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Herpes simplex virus encephalitis (HSE) is the leading cause of non-epidemic encephalitis in the developed world and, despite antiviral therapy, mortality and morbidity is high. The emergence of post-HSE autoimmune encephalitis (AE) reveals a new immunological paradigm in autoantibody-mediated disease. A reductionist evaluation of the immunobiological mechanisms in HSE is crucial to dissect the origins of post-viral autoimmunity and supply rational approaches to the selection of immunotherapeutics. Herein, we review the latest evidence behind the phenotypic progression and underlying immunobiology of HSE including the cytokine/chemokine environment, the role of pathogen-recognition receptors, T- and B-cell immunity and relevant inborn errors of immunity. Secondly, we provide a contemporary review of published patients with post-HSE AE from a combined cohort of 110 patients. Thirdly, we integrate novel mechanisms of autoimmunisation in deep cervical lymph nodes to explore hypotheses around post-HSE AE and challenge these against mechanisms of molecular mimicry and others. Finally, we explore translational concepts where neuroglial surface autoantibodies have been observed with other neuroinfectious diseases and those that generate brain damage including traumatic brain injury, ischaemic stroke and neurodegenerative disease. Overall, the clinical and immunological landscape of HSE is an important and evolving field, from which precision immunotherapeutics could soon emerge.
\n \n\n \n \nBACKGROUND: Stroke survivors rate longer-term (>\u20092\u00a0years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. METHODS: N\u2009=\u2009105 long-term stroke survivors (M [SD] age\u2009=\u200972.92 [13.01]; M [SD] acute NIH Stroke Severity Score\u2009=\u20097.39 [6.25]; 59.0% Male; M [SD] years post-stroke\u2009=\u20094.57 [2.12]) were recruited (potential N\u2009=\u2009208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen's d effect size estimates and percent Minimal Clinically Important Difference changes between time points. RESULTS: On the Montreal Cognitive Assessment 65.3% scored\u2009\u20092\u00a0years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.
\n \n\n \n \nAbstract\nSubthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) with less energy delivered to the brain and less stimulation induced side-effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement in people with Parkinson\u2019s disease (PD) and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over a time period of 400\u2005ms in most previous ADBS studies, but a shorter smoothing period could have the advantage of being more sensitive to changes in beta power which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400\u2005ms and a shorter 200\u2005ms smoothing window during reaching movements. Results from 13 people with PD showed that reducing the smoothing window for quantifying beta did lead to shortened beta burst durations by increasing the number of beta bursts shorter than 200\u2005ms and more frequent switching on/off of the stimulator but had no behavioural effects. Both ADBS and CDBS improved motor performance to an equivalent extent compared to no DBS. Secondary analysis revealed that there were independent effects of a decrease in beta power and an increase in gamma power in predicting faster movement speed, while a decrease in beta event related desynchronization (ERD) predicted quicker movement initiation. CDBS suppressed both beta and gamma more than ADBS, whereas beta ERD was reduced to a similar level during CDBS and ADBS compared with no DBS, which together explained the achieved similar performance improvement in reaching movements during CDBS and ADBS. In addition, ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. These results suggest that STN beta-triggered ADBS is effective in improving motor performance during reaching movements in people with PD, and that shortening of the smoothing window does not result in any additional behavioural benefit. When developing ADBS systems for PD, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and information from motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.
\n \n\n \n \nThe spatial organisation of cellular protein expression profiles within tissue determines cellular function and is key to understanding disease pathology. To define molecular phenotypes in the spatial context of tissue, there is a need for unbiased, quantitative technology capable of mapping proteomes within tissue structures. Here, we present a workflow for spatially-resolved, quantitative proteomics of tissue that generates maps of protein abundance across tissue slices derived from a human atypical teratoid-rhabdoid tumour at three spatial resolutions, the highest being 40\u2009\u00b5m, to reveal distinct abundance patterns of thousands of proteins. We employ spatially-aware algorithms that do not require prior knowledge of the fine tissue structure to detect proteins and pathways with spatial abundance patterns and correlate proteins in the context of tissue heterogeneity and cellular features such as extracellular matrix or proximity to blood vessels. We identify PYGL, ASPH and CD45 as spatial markers for tumour boundary and reveal immune response-driven, spatially-organised protein networks of the extracellular tumour matrix. Overall, we demonstrate spatially-aware deep proteo-phenotyping of tissue heterogeneity, to re-define understanding tissue biology and pathology at the molecular level.
\n \n\n \n \nEIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5' untranslated regions. However, very little is known of their roles in nonmalignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells, we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. After B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression, and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable, whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.
