Pre‐ and post‐conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta‐analysis

BackgroundToll‐like receptor (TLR) agonist polyinosinic–polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.MethodsWe evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.ResultsPoly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre‐ and post‐conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor‐κB (NF‐κB) [SMD = −1.78; CIs (−2.67, −0.88); p = 0.0)], and tumor necrosis factor alpha (TNF‐α) [SMD = −16.83; CIs (−22.63, −11.02); p = 0.00].ConclusionWe showed that poly I:C is neuroprotective and acts via the TLR3/NF‐κB/TNF‐α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.     

Immunotherapy choice and maintenance for generalized myasthenia gravis in China

AimsTo compare long‐term efficacy and safety of immunotherapeutic strategies as maintenance to prevent disease relapses of generalized myasthenia gravis (MG) in real‐world settings.MethodsThis is a retrospective cohort study on generalized MG conducted in seven major neurological centers across China. Eligible participants were patients with generalized MG who were under minimal manifestation status or better. Main outcome measures were probability of patients free of relapses and causes of drug discontinuation.ResultsAmong 1064 patients enrolled, the median (interquartile range) age was 50.3 (37.0‐62.5) years and 641 (60.2%) were women. Disease relapse was significantly lower for rituximab (6.1%) compared with all the other monotherapies (hazard ratio [HR] = 0.18, 95% confidence interval [CI] 0.06 to 0.56, P = .0030). As combination therapies, tacrolimus in combination with corticosteroids reduced risk of disease relapses compared with azathioprine with corticosteroids (HR = 0.45, 95% CI 0.25 to 0.81, P = .0077) or mycophenolate mofetil with corticosteroids (HR = 0.32, 95% CI 0.15 to 0.67, P = .0020). Otherwise, lower‐dose corticosteroids or azathioprine as monotherapy significantly increased risk of disease relapses (HR = 2.78, 95% CI 1.94 to 3.99, P < .0001; HR = 2.14, 95% CI 1.42 to 3.23, P = .0003, respectively). The proportion of discontinuation was lowest in patients with rituximab (20.4%) as monotherapy and tacrolimus with corticosteroids (23.6%). Overall, combination treatment of immunosuppressants with corticosteroids had a lower rate of discontinuation compared with corresponding monotherapy (HR = 0.51, 95% CI 0.36 to 0.71, P < .0001).ConclusionsRituximab as monotherapy and tacrolimus with corticosteroids displayed better clinical efficacy as well as drug maintenance to prevent disease relapses in patients with generalized MG.     

Stress hyperglycemia is associated with in‐hospital mortality in patients with diabetes and acute ischemic stroke

Background and ObjectiveStress hyperglycemia may occur in diabetic patients with acute severe cerebrovascular disease, but the results regarding its association with stroke outcomes are conflicting. This study aimed to examine the association between stress‐induced hyperglycemia and the occurrence of in‐hospital death in patients with diabetes and acute ischemic stroke.Research Design and MethodsAll data were from the Chinese Stroke Center Alliance (CSCA) database and were collected between 2016 and 2018 from >300 centers across China. Patients’ demographics, clinical presentation, and laboratory data were extracted from the database. The primary endpoint was in‐hospital death. The ratio of fasting blood glucose (FBG) to HbA1c was calculated, that is, the stress‐induced hyperglycemia ratio (SHR), to determine stress hyperglycemia following acute ischemic stroke.ResultsA total of 168,381 patients were included. The mean age was 66.2 ± 10.7, and 77,688 (43.0%) patients were female. The patients were divided into two groups: survivors (n = 167,499) and non‐survivors (n = 882), as well as into four groups according to their SHR quartiles (n = 42,090–42,099/quartile). There were 109 (0.26%), 142 (0.34%), 196 (0.47%), and 435 (1.03%) patients who died in the Q1, Q2, Q3, and Q4 quartiles, respectively. Compared with Q1 patients, the death risk was higher in Q4 patients (odds ratio (OR) = 4.02) (adjusted OR = 1.80, 95% confidence interval [CI] = 1.10–2.92, p = 0.018 after adjustment for traditional cardiovascular risk factors). The ROC analyses showed that SHR (AUC = 0.667, 95% CI: 0.647–0.686) had a better predictive value for mortality than that of fasting blood glucose (AUC = 0.633, 95% CI: 0.613–0.652) and HbA1c (AUC = 0.523, 95% CI: 0.504–0.543).ConclusionsThe SHR may serve as an accessory parameter for the prognosis of patients with diabetes after acute ischemic stroke. Hyperglycemia in stroke patients with diabetes mellitus is associated with a higher risk of in‐hospital death.     

