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Abstract Background Studies have demonstrated that exercise can mitigate the intensity of menstrual pain in primary dysmenorrhea, but the most effective type of exercise remains unclear. The objective of this systematic review and network meta-analysis was to evaluate the effectiveness of different exercise regimens in reducing pain associated with primary dysmenorrhoea. Methods Randomized controlled trials investigating the relationship between menstrual pain and exercise were selected from major electronic databases until February 2, 2024. The primary outcome was the effect of exercise on pain intensity measured by the mean difference on a 10-cm visual analogue scale at 4 and 8 weeks after intervention. The secondary outcome was the difference in risk of dropout at 8 weeks. The study protocol was registered as INPLASY202330050. Results This systematic review and network meta-analysis included 29 randomized controlled trials, which involved 1808 participants with primary dysmenorrhea. Exercise interventions included relaxation exercise, strength training, aerobic activity, yoga, mixed exercise, and the Kegel maneuver. Relaxation exercise was the most effective in reducing menstrual pain in 4 weeks (− 3.56; 95% confidence interval: − 5.03 to − 2.08). All exercise interventions were effective in reducing menstrual pain at 8 weeks, with reductions ranging from − 3.87 (95% CI − 5.51 to − 2.22) for relaxation exercise to − 2.75 (95% CI − 4.00 to − 1.51) for yoga, compared to the control group. Relaxation exercises were found to have a significantly lower dropout risk (− 0.11; 95% CI − 0.20 to 0.02), while none of the exercise types was associated with a higher dropout risk than the control group. Conclusion All exercise interventions were effective in reducing menstrual pain in primary dysmenorrhea after 8 weeks of intervention. However, relaxation exercise was found to be the most effective intervention at 4 and 8 weeks and had the lowest risk of dropout. Graphical Abstract

ObjectivePsilocybin-assisted therapy has shown promising efficacy on clinical depressive symptoms. However, diverse psychological support or psychotherapy was performed with psilocybin treatment. This study aimed to explore the association of psychological protocols with the efficacy of psilocybin-assisted therapy for depressive symptoms.MethodFive major databases were systemic searched for clinical trials addressing psilocybin-assisted therapy for patients with clinical depressive symptoms. A Bayesian random-effects meta-analysis and meta-regression were performed. The effect size was mean difference (with 95% credible interval) measured by 17-Item Hamilton Depression Rating Scale.ResultsThere were 10 eligible studies including 515 adult patients with clinically diagnosed depression. The psychological protocols could be categorized into four types: (i) manualized directive psychotherapy(k=1); (ii) manualized nondirective psychological support(k=3), (iii) non-manualized nondirective psychological support(k=5); and (iv) non-manualized supportive psychotherapy(k=1). The pooled standard mean difference of psilocybin-assisted therapy was 10.08 (5.03-14.70).ConclusionCompared with manualized nondirective psychological support, the other three psychological approaches did not differ significantly. The improvement of depressive symptoms was not associated with the psychological protocols in adult patients receiving psilocybin-assisted therapy.Systemic review registrationOpen Science Framework: identifier (osf.io/3YUDV).

