Long-term Disability In Patients Research Articles

Sex Differences in the Role of Multimorbidity on Poststroke Disability: The Taiwan Stroke Registry.

Multimorbidity is common in patients who experience stroke. Less is known about the effect of specific multimorbidity patterns on long-term disability in patients with stroke. Furthermore, given the increased poststroke disability frequently seen in female vs male patients, it is unknown whether multimorbidity has a similar association with disability in both sexes. We assessed whether specific multimorbidity clusters were associated with greater long-term poststroke disability burden overall and by sex. In the Taiwan Stroke Registry, an ongoing nationwide prospective registry, patients with first-ever ischemic stroke were enrolled; this analysis is restricted to those individuals surviving to at least 6 months poststroke. Using a hierarchical clustering approach, clusters of prestroke multimorbidity were generated based on 16 risk factors; the algorithm identified 5 distinct clusters. The association between clusters and 12-month poststroke disability, defined using the modified Rankin Scale (mRS), was determined using logistic regression models, with additional models stratified by sex. The longitudinal association between multimorbidity and functional status change was assessed using mixed-effects models. Nine-thousand eight hundred eighteen patients with first-ever ischemic stroke were included. The cluster with no risk factors was the reference, "healthier" risk group (N = 1,373). Patients with a cluster profile of diabetes, peripheral artery disease (PAD), and chronic kidney disease (CKD) (N = 1882) had significantly greater disability (mRS ≥ 3) at 1 month (OR [95% CI] = 1.36 [1.13-1.63]), 3 months (OR [95% CI] = 1.27 [1.04-1.55]), and 6 months (OR [95% CI] = 1.30 [1.06-1.59]) but not at 12 months (OR [95% CI] = 1.16 [0.95-1.42]) than patients with a healthier risk factor profile. In the sex-stratified analysis, the associations with this risk cluster remained consistent in male patients (OR [95% CI] = 1.42 [1.06-1.89]) at 12 months, who also had a higher comorbidity burden, but not in female patients (OR [95% CI] = 0.95 [0.71-1.26]), who had higher proportions of severe strokes and severe disability (p-interaction = 0.04). Taiwanese patients with multimorbidity, specifically the concurrent presence of diabetes, PAD, and CKD, had higher odds of a worse functional outcome in the first 6 months poststroke. Clusters of multimorbidity may be less informative for long-term disability in female patients. Further studies should evaluate other mechanisms for worse disability in female patients poststroke.

Multipl sklerozda uzun dönem yeti yitimi: 20 yıllık uzunlamasına bir çalışma

Purpose: This study investigated the long-term clinical and demographic characteristics of multiple sclerosis (MS) patients to predict disease prognosis.
 Materials and Methods: Two hundred and seventy-five MS patients diagnosed using the Poser or McDonald criteria were retrospectively analyzed. They were categorized based on their Expanded Disability Status Scale (EDSS) scores: below 4 (group 1) and 4 or above (group 2).
 Results: The average patient age was 55.45 ± 9.63 years, with a disease duration of 26.76 ± 6.08 years. The initial EDSS scores increased from 2.56 ± 2.36 to 4.23 ± 1.8 after 20 years. Of the patients, 69.1% had EDSS scores of 4 or higher after 20 years. Notably, patients with supratentorial and spinal cord involvement at onset had higher EDSS scores. Logistic regression analysis revealed that a higher initial EDSS score, no full recovery after the first attack, and a longer duration between attacks were associated with a higher risk of an EDSS score of 4 or above. 
 Conclusion: Thisr study shows that an increase in the initial EDSS score is predictive of long-term disability in patients with MS. Having information on long-term, real-life data in MS is highly valuable in terms of understanding the course of the disease, its monitoring, and treatment selection.

Association of Very Early Treatment Initiation With the Risk of Long-term Disability in Patients With a First Demyelinating Event.