Urinary albumin creatinine ratio associated with postoperative delirium in elderly patients undergoing elective non‐cardiac surgery: A prospective observational study

IntroductionThe blood‐brain barrier (BBB) disruption contributes to postoperative delirium, but cost‐effective and non‐invasive assessment of its permeability is not practicable in the clinical settings. Urine albumin to creatinine ratio (UACR), reflecting systemic vascular endothelial dysfunction, may be a prognostic and predictive factor associated with postoperative delirium. The aim was to analyze the relationship between UACR and postoperative delirium in elderly patients undergoing elective non‐cardiac surgery.Materials and methodsThrough stratified random sampling, a cohort of 408 individuals aged 60 years and older scheduled for elective non‐cardiac surgery were included between February and August 2019 in the single‐center, prospective, observational study. The presence of delirium was assessed using the Confusion Assessment Method (CAM) or Confusion Assessment Method for the ICU (CAM‐ICU) on the day of surgery, at 2 h after the surgery ending time and on the first 3 consecutive days with repeated twice‐daily, with at least 6‐h intervals between assessments. Urine samples were collected on one day before surgery, and 1st day and 3rd day after surgery. The primary outcome was the presence of postoperative delirium, and association of the level of UACR with postoperative delirium was evaluated with unadjusted/adjusted analyses and multivariable logistic regression.ResultsPostoperative delirium was observed in 26.75% (107 of 400) of patients within 3 days post‐surgery. UACR‐Pre (OR, 1.30; 95% CI, 1.14–1.49, p < 0.001), UACR‐POD1 (OR, 1.20; 95% CI, 1.13–1.27, p < 0.001), and UACR‐POD3 (OR, 1.14; 95% CI, 1.08–1.20, p < 0.001) between the delirium and non‐delirium groups show a significant difference, even after adjusting for age, education levels, and other factors.ConclusionAs the marker of endothelial dysfunction, the high perioperative UACR value may be linked to the postoperative delirium in elderly patients undergoing elective non‐cardiac surgery.     

Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: A 2-year naturalistic follow-up study

BackgroundPaliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses.MethodsAll patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M. Post hoc we examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection.ResultsOverall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) – 0.21, 0.87 p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI – 1.05, 3.30 p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI – 0.06, 0.50; p = 0.001]; HR 0.21 [95% CI – 0.08, 0.58 p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI – 3.73, 22.9; p < 0.001]) and PPLAI patients (HR for relapse 6.45 [95% CI – 2.49, 16.5; p < 0.001]), and prior clozapine use in PP3M patients (HR for relapse 6.11 [95% CI – 1.82, 20.5; p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI – 1.51, 13.5; p = 0.007).ConclusionsOutcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.     

Effect of stress‐induced hyperglycemia after non‐traumatic non‐aneurysmal subarachnoid hemorrhage on clinical complications and functional outcomes