Summary: Tissue clearing is an essential prerequisite for 3D volumetric imaging of larger tissues or organs. Here, we present a detailed protocol for optical, aqueous-based clearing of adult murine tissues using EZ Clear. We describe steps to ensure successful perfusion and fixation of organs from the adult mouse and supply guidelines for optimal lipid removal, refractive index matching, and tissue clearing. Finally, we provide imaging parameters for visualizing both exogenous perfused fluorescent dyes and endogenous fluorescence reporters in the adult mouse.For complete details on the use and execution of this protocol, please refer to Hsu et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract The combination of mirror therapy (MT) and neuromuscular electrical stimulation (NMES) has been devised as an intervention method in stroke rehabilitation; however, few studies have investigated its efficacy in lower extremity motor function recovery. In this systematic review and meta-analysis, we examined the effectiveness of combined MT and NMES therapy in improving poststroke walking speed, spasticity, balance and other gait parameters. Randomized controlled trials (RCTs) were selected from PubMed, Cochrane Library, EMBASE, and Scopus databases. In total, six RCTs which involving 181 participants were included. Our findings indicate that MT combined with NMES elicits greater improvement relative to control group in walking speed (SMD = 0.67, 95% confidence interval [CI] 0.26–1.07, P = 0.001), Berg Balance Scale (SMD = 0.72; 95% CI 0.31–1.13; P = 0.0007), cadence (SMD = 0.59, 95% CI 0.02–1.16, P = 0.04), step length (SMD = 0.94, 95% CI 0.35–1.53, P = 0.002), and stride length (SMD = 0.95, 95% CI 0.36–1.54, P = 0.002) but not in modified Ashworth scale (SMD = − 0.40, 95% CI − 1.05 to 0.26, P = 0.23). Our findings suggest that MT combined with NMES may be a suitable supplemental intervention to conventional therapy in stroke survivors.

Audiovestibular dysfunction in patients with systemic lupus erythematosus has been underestimated for decades. Systemic lupus erythematosus can affect both the auditory and vestibular systems simultaneously. Several potential pathophysiological mechanisms behind systemic lupus erythematosus-related audiovestibular dysfunction have been proposed, including antibody-mediated immune responses, cell-mediated cytotoxicity, immune complex deposition in microvessels, central involvement in the audiovestibular pathway, and ototoxicity from medications used in systemic lupus erythematosus treatment. Currently available tests to evaluate audiovestibular function in systemic lupus erythematosus patients are neither specific nor sensitive. Nevertheless, there is no consensus regarding the efficacy of treatments for audiovestibular dysfunction in such patients. In this systematic review, we electronically searched the PubMed, Embase, ClinicalKey, Web of Science, and ScienceDirect platforms to find eligible articles. The first inspection date was on 29 December 2023 and the final update search date was on 11 June 2024. Further, we rated the quality of the included articles with Newcastle–Ottawa Scale. Based upon the aforementioned systematic review process, we have summarized the currently available evidence on the characteristics, pathophysiology, examination, and treatment of audiovestibular dysfunction related to systemic lupus erythematosus. Furthermore, we have proposed a specific steroid treatment protocol to manage audiovestibular dysfunction related to systemic lupus erythematosus. Audiovestibular dysfunction related to systemic lupus erythematosus may be responsive to adequate treatments, potentially allowing for reversibility if the disease is recognized and managed in a timely manner. Therefore, to provide clinically relevant evidence to clinicians, we have organized this literature review article to summarize the available evidence on the characteristics, pathophysiology, examination, and treatment of audiovestibular dysfunction in patients with systemic lupus erythematosus. Finally, based on our modified steroid treatment protocol, we would like to provide a new treatment strategy to clinicians to manage systemic lupus erythematosus-related audiovestibular dysfunction.

This meta-analysis investigated the effects of intravenous magnesium sulfate on the postoperative recovery quality, as assessed using the Quality of Recovery (QoR) questionnaire, in adult surgical patients. Seven randomized controlled trials involving 622 patients were included. Compared with the placebo, magnesium sulfate significantly improved the global QoR score on postoperative day 1 (standardized mean difference [SMD]: 1.24; 95% confidence interval: 0.70—1.78; p < 0.00001). It also enhanced specific QoR dimensions, with substantial effects on pain (SMD: 1, p < 0.00001) and physical comfort (SMD: 0.85, p < 0.0001), a moderate effect on emotional state (SMD: 0.65, p = 0.002), and small improvements in physical independence (SMD: 0.43, p < 0.00001) and psychological support (SMD: 0.37, p < 0.0001). In addition, magnesium sulfate reduced the intraoperative opioid consumption (SMD: −0.66, p < 0.0001), postoperative pain severity, and the incidence of postoperative nausea and vomiting (risk ratio: 0.48, p = 0.008). The extubation times were unaffected, whereas the post-anesthesia care unit stay was slightly prolonged. These findings highlight the potential of magnesium sulfate as a valuable adjunct for multimodal analgesia and enhanced recovery. Future studies should aim to elucidate the optimal dosing strategies, timing of administration, and specific surgical populations that may derive maximum benefits.

