention, identification and treatment of physical problems among people with pre-existing mental health disorders in primary care in Europe.Methods:The scoping review framework comprised a five-stage process developed by Arksey & O’Malley (2005). The search process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Both quantitative and qualitative studies were included, with no restriction on study design.Results:The initial search identified 299 studies, with a further 28 added from the hand-search (total n= 327) of which 19 were considered relevant to the review research question and included for full analysis. Depression was the mental health condition most commonly studied (nine studies), followed by depression and anxiety (seven studies), with three studies examining any mental disorder. Eleven studies examined the effects of various interventions to address physical and mental comorbidity, with the most commonly studied intervention being collaborative care.Conclusions:With just 19 studies meeting our criteria for inclusion, there is clearly a paucity of research in this area. Further research is essential in order to understand the pathophysiological mechanisms underlying the association between mental disorders and chronic conditions.

Language disorders are increasingly recognised in Amyotrophic lateral sclerosis (ALS), supporting the view of ALS as a multi-system disorder, impacting cognitive and motor function. However, the language impairments are heterogeneous and recent focus has been on determining the language profile across the ALS spectrum with little focus on spontaneous speech. The current study systematically investigated a wide range of language abilities in an unselected ALS sample (N = 22), including spontaneous speech. We analysed the ALS patients' performance as a group, compared to age-, education- and IQ-matched healthy controls (N = 21), and as a case series to identify dementia and specific language profiles. The ALS group was impaired on measures of spontaneous speech, word fluency and action naming. By contrast, object naming, semantic memory (object and actions), sentence comprehension and repetition (word and sentences) were comparable to healthy controls. In line with recent suggestions, our ALS patients’ action naming (but not action semantic) deficit does not support the notion that action processing may be selectively impaired in ALS. The case series demonstrated that 14% of patients had probable dementia, 31% showed significant cognitive and/or language impairment and 55% were unimpaired, consistent with the spectrum of cognitive and language impairments reported in the literature. In addition, 36% of ALS patients produced significantly fewer words per minute on a spontaneous speech task than the control group, with this difference remaining when the ALS patients with frontotemporal dementia were excluded from the analysis. This pattern was observed across the ALS spectrum and in both limb and bulbar onset patients. The pattern of performance observed in the present study suggests that spontaneous speech is reduced across the ALS spectrum even in those with intact core language abilities.

The purpose of this study was to report the outcomes of scaphocapitate fusion without lunate excision for the treatment of stage III Kienböck's disease and to compare these results with historical results of limited wrist arthrodesis and proximal row carpectomy. Clinical and radiographic evaluations were performed preoperatively and at a mean of 5.8-years’ follow-up (range 1.5 to 10.5years) on 17 patients with advanced Kienböck's disease (Lichtman stages: IIIA n=4 and IIIB n=13) treated by scaphocapitate fusion without lunate excision between January 2000 and July 2015. The average DASH score was 19 points (range 2 to 61) and the PRWE score was 23 points (range 0 to 77). The average preoperative VAS for pain of 8 was significantly reduced to an average of 4 with activity (P=0.002) and 1 at rest (P=0.001). The flexion/extension arc was 91° and grip strength was 76% of the contralateral side. The preoperative mean modified carpal height ratio decreased significantly to an average of 1.14 at the latest follow-up (P=0.02). The average carpal-ulnar distance ratio was not altered (P=0.89). The radioscaphoid and scapholunate angles were restored to their normal range. Four scaphocapitate joints failed to fuse. No re-operations were performed. Scaphocapitate fusion for advanced Kienböck's disease maintains wrist motion and significantly relieves pain. Lunate excision is not necessary. Based on a literature review, our results were comparable to those of scaphotrapeziotrapezoid fusion. Proximal row carpectomy is still an option when the radius and capitate articular surfaces are free of significant chondral lesions.

•Early serologic diagnosis of AQP4+ NMOSD is key for initiating appropriate therapy.•In this Canadian cohort, we evaluated time from NMOSD onset to serologic diagnosis.•Female sex and Asian ethnicity predicted shorter time to diagnosis.•Later calendar year and hospitalization also predicted shorter time to diagnosis.•Social determinants of health require further investigation in NMOSD.

ABSTRACTThe New Zealand endemic southern ant (Monomorium antarcticum) excavates subterranean nests in various soil types, with brood distributed throughout excavated cavities connected by tunnels. Because cavities are often constructed near the soil surface, variation in rainfall patterns will affect soil moisture, and potentially lead to regular flooding of cavities. We examined how M. antarcticummake colony emigration decisions as soil moisture changes over time, and investigated how colonies manage brood underground during simulated rainfall events. We show that colonies will emigrate to wetter soil and excavate a new nest when their environment becomes too dry. After we add water to the surface of the nest (i.e. simulate rainfall), workers transport brood from cavities into tunnels, and move them back into the cavities as soon as the ‘rain’ stops. Workers tend to prioritise moving brood from cavities with higher densities of brood, regardless of the depth of the cavity from the soil surface. We discuss how the ability to emigrate in response to changes in soil environment, and to effectively respond to unpredictable rainfall/flooding events, can help us understand how this species persists in a wide-range of habitat types.

Unlike the extensively studied, spatially direct, quantum dots (QDs) with type-I band alignment where both electrons and holes are confined in the QD, in ZnTe QDs embedded in a (Zn,Mn)Se matrix only the holes are confined in the QDs. This spatially indirect type-II system provides unexplored opportunities to control the magnetic interactions between the hole spins in the nonmagnetic QDs and the spins of the magnetic ions in the matrix. Photoluminescence (PL) was excited either with photons of energy 3.06 eV [above band gap of the (Zn,Mn)Se matrix] or with photons of energy 2.54 eV [below the (Zn,Mn)Se band gap]. In the presence of an external magnetic field, the saturation red shift of the PL peak under 2.54 eV excitation exhibits an up to three-fold increase compared to the shift observed with 3.06 eV excitation. This increase is attributed to multiple hole occupancy of the QDs and the resulting increased penetration of the hole wavefunction tail further into the (Zn,Mn)Se matrix. The proposed model is supported by calculations which include the hole–hole Coulomb interactions as well as the hole–Mn spin exchange interactions.

Immune checkpoint inhibitors such as antibodies to cytotoxic lymphocyte-associated protein 4 (ipilimumab) and programmed cell-death 1 (pembrolizumab, nivolumab) molecules have been used in non-small cell lung cancer, metastatic melanoma, and renal-cell carcinoma, among others. With these agents, immune-related adverse events (irAEs) can occur, including those affecting the neurological axis. In this review, high-grade neurological irAEs associated with immune checkpoint inhibitors including cases of Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) are analyzed. Based on current literature and experience at our institution with 4 cases of high-grade neurological irAEs associated with immune checkpoint inhibitors (2 cases of GBS, 1 case of meningo-radiculitis, and 1 case of myelitis), we propose an algorithm for the investigation and treatment of high-grade neurological irAEs. Our algorithm incorporates both peripheral nervous system (meningo-radiculitis, GBS, MG) and central nervous system presentations (myelitis, encephalopathy). It is anticipated that our algorithm will be useful both to oncologists and neurologists who are likely to encounter neurological irAEs more frequently in the future as immune checkpoint inhibitors become more widely used.

Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.

ObjectiveOral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.MethodsWe identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).ResultsThe eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).ConclusionThe effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.

To describe the anatomic and visual outcomes of eyes undergoing reoperation after failed primary surgery for idiopathic macular hole.