BackgroundDespite having an overall benign course, non‐traumatic non‐aneurysmal subarachnoid hemorrhage (naSAH) is still accompanied by a risk of clinical complications and poor outcomes. Risk factors and mechanisms of complications and poor outcomes after naSAH remain unknown. Our aim was to explore the effect of stress‐induced hyperglycemia (SIH) on complication rates and functional outcomes in naSAH patients.MethodsWe retrospectively reviewed patients with naSAH admitted to our institution between 2013 and 2018. SIH was identified according to previous criterion. Symptomatic vasospasm, delayed cerebral infarction, and hydrocephalus were identified as main complications. Outcomes were reviewed using a modified Rankin Scale (mRS) at discharge, 3 months, and 12 months. A statistical analysis was conducted to reveal the associations of SIH with complications and outcomes.ResultsA total of 244 naSAH patients were included in the cohort with 74 (30.3%) SIH. After adjusting for age, gender, hypertension, Hunt and Hess (HH) grade, modified Fisher Scale (mFS), intraventricular hemorrhage (IVH), and subarachnoid blood distribution, SIH was significantly associated with symptomatic vasospasm (p < 0.001, 12.176 [4.904–30.231]), delayed cerebral infarction (p < 0.001, 12.434 [3.850–40.161]), hydrocephalus (p = 0.008, 5.771 [1.570–21.222]), and poor outcome at 12 months (p = 0.006, 5.506 [1.632–18.581]), whereas the correlation between SIH and poor outcome at discharge (p = 0.064, 2.409 [0.951–6.100]) or 3 months (p = 0.110, 2.029 [0.852–4.833]) was not significant. Incorporation of SIH increased the area under curve (AUC) of ROC in the combined model for predicting symptomatic vasospasm (p = 0.002), delayed cerebral infarction (p = 0.024), hydrocephalus (p = 0.037), and 12‐month poor outcome (p = 0.087).ConclusionsSIH is a significant and independent risk factor for symptomatic vasospasm, delayed cerebral infarction, hydrocephalus, and long‐term poor outcome in naSAH patients. Identifying SIH early after naSAH is important for decision‐making and treatment planning.     

Loss of long‐term benefit from VIM‐DBS in essential tremor: A secondary analysis of repeated measurements

AimsDeep brain stimulation (DBS) in the ventral intermediate nucleus (Vim‐DBS) is the preferred surgical therapy for essential tremor (ET). Tolerance and disease progression are considered to be the two main reasons underlying the loss of long‐term efficacy of Vim‐DBS. This study aimed to explore whether Vim‐DBS shows long‐term loss of efficacy and to evaluate the reasons for this diminished efficacy from different aspects.MethodsIn a repeated‐measures meta‐analysis of 533 patients from 18 studies, Vim‐DBS efficacy was evaluated at ≤6 months, 7–12 months, 1–3 years, and ≥4 years. The primary outcomes were the score changes in different components of the Fahn‐Tolosa‐Marin Tremor Rating Scale (TRS; total score, motor score, hand‐function score, and activities of daily living [ADL] score). Secondary outcomes were the long‐term predictive factors.ResultsThe TRS total, motor, and ADL scores showed significant deterioration with disease progression (p = 0.002, p = 0.047, and p < 0.001, respectively), while the TRS total (p < 0.001), hand‐function (p = 0.036), and ADL (p = 0.004) scores indicated a significant long‐term reduction in DBS efficacy, although the motor subscore indicated no loss of efficacy. Hand‐function (p < 0.001) and ADL (p = 0.028) scores indicated DBS tolerance, while the TRS total and motor scores did not. Stimulation frequency and preoperative score were predictive factors for long‐term results.ConclusionThis study provides level 3a evidence that long‐term Vim‐DBS is effective in controlling motor symptoms without waning benefits. The efficacy reduction for hand function was caused by DBS tolerance, while that for ADL was caused by DBS tolerance and disease progression. More attention should be given to actual functional recovery rather than changes in motor scores in patients with ET.     

Selective outcome reporting across psychopharmacotherapy randomized controlled trials

ObjectiveSelective reporting impairs the valid interpretation of trials and leads to bias with regards to the clinical evidence. We aimed to examine factors associated with selective reporting in psychopharmacotherapy trials and thus enable solutions to prevent such selective reporting in the future.MethodsWe retrieved all registry records of trials investigating medication for depressive, bipolar and psychotic disorders. Multivariate logistic regression was performed with selective reporting as outcome, and funding source, psychiatric disorder, year of study start date, participating centers, and anticipated sample size as explanatory variables, after testing for multicollinearity. Adjusted odds ratios (AOR) were calculated. Two‐sided Fisher exact test was used to compare the proportions of newly added positive primary outcomes with the proportions of positive results in the overall group of primary outcomes.ResultsOf 151 included trials (N = 94,303 participants), 21 (14%) showed irregularities between registered and published primary outcomes. Higher odds of such irregularities were associated with non‐industry‐funded RCTs (AOR 5.3; p = 0.014) and trials investigating major depressive disorder (AOR 12.7; p = 0.024) or schizophrenia (AOR 14.5; p = 0.016; Table 1).ConclusionWe demonstrate discrepancies between trial registrations and publications across RCTs investigating debilitating psychiatric disorders, especially in non‐industry funded RCTs.     