BackgroundThis meta-analysis aimed to synthesize current evidence on the association between the Geriatric Nutritional Risk Index (GNRI) and long-term outcomes in patients undergoing hemodialysis.MethodsElectronic databases were systematically searched for relevant studies that investigated the association between GNRI and long-term outcomes in hemodialysis patients until November 2023. The primary outcome was the association between the GNRI (i.e., low versus high) and overall mortality risk, while the secondary outcome was the relationship between the GNRI and cardiovascular mortality risk.ResultsThirty cohort studies involving 55,864 patients were included. A low GNRI was found to be significantly associated with increased overall mortality (hazard ratio [HR]: 2.42, 95% confidence interval [CIs]: 2.10–2.79, p

BackgroundChatGPT may act as a research assistant to help organize the direction of thinking and summarize research findings. However, few studies have examined the quality, similarity (abstracts being similar to the original one), and accuracy of the abstracts generated by ChatGPT when researchers provide full-text basic research papers. ObjectiveWe aimed to assess the applicability of an artificial intelligence (AI) model in generating abstracts for basic preclinical research. MethodsWe selected 30 basic research papers from Nature, Genome Biology, and Biological Psychiatry. Excluding abstracts, we inputted the full text into ChatPDF, an application of a language model based on ChatGPT, and we prompted it to generate abstracts with the same style as used in the original papers. A total of 8 experts were invited to evaluate the quality of these abstracts (based on a Likert scale of 0-10) and identify which abstracts were generated by ChatPDF, using a blind approach. These abstracts were also evaluated for their similarity to the original abstracts and the accuracy of the AI content. ResultsThe quality of ChatGPT-generated abstracts was lower than that of the actual abstracts (10-point Likert scale: mean 4.72, SD 2.09 vs mean 8.09, SD 1.03; P

Summary: Background: Zuranolone is recognised as a promising antidepressant agent. Our study aimed to investigate the efficacy and safety of zuranolone in treating major depressive disorder (MDD). Methods: A systematic review was conducted by searching major databases from inception to August 20, 2023 (INPLASY: 202360087). A meta-analysis was performed by using a random-effects model to calculate effect sizes, expressed as standardised mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome was improvement in depressive symptoms, while secondary outcomes included response and remission rates of depression, improvement in anxiety symptoms, incidence of dropouts, and any side effects. We conducted subgroup analyses for general MDD and postpartum-onset MDD and a dose-response meta-analysis to estimate the relationship between zuranolone dose and outcomes. Findings: The study included seven randomised control trials involving 1789 patients. Zuranolone reduced depressive symptoms (SMD = −0.37, 95% CIs = −0.51 to −0.23), increased response rate (OR = 2.06, 95% CIs = 1.48–2.85) and remission rate (OR = 2.04, 95% CIs = 1.38–3.02), and reduced anxiety symptoms (SMD = −0.26, 95% CIs = −0.39 to −0.14). Furthermore, zuranolone-treated patients experienced more side effects than those in the control group (OR = 1.40, 95% CIs = 1.10–1.78), although dropout rate did not significantly differ between the two groups (OR = 1.13, 95% CIs = 0.85–1.49). According to the dose-response meta-analysis, zuranolone could effectively improve depression and anxiety at increasing doses up to a maximum daily dose of 30 mg; however, side effects increased with doses exceeding 30 mg. Based on subgroup analyses, zuranolone showed greater efficacy in treatment of postpartum-onset MDD than general MDD, but the difference did not reach statistical significance. Interpretation: Our findings suggested that zuranolone is effective in alleviating depression and anxiety. Nevertheless, there is a potential risk of adverse effects. Given its therapeutic efficacy and risk of side effects, a daily dose of 30 mg appears to be the optimal choice. Funding: Chang Gung Medical Foundation.