Early treatment is associated with better long-term outcomes in patients with a first demyelinating event and early multiple sclerosis (MS). However, magnetic resonance (MR) findings are not usually integrated to construct propensity scores (PSs) when evaluating outcomes. We assessed the association of receiving very early treatment with the risk of long-term disability including an MR score (MRS) in patients with a first demyelinating event. We included 580 patients with a first demyelinating event prospectively collected between 1994 and 2021, who received at least 1 disease-modifying drug (DMD). Patients were classified into tertiles according to the cohort's distribution of the time from the first demyelinating event to the first DMD: first tertile (FT) or very early treatment (6 months; n = 194), second tertile (6.1-16 months, n = 192), and third tertile (TT) (16.1 months, n = 194). A 5-point MRS was built according to the sum of the following indicators: ≥9 brain lesions (1 point); ≥1 infratentorial lesion (1 point); ≥1 spinal cord (SC) lesion (1 point); ≥1 contrast-enhancing (CE) brain lesion (1 point); and ≥1 CE SC lesion (1 point). PS based on covariates and the MRS was computed for each of the outcomes. Inverse PS-weighted Cox and linear regression models assessed the risk of different outcomes between tertile groups. Finally, to confirm the role of MR in treatment decision, we studied the time elapsed from the first demyelinating event to treatment initiation according to the MRS in all patients with radiologic available information, renamed as raw-MRS. Very early treatment decreased the risk of reaching Expanded Disability Status Scale 3.0 (hazard ratio [HR] 0.55, 95% CI 0.32-0.97), secondary progressive MS (HR 0.40, 95% CI 0.19-0.85), and sustained disease progression at 12 months after treatment initiation (HR 0.50, 95% CI 0.29-0.84), when compared with patients from the TT group. Patients from the FT group had a lower disability progression rate (β estimate -0.009, 95% CI -0.016 to -0.002) and a lower severe disability measured by the Patient-Determined Disease Step (β estimate -0.52, 95% CI -0.91 to -0.13) than the TT group. Finally, there was a 62.4% reduction in the median time between the first demyelinating event and the first-ever treatment initiation from patients displaying a raw-MRS 1 to patients with a raw-MRS 5. Using PS models with and without MRS, we showed that treatment initiation at very early stages is associated with a reduction in the risk of long-term disability accrual in patients with a first demyelinating event. This study provides Class III evidence that earlier treatment of patients with MS presenting with a first demyelinating event is associated with improved clinical outcomes.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses,...

Cognitive reserve index and long-term disability in patients with severe traumatic brain injury discharged from the intensive rehabilitation unit.

The "cognitive reserve" (CR) theory posits that higher premorbid cognitive activities can mitigate the effects of brain damage. This study aimed to investigate the association between CR and long-term functional autonomy in patients surviving a severe traumatic brain injury (sTBI). Data were collected from the database of inpatients with severe acquired brain injury in a rehabilitation unit admitted from August 2012 to May 2020. Patients that had incurred an sTBI, aged 18+ years, completing the phone Glasgow Outcome Scale-Expanded at follow-up (pGOS-E) in absence of previous brain trauma or neurological disease, or cognitive disorders were included. Patients with severe brain injury from non-traumatic etiologies were not included in the study. In this longitudinal study, all patients underwent a multidimensional assessment including the cognitive reserve index questionnaire (CRIq), the coma recovery scale-revised, the level of cognitive functioning, the Disability Rating Scale (DRS), and the Galveston Orientation and Amnesia Test at admission. At discharge, functional scales were administered again together with the Glasgow Outcome Scale. The pGOS-E was assessed at follow-up. pGOS-E. A total of 106 patients/caregivers underwent the pGOS-E after 5.8 [3.6] years from the event. Among them, 46 (43.4%) died after discharge, and 60 patients [men: 48 (80%); median age: 54 years; median time post-onset: 37 days; median education level: 10 years; median CRIq total score: 91] were included in the analysis exploring the association between pGOS-E and demographic data, cognitive reserve surrogates, and clinical variables at admission and discharge from the rehabilitation unit. A younger age (B = -0.035, p = 0.004) and a lower DRS category at discharge (B = -0.392, p = 0.029) were significantly related to a higher long-term functional autonomy in the multivariate analysis. Long-term functional autonomy was not influenced by CR as assessed through the educational level and the CRIq.