Pre‐supplementary motor network connectivity and clinical outcome of magnetic stimulation in obsessive–compulsive disorder

A large proportion of patients with obsessive–compulsive disorder (OCD) respond unsatisfactorily to pharmacological and psychological treatments. An alternative novel treatment for these patients is repetitive transcranial magnetic stimulation (rTMS). This study aimed to investigate the underlying neural mechanism of rTMS treatment in OCD patients. A total of 37 patients with OCD were randomized to receive real or sham 1‐Hz rTMS (14 days, 30 min/day) over the right pre‐supplementary motor area (preSMA). Resting‐state functional magnetic resonance imaging data were collected before and after rTMS treatment. The individualized target was defined by a personalized functional connectivity map of the subthalamic nucleus. After treatment, patients in the real group showed a better improvement in the Yale–Brown Obsessive Compulsive Scale than the sham group (F _1,35 = 6.0, p = .019). To show the neural mechanism involved, we identified an “ideal target connectivity” before treatment. Leave‐one‐out cross‐validation indicated that this connectivity pattern can significantly predict patients'' symptom improvements (r = .60, p = .009). After real treatment, the average connectivity strength of the target network significantly decreased in the real but not in the sham group. This network‐level change was cross‐validated in three independent datasets. Altogether, these findings suggest that personalized magnetic stimulation on preSMA may alleviate obsessive–compulsive symptoms by decreasing the connectivity strength of the target network.     

Transition to psychosis in randomized clinical trials of individuals at clinical high risk of psychosis compared to observational cohorts: a systematic review and meta-analysis

BackgroundIndividuals at clinical high risk of psychosis (CHR-P) recruited in randomized clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analysis has ever addressed this issue.Methods“Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) and “Meta-analysis Of Observational Studies in Epidemiology” (MOOSE)–compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included nonoverlapping longitudinal studies (RCTs-control condition and observational cohorts) reporting the transition to psychosis in CHR-P individuals. The primary effect size measure was the cumulative risk of transition at 0.5, 1, and 2 years follow-up in RCTs compared to observational cohorts. Random effects meta-analyses, heterogeneity assessment, quality assessment, and meta-regressions were conducted.ResultsNinety-four independent studies (24 RCTs, 70 observational cohorts) and 9,243 individuals (mean age = 20.1 ± 3.0 years; 43.7% females) were included. The meta-analytical risk of transitioning to psychosis from a CHR-P stage was 0.091 (95% confidence intervals [CI] = 0.068–0.121) at 0.5 years, 0.140 (95% CI = 0.101–0.191) at 1 year and 0.165 (95% CI = 0.097–0.267) at 2 years follow-up in RCTs, and 0.081 (95% CI = 0.067–0.099) at 0.5 years, 0.138 (95% CI = 0.114–0.167) at 1 year, and 0.174 (95% CI = 0.156–0.193) at 2 years follow-up in observational cohorts. There were no between-group differences in transition risks (p > 0.05). The proportion of CHR-P individuals with substance use disorders (excluding alcohol and cannabis) was higher in observational cohorts (16.8, 95% CI = 13.3–21.0%) than in RCTs (3.4, 95% CI = 0.8–12.7%; p = 0.018).ConclusionsThere is no meta-analytic evidence supporting sampling biases in RCTs of CHR-P individuals. Further RCTs are needed to detect effective interventions to prevent psychosis in this at-risk group.     