The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.

Background: Irritable bowel syndrome (IBS) was found in 11% of the general population worldwide. The current pharmacologic management of IBS was unsatisfactory, and it was accompanied by a number of adverse events. Melatonin was found to play an important role in gastrointestinal smooth muscle motility. Dysregulation of endogenous melatonin secretion has been found in IBS patients. Exogenous melatonin supplement has become one alternative treatment for IBS, but the evidence is inconclusive. The current meta-analysis sought to determine the efficacy of exogenous melatonin supplement in improving IBS severity in IBS patients. Methods: We included randomized controlled trials (RCTs) that investigated the efficacy of exogenous melatonin supplement in ameliorating IBS severity in IBS patients. This meta-analysis was conducted using a random effects model. The primary target outcomes were changes in IBS severity associated with melatonin or placebo. Results: This meta-analysis of 4 RCTs and 115 participants revealed that exogenous melatonin supplement was associated with significantly better improvement in overall IBS severity than placebo (k = 4, Hedges’ g = 0.746, 95% confidence intervals = 0.401–1.091, p

Abstract Background Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Abstract Background Dementia [i.e., Alzheimer disease (AD)], the most common neurodegenerative disease, causes profound negative impacts on executive function and quality of life. Available pharmacological treatments often fail to achieve satisfactory outcomes. Noninvasive brain stimulation (NIBS) techniques, which focally modify cortical function and enhance synaptic long-term potentiation, are potentially beneficial for the cognition in patients with AD. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and safety of different NIBS interventions in patients with AD through NMA. Methods Only randomized controlled trials (RCTs) examining NIBS interventions in patients with AD had been included. All NMA procedures were performed under the frequentist model. The primary and secondary outcomes were changes in cognitive function and quality of life, respectively. Results Nineteen RCTs (639 participants) were included. The mean treatment and follow-up durations were 5.7 and 10.5 weeks, respectively. The combination of cathodal tDCS of the left dorsolateral prefrontal cortex and anodal tDCS over the right supraorbital region (c-tDCS-F3 + a-tDCS-Fp2) was associated with a significant beneficial effect on cognition compared with sham controls (standardized mean difference=2.43, 95% confidence interval=0.61–4.26, n=12 and 11). It was also associated with the greatest beneficial effect on cognition among all the investigated NIBS approaches. All the methods were well tolerated with regard to the safety profile, as reflected in the rates of adverse events or local discomfort, as well as acceptability, as indicated by dropout rate. Conclusions The present findings provide evidence of the benefits of NIBS, especially tDCS, for beneficial effect on cognition in patients with AD. However, because of few studies included, this effect was not replicated yet in the other studies. Therefore, future larger-scale and longer follow-up duration RCTs should be warranted. Trial registration PROSPERO CRD42020209516. The current study had been approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

Abstract Background The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Methods Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. Results We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Conclusions Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.

Abstract This meta-analysis aimed at investigating the effectiveness of laryngeal mask airway (LMA) against postoperative pharyngolaryngeal complications after thyroidectomy. MEDLINE, Cochrane Library, google scholar, and EMBASE databases were searched from inception through February, 2021, for randomized controlled trials (RCTs) comparing the incidence of pharyngolaryngeal complications following the use of LMA or endotracheal tube (ETT). Pooled results from seven RCTs involving 600 patients showed an association of LMA with a reduced risk of postoperative sore throat (POST) at 24 h [risk ratio (RR) 0.75, p = 0.006, four trials], but not at 1 h and 48 h after thyroidectomy. POST severity and hoarseness risk were lower in the LMA group than the ETT group at 1 h, 24 h, and 48 h (all p