\n \n\n \n \nBACKGROUND: The frequency of nodal-paranodal antibodies in HIV-infected patients with chronic immune-mediated radiculo-neuropathies (IMRN) has not been previously described. METHODS: HIV-infected patients who met the inclusion criteria for chronic IMRN were screened for immunoglobulin G (IgG) antibodies directed against nodal (neurofascin (NF)186) and paranodal (NF155, contactin-1 (CNTN1) and contactin-associated protein(Caspr1)) cell adhesion molecules, using a live, cell-based assay. To explore potential pathogenicity, binding of human IgG to myelinated co-cultures was assessed by incubation with patients' sera positive for nodal or paranodal antibodies. Normal human serum was added as a source of complement to assess for complement activation as a mechanism for myelin injury. RESULTS: Twenty-four HIV-infected patients with IMRN were included in the study, 15 with chronic inflammatory demyelinating polyneuropathy (CIDP), 4 with ventral root radiculopathies (VRR), and 5 with dorsal root ganglionopathies (DRG). Five patients with CIDP had combined central and peripheral demyelination (CCPD). Three patients (12.7%) tested positive for neurofascin IgG1 antibodies in the following categories: 1 patient with VRR was NF186 positive, and 2 patients were NF155 positive with DRG and mixed sensory-motor demyelinating neuropathy with optic neuritis, respectively. CONCLUSION: The frequency of nodal-paranodal antibodies is similar among IMRN regardless of HIV status. Interpretation of the results in the context of HIV is challenging as there is uncertainty regarding pathogenicity of the antibodies, especially at low titres. Larger prospective immune studies are required to delineate pathogenicity in the context of HIV, and to establish a panel of antibodies to predict for a particular clinical phenotype.
\n \n\n \n \nIMPORTANCE: Red blood cell (RBC) transfusion is common among patients admitted to the intensive care unit (ICU). Despite multiple randomized clinical trials of hemoglobin (Hb) thresholds for transfusion, little is known about how these thresholds are incorporated into current practice. OBJECTIVE: To evaluate and describe ICU RBC transfusion practices worldwide. DESIGN, SETTING, AND PARTICIPANTS: International, prospective, cohort study that involved 3643 adult patients from 233 ICUs in 30 countries on 6 continents from March 2019 to October 2022 with data collection in prespecified weeks. EXPOSURE: ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was the occurrence of RBC transfusion during ICU stay. Additional outcomes included the indication(s) for RBC transfusion (consisting of clinical reasons and physiological triggers), the stated Hb threshold and actual measured Hb values before and after an RBC transfusion, and the number of units transfused. RESULTS: Among 3908 potentially eligible patients, 3643 were included across 233 ICUs (median of 11 patients per ICU [IQR, 5-20]) in 30 countries on 6 continents. Among the participants, the mean (SD) age was 61 (16) years, 62% were male (2267/3643), and the median Sequential Organ Failure Assessment score was 3.2 (IQR, 1.5-6.0). A total of 894 patients (25%) received 1 or more RBC transfusions during their ICU stay, with a median total of 2 units per patient (IQR, 1-4). The proportion of patients who received a transfusion ranged from 0% to 100% across centers, from 0% to 80% across countries, and from 19% to 45% across continents. Among the patients who received a transfusion, a total of 1727 RBC transfusions were administered, wherein the most common clinical indications were low Hb value (n\u2009=\u20091412 [81.8%]; mean [SD] lowest Hb before transfusion, 7.4 [1.2] g/dL), active bleeding (n\u2009=\u2009479; 27.7%), and hemodynamic instability (n\u2009=\u2009406 [23.5%]). Among the events with a stated physiological trigger, the most frequently stated triggers were hypotension (n\u2009=\u2009728 [42.2%]), tachycardia (n\u2009=\u2009474 [27.4%]), and increased lactate levels (n\u2009=\u2009308 [17.8%]). The median lowest Hb level on days with an RBC transfusion ranged from 5.2 g/dL to 13.1 g/dL across centers, from 5.3 g/dL to 9.1 g/dL across countries, and from 7.2 g/dL to 8.7 g/dL across continents. Approximately 84% of ICUs administered transfusions to patients at a median Hb level greater than 7 g/dL. CONCLUSIONS AND RELEVANCE: RBC transfusion was common in patients admitted to ICUs worldwide between 2019 and 2022, with high variability across centers in transfusion practices.
\n \n\n \n \nDry film photoresists are widely employed to fabricate high-aspect-ratio microstructures, such as molds for microfluidic devices. Unlike liquid resists, such as SU-8, dry films do not require a cleanroom facility, and it is straightforward to prepare uniform and reproducible films as thick as 500 \u00b5m. Multilayer patterning, however, can be problematic with dry film resists even though it is critical for a number of microfluidic devices. Layer-to-layer mask alignment typically requires the first layer to be fully developed, making the pattern visible, before applying and patterning the second layer. While a liquid resist can flow over the topography of previous layers, this is not the case with dry film lamination. We found that post-exposure baking of dry film photoresists can preserve a flat topography while revealing an image of the patterned features that is suitable for alignment to the next layer. We demonstrate the use of this technique with two different types of dry film resist to fabricate master molds for a hydrophoresis size-sorting device and a cell chemotaxis device.