How to improve the physical health of people with severe mental illness? A multicentric randomized controlled trial on the efficacy of a lifestyle group intervention

Background People with severe mental illnesses (SMI) have a mortality rate two times higher compared to the general population, with a decade of years of life lost. In this randomized controlled trial (RCT), we assessed in a sample of people with bipolar disorder, major depressive disorder, and schizophrenia spectrum disorder, the efficacy of an innovative psychosocial group intervention compared to a brief psychoeducational group intervention on patients’ body mass index (BMI), body weight, waist circumference, Framingham and HOMA-IR indexes. Methods This is a multicentric RCT with blinded outcome assessments carried out in six Italian university centers. After recruitment patients were randomized to receive a 6-month psychosocial intervention to improve patients’ physical health or a brief psychoeducational intervention. All recruited patients were assessed with standardized assessment instruments at baseline and after 6 months. Anthropometric parameters and blood samples have also been collected. Results Four-hundred and two patients with a diagnosis of bipolar disorder (43.3%), schizophrenia or other psychotic disorder (29.9%), or major depression (26.9%) were randomly allocated to the experimental (N = 206) or the control group (N = 195). After 6 months, patients from the experimental group reported a significant reduction in BMI (odds ratio [OR]: 1.93, 95% confidence intervals [CI]: 1.31–2.84; p < 0.001), body weight (OR = 4.78, 95% CI: 0.80–28.27, p < 0.05), and waist circumference (OR = 5.43, 95% CI: 1.45–20.30, p < 0.05). Participants with impaired cognitive and psychosocial functioning had a worse response to the intervention. Conclusions The experimental group intervention was effective in improving the physical health in SMI patients. Further studies are needed to evaluate the feasibility of this intervention in real-world settings.     

Measuring changes in alcohol use in Finland and Norway during the COVID‐19 pandemic: Comparison between data sources

ObjectivesTo examine (1) how a rapid data collection using a convenience sample fares in estimating change in alcohol consumption when compared to more conventional data sources, and (2) how alcohol consumption changed in Finland and Norway during the first months of the COVID‐19 pandemic.MethodsThree different types of data sources were used for the 2nd quarter of 2020 and 2019: sales statistics combined with data on unrecorded consumption; the rapid European Alcohol Use and COVID‐19 (ESAC) survey (Finland: n = 3800, Norway: n = 17,092); and conventional population surveys (Finland: n = 2345, Norway: n1 = 1328, n2 = 2189, n3 = 25,708). Survey measures of change were retrospective self‐reports.ResultsThe statistics indicate that alcohol consumption decreased in Finland by 9%, while little change was observed in Norway. In all surveys, reporting a decrease in alcohol use was more common than reporting an increase (ratios 2–2.6 in Finland, 1.3–2 in Norway). Compared to conventional surveys, in the ESAC survey fewer respondents reported no change and past‐year alcohol consumption was higher.ConclusionThe rapid survey using convenience sampling gave similar results on change in drinking as conventional surveys but higher past‐year drinking, suggesting self‐selection effects. Aspects of the pandemic driving alcohol consumption down were equally strong or stronger than those driving it up.     

Automated machine learning‐based model predicts postoperative delirium using readily extractable perioperative collected electronic data

ObjectivePostoperative delirium (POD) is a common postoperative complication that is relevant to poor outcomes. Therefore, it is critical to find effective methods to identify patients with high risk of POD rapidly. Creating a fully automated score based on an automated machine‐learning algorithm may be a method to predict the incidence of POD quickly.Materials and methodsThis is the secondary analysis of an observational study, including 531 surgical patients who underwent general anesthesia. The least absolute shrinkage and selection operator (LASSO) was used to screen essential features associated with POD. Finally, eight features (age, intraoperative blood loss, anesthesia duration, extubation time, intensive care unit [ICU] admission, mini‐mental state examination score [MMSE], Charlson comorbidity index [CCI], postoperative neutrophil‐to‐lymphocyte ratio [NLR]) were used to established models. Four models, logistic regression, random forest, extreme gradient boosted trees, and support vector machines, were built in a training set (70% of participants) and evaluated in the remaining testing sample (30% of participants). Multivariate logistic regression analysis was used to explore independent risk factors for POD further.ResultsModel 1 (logistic regression model) was found to outperform other classifier models in testing data (area under the curve [AUC] of 80.44%, 95% confidence interval [CI] 72.24%–88.64%) and achieve the lowest Brier Score as well. These variables including age (OR = 1.054, 95%CI: 1.017~1.093), extubation time (OR = 1.027, 95%CI: 1.012~1.044), ICU admission (OR = 2.238, 95%CI: 1.313~3.793), MMSE (OR = 0.929, 95%CI: 0.876~0.984), CCI (OR = 1.197, 95%CI: 1.038~1.384), and postoperative NLR (OR = 1.029, 95%CI: 1.002~1.057) were independent risk factors for POD in this study.ConclusionsWe have built and validated a high‐performing algorithm to demonstrate the extent to which patient risk changes of POD during the perioperative period, thus leading to a rational therapeutic choice.     