IntroductionPost-stroke depression (PSD) is a serious mental disorder after ischemic stroke. Early detection is important for clinical practice. This research aims to develop machine learning models to predict new-onset PSD using real-world data.MethodsWe collected data for ischemic stroke patients from multiple medical institutions in Taiwan between 2001 and 2019. We developed models from 61,460 patients and used 15,366 independent patients to test the models’ performance by evaluating their specificities and sensitivities. The predicted targets were whether PSD occurred at 30, 90, 180, and 365 days post-stroke. We ranked the important clinical features in these models.ResultsIn the study’s database sample, 1.3% of patients were diagnosed with PSD. The average specificity and sensitivity of these four models were 0.83–0.91 and 0.30–0.48, respectively. Ten features were listed as important features related to PSD at different time points, namely old age, high height, low weight post-stroke, higher diastolic blood pressure after stroke, no pre-stroke hypertension but post-stroke hypertension (new-onset hypertension), post-stroke sleep-wake disorders, post-stroke anxiety disorders, post-stroke hemiplegia, and lower blood urea nitrogen during stroke.DiscussionMachine learning models can provide as potential predictive tools for PSD and important factors are identified to alert clinicians for early detection of depression in high-risk stroke patients.

Question Are antipsychotic dose equivalents between acute mania and schizophrenia the same?Study selection and analysis Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre–post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia.Findings We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: −022, 95% CI −0.41 to –0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p

BackgroundThis meta-analysis aimed at investigating the pooled evidence regarding the effects of intravenous vitamin C (IVVC) on mortality rate in critically ill patients.MethodsDatabases including Medline, Embase, and Cochrane Library were searched from inception to October, 2022 to identify RCTs. The primary outcome was the risk of overall mortality. Subgroup analyses were performed based on IVVC dosage (i.e., cut-off value: 100 mg/kg/day or 10000 mg/day). Trial sequential analysis (TSA) was used to examine the robustness of evidence.ResultsA total of 12 trials including 1,712 patients were analyzed. Although meta-analysis demonstrated a lower risk of mortality in patients with IVVC treatment compared to those without [risk ratio (RR): 0.76, 95% CI: 0.6 to 0.97, p = 0.02, I2 = 36%, 1,711 patients), TSA suggested the need for more studies for verification. Moreover, subgroup analyses revealed a reduced mortality risk associated with a low IVVC dosage (RR = 0.72, p = 0.03, 546 patients), while no beneficial effect was noted with high IVVC dosage (RR = 0.74, p = 0.13, I2 = 60%, 1,165 patients). The durations of vasopressor [mean difference (MD): −37.75 h, 404 patients) and mechanical ventilation (MD: −47.29 h, 388 patients) use were shorter in the IVVC group than those in the controls, while there was no significant difference in other prognostic outcomes (e.g., length of stay in intensive care unit/hospital) between the two groups.ConclusionAlthough intravenous vitamin C as a monotherapy reduced pooled mortality, durations of vasopressor use and mechanical ventilation, further research is required to support our findings and to identify the optimal dosage of vitamin C in the critical care setting.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022371090.