Clinical Trajectories in Patients with Severe Acute Brain Injury Requiring Mechanical Ventilation: A Descriptive Analysis of a Single-Center Prospective Observational Cohort Study (P5-7.005)

<h3>Objective:</h3> To describe outcomes for patients with severe acute brain injury (SABI) who require mechanical ventilation (MV). <h3>Background:</h3> Patients with SABI often require MV due to impaired consciousness and insufficient airway protection, reflecting a substantial neurological injury. Outcomes for this high-acuity population have been insufficiently explored. <h3>Design/Methods:</h3> In this single-center prospective, observational cohort study at a level-1 trauma and comprehensive stroke center, we included consecutive adult patients with SABI, including traumatic brain injury (TBI), spontaneous intracranial hemorrhage (sICH), acute ischemic stroke (AIS), and subarachnoid hemorrhage (SAH), who required MV on admission between September-November 2021. We assessed in-hospital and 6–12 months mortality, tracheostomy and percutaneous gastrostomy tube (PEG) placement, and Extended Glasgow Outcome Score (GOS-E) at 6–12 months. <h3>Results:</h3> Overall, 90 patients (age 55 [SD 19], 73% male; median Glasgow Coma Scale on admission 7 [IQR 3,11]; 50% TBI, 20% sICH, 18% AIS, 12% SAH) were included. Median duration of MV was 2 days (IQR 1,7), with 40% requiring MV for £ 24 hours (G1), 37% 1–7 days (G2), and 23% &gt;7 days (G3). In-hospital mortality was 47% (n=42), 79% (33/42) died after withdrawal of life-sustaining treatments (30% £24 hours, 24% 1–7 days, 45% &gt;7 days). One third of survivors (30%, n=13) underwent PEG, 16% (n=7) tracheostomy. At 6–12 months, 51% (n=46) had died (51% TBI, 67% sICH, 44% AIS, 36% SAH; 44% G1, 55% G2, 57% G3); 57% of survivors (64% TBI, 50% sICH, 33% AIS, 71% SAH; 60% G1, 67% G2, 22% G3) had a GOS-E of 5–8. Among survivors who underwent PEG and tracheostomy, 54% and 29% had a GOS-E 5–8; all survivors who initially underwent tracheostomy were decannulated at 6–12 months. <h3>Conclusions:</h3> Mortality and long-term disability in patients with SABI who required MV were high and varied based on SABI subtype and duration of MV. <b>Disclosure:</b> Ms. Smith has nothing to disclose. Ms. JAMES has nothing to disclose. Dr. Matin has nothing to disclose. Dr. Sarhadi has nothing to disclose. Dr. Town has nothing to disclose. The institution of Dr. Creutzfeldt has received research support from NINDS. The institution of Dr. Creutzfeldt has received research support from NINR. Chiara Robba has nothing to disclose. Giuseppe Citerio has nothing to disclose. Dr. Lele has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for LifeCenter Northwest . Dr. Wahlster has nothing to disclose.

Brainstem lesions are associated with diffuse spinal cord involvement in early multiple sclerosis

BackgroundEarly infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume.MethodsWe investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions.ResultsWe found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9–321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002).ConclusionsDiffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

Systolic blood pressure variability within 120 hours of admission predicts the functional outcomes at discharge of patients with acute ischemic stroke

Background: Blood pressure variability (BPV) is a predictor of short- and long-term disability in patients with acute ischemic stroke (AIS). Its effect on more immediate functional outcomes has been seldom studied, and the results are inconsistent. We aimed to determine the role of BPV during the first 5 days of hospitalization in functional status at the time of discharge of patients with AIS.Methods: We enrolled 134 patients diagnosed with AIS and BPV using standard deviation and coefficient of variation (CV %). These were associated with the dichotomized modified Rankin Scale at discharge using logistic regression. Results: Patients with unfavorable outcomes were significantly older (P=0.014), had a lower body mass index (P=0.001), were less likely to present with dyslipidemia (P=0.001), had lower serum triglyceride levels (P=0.012), had a longer hospitalization period (P&lt;0.001), and had a higher mean National Institutes of Health Stroke Scale score at admission (P&lt;0.001). After adjusting for multiple confounders, the CV % of systolic blood pressure (SBP) in the first 120 hours after admission had a significant effect on functional disability at discharge. Conclusion: Variability in SBP in the first 5 days of hospitalization had a deleterious effect on the functional outcomes at discharge of patients with AIS. The role of diabolic blood pressure variability seems to be significant only in the first 24 hours of admission; however, further research is required.