Effects of media stories featuring coping with suicidal crises on psychiatric patients: Randomized controlled trial

BackgroundAccumulating evidence suggests beneficial effects of media stories featuring individuals mastering their suicidal crises, but effects have not been assessed for psychiatric patients.MethodsWe randomized n = 172 adult psychiatric patients (n = 172, 97.1% inpatients) to read an educative article featuring a person mastering a suicidal crisis (n = 92) or an unrelated article (n = 80) in a single-blind randomized controlled trial. Questionnaire data were collected before (T ₁) and after exposure (T ₂) as well as 1 week later (study end-point, T ₃). The primary outcome was suicidal ideation as assessed with the Reasons for Living Inventory; secondary outcomes were help-seeking intentions, mood, hopelessness, and stigmatization. Differences between patients with affective versus other diagnoses were explored based on interaction tests.ResultsWe found that patients with affective disorders (n = 99) experienced a small-sized reduction of suicidal ideation at 1-week follow up (mean difference to control group [MD] at T ₃ = −0.17 [95% CI −0.33, −0.03], d = −0.15), whereas patients with nonaffective diagnoses (n = 73) experienced a small-sized increase (T ₂: MD = 0.24 [95% CI 0.06, 0.42], d = 0.19). Intervention group participants further experienced a nonsustained increase of help-seeking intentions (T ₂: MD = 0.53 [95% CI 0.11, 0.95], d = 0.19) and a nonsustained deterioration of mood (T ₂: MD = −0.14 [95% CI −0.27, −0.02], d = −0.17).ConclusionsThis study suggests that patients with affective disorders appear to benefit from media materials featuring mastery of suicidal crises. More research is needed to better understand which patient groups are at possible risk of unintended effects.     

Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice

BackgroundVasogenic cerebral edema resulting from blood–brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β‐catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β‐catenin signaling.MethodsWe evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV‐induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β‐catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124.ResultsLithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm³ vs. 19.97 ± 3.20 mm³ in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β‐catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin‐5 and ZO‐1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124‐mediated endothelial Wnt/β‐catenin signaling.ConclusionOur findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.     

Effects of bariatric surgery on functional connectivity of the reward and default mode network: A pre‐registered analysis

Obesity imposes serious health risks and involves alterations in resting‐state functional connectivity of brain networks involved in eating behavior. Bariatric surgery is an effective treatment, but its effects on functional connectivity are still under debate. In this pre‐registered study, we aimed to determine the effects of bariatric surgery on major resting‐state brain networks (reward and default mode network) in a longitudinal controlled design. Thirty‐three bariatric surgery patients and 15 obese waiting‐list control patients underwent magnetic resonance imaging at baseline, after 6 and 12 months. We conducted a pre‐registered whole‐brain time‐by‐group interaction analysis, and a time‐by‐group interaction analysis on within‐network connectivity. In exploratory analyses, we investigated the effects of weight loss and head motion. Bariatric surgery compared to waiting did not significantly affect functional connectivity of the reward network and the default mode network (FWE‐corrected p > .05), neither whole‐brain nor within‐network. In exploratory analyses, surgery‐related BMI decrease (FWE‐corrected p = .041) and higher average head motion (FWE‐corrected p = .021) resulted in significantly stronger connectivity of the reward network with medial posterior frontal regions. This pre‐registered well‐controlled study did not support a strong effect of bariatric surgery, compared to waiting, on major resting‐state brain networks after 6 months. Exploratory analyses indicated that head motion might have confounded the effects. Data pooling and more rigorous control of within‐scanner head motion during data acquisition are needed to substantiate effects of bariatric surgery on brain organization.     