Study objectiveTo assess the association between prognostic nutritional index (PNI) and risk of postoperative delirium (POD) in adult patients.MethodsMEDLINE, Google scholar, EMBASE, and Cochrane library databases were searched from inception till April 2022. The primary outcome was the association between PNI and the risk of POD, while the secondary outcomes were correlations of other prognostic factors with POD risk. The correlation between PNI and the incidence of POD was assessed with three approaches: Difference in preoperative PNI between POD and non-POD groups (Model 1) as well as the association of PNI as a continuous parameter (Model 2) or as a binary variable (i.e., low vs. high using a PNI cut-off value of 50) (Model 3) with POD risk.ResultsAnalysis of nine observational studies published from 2010 to 2021 recruiting 3,743 patients showed a POD incidence of 6.4–35%. Our meta-analysis demonstrated a lower PNI among patients in the POD group (MD: −3.78, 95% CI: −4.85 to −2.71, p < 0.0001, I2 = 54.2%) compared to the non-POD group (Model 1). Pooled results revealed a negative association between PNI and POD risk for both Model 2 (OR: 0.91, 95% CI: 0.86–0.97, p = 0.002, I2 = 71%) and Model 3 (OR: 1.68, 95% CI: 1.26–2.23, p < 0.0001, I2 = 0%). Besides, while our results supported an age-dependent increase in POD risk, other factors including body-mass index, surgical time, health status, hypertension, diabetes mellitus, and male gender were non-significant predictors of POD.ConclusionOur results demonstrated a negative association between PNI and POD, which warrant further large-scale studies for validation.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022323809.

Abstract Background Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%–50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability. Methods The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov , ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of June 4th, 2021 for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. All NMA procedures were conducted under the frequentist model. Results Nineteen RCTs were included (N = 1493; mean age = 38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference = − 8.70 days, 95% confidence intervals (95%CIs): − 14.45 to − 2.95 compared to sham/control groups]. Only alternating frequency (2/100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz (RR = 0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did. Conclusions The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS. Trial registration CRD42021252638. The current study had been approval by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

Summary: Background: Acute mania is a psychiatric emergency requiring rapid management. However, randomised controlled trials (RCTs) have shown considerable individual differences in treatment effects on manic symptoms with antimanic drugs. Methods: We searched the MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov to identify RCTs without language restrictions from inception to April 19, 2022. We included double-blind RCTs of oral antimanic monotherapy versus placebo in adult patients. The primary outcome was variability in improvement of manic symptoms (assessed using the coefficient of variation ratio [CVR]). The secondary outcomes were overall improvement of manic symptoms and acceptability (i.e., discontinuation for any reason). The pooled effects of outcomes were calculated by random-effects meta-analyses using restricted maximum likelihood methods. The quality of the included studies was assessed using the Cochrane Risk of Bias (ROB) Assessment Tool. This study was registered with OSF (DOI:10.17605/OSF.IO/G4JNY). Findings: We included 39 RCTs (N=12150; mean age=39·9 years, interquartile range [IQR]=38·7-41·1; mean proportion of female=48·6%, IQR=42·3%-52·3%) and investigated 14 antimanic drugs. We found that eight antimanic drugs compared to placebo were associated with lower CVRs (95% confidence interval [CI]; I2), including risperidone (0·51; 0·37-0·70; 0%), haloperidol (0·54; 0·44-0·67; 4%), olanzapine (0·59; 0·44-0·79; 47%), ziprasidone (0·61; 0·53-0·71; 0%), lithium (0·63; 0·52-0·76; 0%), quetiapine (0·65; 0·48-0·87; 2%), aripiprazole (0·68; 0·56-0·84; 25%), and cariprazine (0·70; 0·49-0·99; 28%). There were nine antimanic drugs associated with greater efficacy than placebo, including risperidone (reported as standardised mean difference; 95% CI; I2: 0·64; 0·31-0·97; 15%), haloperidol (0·57; 0·29-0·85; 64%), cariprazine (0·51; 0·24-0·78; 0%), olanzapine (0·44; 0·30-0·58; 0%), lithium (0·42; 0·29-0·55; 0%), ziprasidone (0·42; 0·26-0·58; 0%), quetiapine (0·40; 0·13-0·67; 0%), asenapine (0·40; 0·13-0·67; 0%), and aripiprazole (0·32; 0·14-0·49; 53%). Ziprasidone (reported as risk ratio; 95% CI; I2: 0·83; 0·79-0·89; 0%) and olanzapine (0·63; 0·49-0·80; 35%) were associated with better acceptability relative to placebo. Among the 39 RCTs, none had a high ROB. Interpretation: We demonstrated that eight antimanic drugs were associated with lower variability and better efficacy than placebo, suggesting that these antimanic drugs were associated with more homogenous and predictable improvements of manic symptoms in patients with acute mania. Funding: The study was supported by from the Ministry of Science and Technology (MOST-110-2314-B-016-035, MOST-111-2314-B-016-054), Medical Affairs Bureau (MND-MAB-D-111102), and Tri-service General Hospital (TSGH-E-111229).