Medicolegal Evaluation of Long-Term Respiratory Functions in Patients Injured Due to Traffic Accidents.

AimBlunt chest trauma is a frequent injury in developing countries, with motor vehicle accidents being the most common cause. Most studies about the effects of post-traumatic injuries on pulmonary functions are related to the acute phase. The aim of this study is to compare the effect of injury type on pulmonary function tests as a long-term disability in patients with severe chest trauma due to traffic accidents.MethodsIn our study, 53 patients were admitted to the Forensic Expert Council with the aim of determining the disability ratio at least six months after the traffic accident. All patients who had a respiratory function test because of respiratory symptoms and whose reporting period was completed were appreciated. A retrospective examination of the forensic committee reports, types of injuries, and current pulmonary function test results were analyzed and the data were evaluated by using the Statistical Package for the Social Sciences (SPSS) 22.0 program (IBM Corp, Armonk, NY).ResultsThirty-two (32) of the patients were male while 21 were female. Their average age was 39.88 ± 15.29. Sixty-six percent (66%; n: 35) of the cases were injured due to in-vehicle traffic accidents, 18.9% (n: 10) due to motorcycle accidents, 15.1% (n: 8) due to non-vehicle traffic accidents. The number of cases with costa fractures was 47 and 74.4% of these cases had three or more rib fractures. The mean forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC-Tiffeneau-Pinelli index) was calculated as 85.3% ± 9.45, and the average FVC was 84.3 ± 14.98%. The average number of rib fractures in all patients was 3.41 ± 2.24. It was observed that tube thoracostomy was performed in seven of 12 cases with FEV1/FVC below 80%, and the average number of rib fractures was 3.75. In 20 cases where the FVC average was below 80%, the mean number of rib fractures was 3.8, and tube thoracostomy was performed in 10 of these cases. The highest FEV1 value was 116%, and the lowest FEV1 value was 35%. The FEV1 value of 23 cases was between 75% and 95%. The highest FEV1/FVC value was 113% and the lowest FEV1/FVC value was 50%. The FEV1/FVC values of 38 cases were between 80% and 100%. ConclusionsIn our study, most patients achieve near-complete recovery in pulmonary function tests; the impact of pre-existing pulmonary compromise on recovery is less known. The number of rib fractures can reflect the severity of the blunt trauma but it would not necessarily predict the resulting pulmonary function. These results are consistent with the previous studies. Further larger prospective studies are required to investigate different factors affecting prognosis.

Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.

Host-directed therapies for COVID-19.

Severe acute respiratory syndrome coronavirus-2-induced hyperinflammation is a major cause of death or end-organ dysfunction in COVID-19 patients. We review adjunct host-directed therapies (HDTs) for COVID-19 management. The use of umbilical cord-derived mesenchymal stem cells as HDT for COVID-19 has been shown to be safe in phase 1 and 2 trials. Trials of anti-interleukin-6 receptor antibodies show promising mortality benefit in hospitalized COVID-19 patients. Repurposed drugs and monoclonal antibodies targeting specific cytokines acting on different aspects of the pro- and anti-inflammatory cascades are under evaluation. A range of HDTs shows promise for reducing mortality and improving long term disability in patients with severe COVID-19, and require evaluation in randomized, controlled trials.

Selective vulnerability of inhibitory networks in multiple sclerosis

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments.

Salivary glands involvement: a new indicator of juvenile idiopathic oligoarticular arthritis (preliminary results).