RAR‐related orphan receptor A: One gene with multiple functions related to migraine

AimsRAR‐related orphan receptor (RORA) involves in regulation of several biological processes including inflammation and circadian rhythm that probably are involved in migraine pathophysiology. In the current study, the association between RORA rs11639084 and rs4774388 variants and susceptibility to migraine were investigated in a sample of Iranian migraine patients for the first time.MethodsIn a case‐control study including 400 participants, 200 migraineurs and 200 healthy controls, genotyping of RORA rs4774388 and rs11639084 polymorphisms was performed using tetra‐primer amplification refractory mutation system–polymerase chain reaction (TP‐ARMS‐PCR).ResultsThe distribution of rs4774388 C/T and T/T genotypes differed significantly between the studied groups. Moreover, an association was observed between rs4774388 and migraine under the recessive mode of inheritance (P = 0.002; OR = 1.89.; CI = 1.25‐2.87). The distribution of rs11639084 alleles and genotypes was not significantly different between migraineurs and healthy controls.ConclusionCurrent results suggest RORA, as a molecular link, may explain inflammation and circadian rhythm dysfunction in migraine. Further studies in different ethnicities are required to confirm the function of RORA in migraine development.     

Long‐term functional prognosis and related factors of spinal cord stimulation in patients with disorders of consciousness

IntroductionThe treatment of patients with disorders of consciousness (DoC) remains a challenging issue, and spinal cord stimulation (SCS) has been reported to be a promising treatment for DoC in some studies.AimsThis study explores the efficiency of SCS in treating patients with DoC at different consciousness levels, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and the minimally conscious state (MCS) and summarizes and analyzes the long‐term effect and related factors of SCS in patients with DoC.ResultsAn overall positive outcome was reached in 35 of 110 patients (31.8%). Among patients with positive outcomes, the MCS group improved 45.53% more than VS/UWS group, and this difference was statistically significant. In terms of the recommendation standard, positive outcomes occurred in 33 patients (94.3%) in the highly recommended group and 2 patients (5.7%) in the weakly recommended group (p < 0.001). After adjustment for potential covariables, young age (age ≤ 19 years old) (p = 0.045) and MCS (p < 0.001) were significantly correlated with positive outcome. A nomogram based on age, state of consciousness, and pathogeny showed good predictive performance, with a c‐index of 0.794. The Hosmer–Lemeshow goodness‐of‐fit test showed that the model was well calibrated (χ ² = 3.846, p = 0.871).ConclusionsSCS is one of the most feasible treatments for patients with DoC, especially for patients with MCS. Younger age is significantly associated with better outcomes and could therefore serve as a basis for preoperative screening. However, more evidence‐based randomized controlled trials are needed to confirm the efficacy of the treatment.     

Tracking the psychological and socio‐economic impact of the COVID‐19 pandemic in the UK: A methodological report from Wave 5 of the COVID‐19 Psychological Research Consortium (C19PRC) Study

ObjectivesThe COVID‐19 Psychological Research Consortium (C19PRC) Study was established in March 2020 to monitor the psychological and socio‐economic impact of the pandemic in the UK and other countries. This paper describes the protocol for Wave 5 (March–April 2021).MethodsThe survey assessed: COVID‐19 related experiences; experiences of common mental health disorders; psychological characteristics; and social and political attitudes. Adults who participated in any previous wave (N = 4949) were re‐invited to participate. Weights were calculated using a survey raking algorithm to ensure the longitudinal panel was nationally representative in terms of gender, age, and household income, amongst other factors.ResultsOverall, 2520 adults participated. A total of 2377 adults who participated in the previous survey wave (November–December 2020) were re‐interviewed at Wave 5 (61.5% retention rate). Attrition between these two waves was predicted by younger age, lower household income, children living in the household, and treatment for mental health difficulties. Of the adults recruited into the C19PRC study at baseline, 57.4% (N = 1162) participated in Wave 5. The raking procedure re‐balanced the longitudinal panel to within 1.5% of population estimates for selected socio‐demographic characteristics.ConclusionThis paper outlines the growing strength of the publicly available C19PRC Study data for COVID‐19‐related interdisciplinary research.