Summary: Background: There is a lack of consensus on the optimal serum valproic acid (VPA) concentration for maintenance therapy in bipolar disorder (BD). We aimed to investigate the association between serum VPA levels and risk of mood episode recurrence. Methods: We enrolled patients with BD from multiple medical institutions in Taiwan between January 1, 2001 and December 31, 2019. Patients were divided into three groups according to their serum VPA concentrations (< 50 μg/ml, 50–74 μg/ml, and 75–104 μg/ml). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) compared times to mood episode recurrence using the < 50 μg/ml group as reference. A systematic review found relevant articles published before February 2022 (PROSPERO: CRD42022309661), and corresponding results were compared. Findings: This cohort included 896 patients for an intention-to-treat analysis. Compared with the < 50 μg/ml group, a non-significantly lower risk of mood episode recurrence was found in the 50–74 μg/ml (aHR, 95% CI: 0·86, 0·71–1·05) and 75–104 μg/ml (0·91, 0·71–1·18) groups. A per-protocol analysis of 481 patients found a significant risk reduction in the 50–74 μg/ml group (0·76, 0·60–0·97), with inconclusive results in the ≥ 75 μg/ml group (1·03, 0·73–1·46). A meta-analysis including two studies (254 patients) and our cohort found a similar significantly lower risk of mood episode recurrence in the 50–74 μg/ml group (HR, 95% CI: 0·83, 0·69–0·99), while risk reduction in the 75–99 μg/ml group (0·62, 0·26–1·48) did not differ significantly from that in the < 50 μg/ml group or the 50–74 μg/ml group. Interpretation: The combined results of this cohort and previous studies suggest that VPA between 50–74 μg/ml may be a more effective concentration to prevent acute mood episodes during maintenance therapy in patients with BD compared with VPA < 50 μg/ml. Funding: Ministry of Science and Technology, Taiwan, and Chang Gung Medical Research Project.

Tissue clearing for whole organ cell profiling has revolutionized biology and imaging for exploration of organs in three-dimensional space without compromising tissue architecture. But complicated, laborious procedures, or expensive equipment, as well as the use of hazardous, organic solvents prevent the widespread adoption of these methods. Here, we report a simple and rapid tissue clearing method, EZ Clear, that can clear whole adult mouse organs in 48 hr in just three simple steps. Samples stay at room temperature and remain hydrated throughout the clearing process, preserving endogenous and synthetic fluorescence, without altering sample size. After wholemount clearing and imaging, samples processed with EZ Clear can be subjected to downstream applications, such as tissue embedding and cryosectioning followed by standard histology or immunofluorescent staining without loss of fluorescence signal from endogenous or synthetic reporters. Furthermore, we demonstrate that wholemount adult mouse brains processed with EZ Clear can be successfully immunolabeled for fluorescent imaging while still retaining signal from endogenous fluorescent reporters. Overall, the simplicity, speed, and flexibility of EZ Clear make it easy to adapt and implement in diverse imaging modalities in biomedical research.