Early diagnosis is critical to reduce long-term disability in patients with JIA by ensuring prompt treatment. The aim of this cross-sectional study was to evaluate the salivary gland function in JIA, addressing specifically oligoarticular (JIA1) and polyarticular (JIA2) subtypes, compared with healthy controls. This may contribute to the identification of salivary risk indicators of the disease that may help diagnosis at an early stage or even before the onset of other clinical evidence. Twenty-eight patients with JIA1, 28 patients with JIA2, according to the ILAR criteria, and 28 healthy controls (C) were included in the study. Exclusion criteria were any concurrent medical condition. Data on medication, dietary and oral hygiene habits were collected using a questionnaire. All patients underwent oral examination and saliva measurement. While stimulated salivary flow rate (SFR) was significantly lower in JIA1 compared with JIA2 and C (P < 0.001), both salivary buffer capacity and pH were similar in the two JIA groups but statistically different from C (P = 0.002 and P = 0.010, respectively). Children with very low SFR (<3.5 ml) exhibited a 16-fold higher likelihood of being affected by JIA1 rather than JIA2 (P = 0.003), while no association was observed between low flow rate and JIA subtype (P = 0.744). These preliminary data suggest impairment of salivary gland function as a risk indicator for JIA1 with no association with dietary habits and drug intake.

The effect of an integrated multidisciplinary rehabilitation programme for patients with chronic low back pain: Long-term follow up of a randomised controlled trial

Objective: To compare the long-term effectiveness of an integrated rehabilitation programme with an existing rehabilitation programme, in terms of back-specific disability, in patients with chronic low back pain. Design: A single-centre, pragmatic, two-arm parallel, randomised controlled trial. Setting: A rheumatology rehabilitation centre in Denmark. Subjects: A total of 165 adults (aged ⩾ 18 years) with chronic low back pain. Interventions: An integrated programme (a pre-admission day, two weeks at home, two weeks inpatient followed by home-based activities, plus two 2-day inpatient booster sessions, and six-month follow-up visit) was compared with an existing programme (four-week inpatient, and six-month follow-up visit). Main measure: The primary outcome was disability measured using the Oswestry Disability Index after one year. Secondary outcomes included pain intensity (Numerical Rating Scale), pain self-efficacy (Pain Self-Efficacy Questionnaire), health-related quality of life (EuroQol-5 Domain 5-level (EQ-5D)), and depression (Major Depression Inventory). Analysis was by intention-to-treat, using linear mixed models. Results: 303 patients were assessed for eligibility of whom 165 patients (mean age 50 years (SD 13) with a mean Oswestry Disability Index score of 42 (SD 11)) were randomly allocated (1:1 ratio) to the integrated programme (n = 82) or the existing programme (n = 83). The mean difference (integrated programme minus existing programme) in disability was –0.53 (95% CI –4.08 to 3.02); p = 0.770). No statistically significant differences were found in the secondary outcomes. Conclusion: The integrated programme was not more effective in reducing long-term disability in patients with chronic low back pain than the existing programme.

The Association of MRI Findings and Long-Term Disability in Patients With Chronic Low Back Pain.

Study Design:Longitudinal cohort study with 13-year follow-up.Objective:To assess whether long-term disability is associated with baseline degenerative magnetic resonance imaging (MRI) findings in patients with low back pain (LBP).Methods:In 2004-2005, patients aged 18 to 60 years with chronic LBP were enrolled in a randomized controlled trial and lumbar MRI was performed. Patients completed the Roland-Morris Disability Questionnaire (RMDQ) and the LBP Rating Scale, at baseline and 13 years after the MRI. Multivariate regression analysis was performed with 13-year RMDQ as the dependent variable and baseline disc degeneration (DD, Pfirrmann grade), Modic changes (MC), facet joint degeneration (FJD, Fujiwara grade) smoking status, body mass index, and self-reported weekly physical activity at leisure as independent variables.Results:Of 204 patients with baseline MRI, 170 (83%) were available for follow-up. Of these, 88 had Pfirrmann grade >III (52%), 67 had MC (39%) and 139 had Fujiwara grade >2 (82%) on at least 1 lumbar level. Only MC (β = −0.15, P = .031) and weekly physical activity at leisure (β = −0.51, P < .001) were significantly, negatively, associated with 13-year RMDQ-score (R2 = 0.31).Conclusion:DD and FJD were not associated with long-term disability. Baseline MC and weekly physical activity at leisure were statistically significantly associated with less long-term disability.