\n \n\n \n \nIMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether \u03b1-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n\u2009=\u2009170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n\u2009=\u2009122) included participants with iRBD and controls and the second (n\u2009=\u2009263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. \u03b1-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV \u03b1-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV \u03b1-synuclein distinguished participants with iRBD from controls (AUC\u2009=\u20090.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC\u2009=\u20090.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV \u03b1-synuclein levels. Across all cohorts, L1EV \u03b1-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC\u2009=\u20090.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV \u03b1-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n\u2009=\u200940) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV \u03b1-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.
\n \n\n \n \nOBJECTIVE: The Oxford Cognitive Screen (OCS) is a screening tool to assess stroke patients for deficits in attention, executive functions, language, praxis, numeric cognition, and memory. In this study, the OCS was culturally and linguistically adapted to Tamil, for use in India (OCS TA), considering the differences between formal and spoken versions of Tamil and consideration of its phonetic complexity. METHOD: We adopted two-parallel form versions of the OCS and generated normative data for them. We recruited 181 healthy controls (Mean = 39.27 years, SD 16.52) (141 completed version A, 40 completed version B, 33 completed version A and B) and compared the data with the original UK normative sample. In addition, 28 native Tamil-speaking patients who had a stroke in the past three years (Mean = 62.76 years, SD 9.14) were assessed. Convergent validity was assessed with subtasks from Addenbrooke's Cognitive Examination III (ACE-III). RESULTS: We found significant differences between the UK normative group and the OCS TA normative group in age and education. Tamil-specific norms were used to adapt the cutoffs for the memory, gesture imitation, and executive function tasks. When domain-specific scores on the ACE-III were compared, OCS TA exhibited strong convergent validity. CONCLUSIONS: The OCS TA has shown the potential to be a useful screening tool for stroke survivors among Tamil speakers with the two-parallel forms demonstrating good equivalence. Further empirical evidence from larger studies is required to establish their psychometric performance and clinical validity.
\n \n\n \n \nAn increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson's disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson's disease, a multi-arm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson's disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson's disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson's disease.
\n \n\n \n \nIMPORTANCE: There is a lack of consensus regarding the interval of time-dependent postoperative mortality risk following acute coronary syndrome or stroke. OBJECTIVE: To determine the magnitude and duration of risk associated with the time interval between a preoperative cardiovascular event and 30-day postoperative mortality. DESIGN, SETTING, AND PARTICIPANTS: This is a longitudinal retrospective population-based cohort study. This study linked data from the Hospital Episode Statistics for National Health Service England, Myocardial Ischaemia National Audit Project and the Office for National Statistics mortality registry. All adults undergoing a National Health Service-funded noncardiac, nonneurologic surgery in England between April 1, 2007, and March 31, 2018, registered in Hospital Episode Statistics Admitted Patient Care were included. Data were analyzed from July 2021 to July 2022. EXPOSURE: The time interval between a previous cardiovascular event (acute coronary syndrome or stroke) and surgery. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. Secondary outcomes were postoperative mortality at 60, 90, and 365 days. Multivariable logistic regression models with restricted cubic splines were used to estimate adjusted odds ratios. RESULTS: There were 877\u202f430 patients with and 20\u202f582\u202f717 without a prior cardiovascular event (overall mean [SD] age, 53.4 [19.4] years; 11\u202f577\u202f157 [54%] female). Among patients with a previous cardiovascular event, the time interval associated with increased risk of postoperative mortality was surgery within 11.3 months (95% CI, 10.8-11.7), with subgroup risks of 14.2 months before elective surgery (95% CI, 13.3-15.3) and 7.3 months for emergency surgery (95% CI, 6.8-7.8). Heterogeneity in these timings was noted across many surgical specialties. The time-dependent risk intervals following stroke and myocardial infarction were similar, but the absolute risk was greater following a stroke. Regarding surgical urgency, the risk of 30-day mortality was higher in those with a prior cardiovascular event for emergency surgery (adjusted hazard ratio, 1.35; 95% CI, 1.34-1.37) and an elective procedure (adjusted hazard ratio, 1.83; 95% CI, 1.78-1.89) than those without a prior cardiovascular event. CONCLUSIONS AND RELEVANCE: In this study, surgery within 1 year of an acute coronary syndrome or stroke was associated with increased postoperative mortality before reaching a new baseline, particularly for elective surgery. This information may help clinicians and patients balance deferring the potential benefits of the surgery against the desire to avoid increased mortality from overly expeditious surgery after a recent cardiovascular event.
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