Shortening Duration of Treatment Resistance: The Next Step in the Treatment of Schizophrenia

Abstract The early psychosis movement was fuelled by the concept that early recognition and treatment of patients with psychosis could prevent long-term chronic impairment. Indeed, duration of untreated psychosis (DUP) predicts treatment response and early intervention services have since shown added value. However, considerable chronic impairment remains, with about 20%–30% of the patients with schizophrenia not responding to 2 different conventional antipsychotics in adequate doses and duration. In contrast to the research on DUP and early intervention in schizophrenia in general, far less research has systemically assessed the benefits of shortening the time between treatment onset and adequate treatment response. Yet timely recognition of treatment-resistant schizophrenia (TRS) could be vital since studies have indicated that a critical time window in which clozapine is most effective for TRS patients could exist. We believe that introducing the concept of Duration of Treatment Resistance (DTR) may help to investigate whether shortening of DTR by optimizing medication schedules can further prevent or mitigate long-term disability in patients with schizophrenia. In this editorial, we propose a definition of DTR and encourage the field to investigate the potential merits of this concept in future studies.

Association of Pharmacological Biomarkers with Treatment Response and Longterm Disability in Patients with Psoriatic Arthritis: Results from OUTPASS.

To identify (1) whether tumor necrosis factor inhibitor (TNFi) drug levels/anti-drug antibodies (ADAb) are associated with treatment response and disability in patients with psoriatic arthritis (PsA); and (2) the factors associated with TNFi drug levels. Patients were recruited from a national multicenter prospective cohort with longitudinal serum samples and 28-joint count Disease Activity Scores (DAS28)/Health Assessment Questionnaire (HAQ) measurement over 12 months. Adalimumab (ADA) drug levels were significantly associated with ΔDAS28 (β 0.055, 95% CI 0.011-0.099; p = 0.014) and inversely with HAQ over 12 months (β -0.022, 95% CI -0.043 to -0.00063). Factors significantly associated with ADA drug levels were ADAb levels and body mass index. Drug level testing in ADA-initiated PsA patients may be useful in determining treatment response/disability over 12 months.

Contemporary management of orbital blowout fractures

Orbital floor blowout fractures may lead to significant morbidity, including debilitating double vision and globe malposition. Thorough evaluation and timely surgical intervention may prevent long-term sequelae. New studies have demonstrated certain patients with orbital floor fractures to do well when managed conservatively. In those necessitating operative repair, precise surgical dissection and adequate fracture reduction are essential to restoring orbital anatomy and function. Novel surgical techniques and orbital floor reconstruction materials, described in this review, will further optimize patient outcomes. A knowledgeable evaluation, thoughtful management strategy and modernized surgical technique can prevent long-term disability in patients with orbital floor blowout fractures.

Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan

BackgroundAxonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.MethodsThe ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.DiscussionWe hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism.Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.Trial registrationClinical Trials Register, EudraCT 2017-001253-13. Registered on 15 February 2018.

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors.

Pain is an essential protective mechanism meant to prevent tissue damages in organisms. On the other hand, chronic or persistent pain caused, for example, by inflammation or nerve injury is long lasting and responsible for long-term disability in patients. Therefore, chronic pain and its management represents a major public health problem. Hence, it is critical to better understand chronic pain molecular mechanisms to develop innovative and efficient drugs. Over the past decades, accumulating evidence has demonstrated a pivotal role of glutamate in pain sensation and transmission, supporting glutamate receptors as promising potential targets for pain relieving drug development. Glutamate is the most abundant excitatory neurotransmitter in the brain. Once released into the synapse, glutamate acts through ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels triggering fast excitatory neurotransmission, and metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors modulating synaptic transmission. Eight mGluRs subtypes have been identified and are divided into three classes based on their sequence similarities and their pharmacological and biochemical properties. Of note, all mGluR subtypes (except mGlu6 receptor) are expressed within the nociceptive pathways where they modulate pain transmission. This review will address the role of mGluRs in acute and persistent pain processing and emerging pharmacotherapies for pain management.