Background/purpose: In 2017, Long-Fa Temple, an illegal religious asylum in Taiwan, was forced to shut down. Hundreds of chronic mentally ill patients were incarcerated there but provided with no modern psychiatric treatment. This study investigated the effectiveness of providing psychiatric intervention for patients subsequently transferred from Long-Fa Temple to a medical center. Methods: In total, 88 patients (mean age: 57.2 years, 52.3% male) who had been incarcerated at Long-Fa Temple were transferred to a southern medical center. The patients underwent comprehensive biological, psychological, and social treatment for 18 months. The patients were evaluated once a month in terms of their psychotic symptoms, self-care, nutrition status, cognitive function, occupational function, and family function. Results: Regarding the patients' length of stay, 18.2% were incarcerated in Long-Fa Temple for less than 10 years, 21.6% for 10–20 years, and 60.2% for more than 20 years. In terms of psychiatric diagnosis, 98.9% of the patients had been diagnosed with a schizophrenia spectrum disorder. During the 18-month treatment period, negative symptoms decreased significantly, while the patients’ self-care ability, nutrition status, cognition, occupational function, and family function all significantly improved over time. Patients who had been incarcerated for less than 10 years demonstrated better improvements in psychotic symptoms, self-care, nutrition status, and cognitive function. Conclusion: Contemporary psychiatric intervention is beneficial for chronically untreated mentally ill patients, and the patients who had a shorter duration of illness had a better reserve of recovery. These findings can serve as an important reference for psychiatric intervention in developing countries.

Coenzyme Q10 (CoQ10) is a popular nutritional supplement, an antioxidant and an essential component of the mitochondrial electron transport chain. Several clinical studies have suggested that fatigue can be reduced by antioxidant supplementation. However, the data on this topic has been sparse to date. Hence, we conducted this meta-analysis with the aim of investigating the effectiveness of fatigue reduction via CoQ10 supplementation. More specifically, we searched electronic databases for randomized controlled trials (RCTs) published from the database inception to January 2022. A random effects model was implemented to conduct the meta-analysis among 13 RCTs (with a total of 1,126 participants). As compared with the placebo groups evaluated in each RCT, the CoQ10 group showed a statistically significant reduction in fatigue scores (Hedges’ g = −0.398, 95% confidence interval = −0.641 to −0.155, p = 0.001). The directions of the treatment effects were consistent between the healthy and diseased participants. Compared with the placebo group, the effect of reducing fatigue was statistically significant in the subgroup using the CoQ10-only formulation but not in the subgroup using CoQ10 compounds. The results of our meta-regression demonstrate that increases in the daily dose (coefficient = −0.0017 per mg, p < 0.001) and treatment duration (coefficient = −0.0042 per day, p = 0.007) of CoQ10 supplementation were correlated with greater fatigue reduction. There was only one adverse (gastrointestinal) event in the 602 participants who underwent the CoQ10 intervention. Based on the results of this meta-analysis, we conclude that CoQ10 is an effective and safe supplement for reducing fatigue symptoms.Systematic Review Registration:https://inplasy.com/inplasy-2022-1-0113/, identifier INPLASY202210113

Abstract Cryptococcal meningitis (CM) is the most fatal adult meningitis in patients with human immunodeficiency virus (HIV). There is no conclusive evidence for the superiority of 1-week amphotericin B deoxycholate (AmphB) + flucytosine (5-FC) regimen over other antifungals in the management of HIV patients with CM (HIV–CM patients). We aimed to evaluate the differences in efficacy and tolerability of different antifungal agents in HIV–CM patients by conducting a current network meta-analysis NMA. Overall, 19 randomized controlled trials were included with 2642 participants. A regimen indicated a possibly lower early mortality rate, namely, AmphB + 5-FC + Azole (OR = 1.1E−12, 95% CIs = 1.3E−41 to 0.06) comparing to AmphB + 5-FC. The current NMA provides evidence that AmphB + 5-FC + Azole are superior to all the investigated treatments for induction regimen in HIV–CM patients.

Background: Guidelines recommend fluoxetine as a first-line medication for youths diagnosed with major depressive disorder (MDD). However, little is known about the long-term effectiveness of different antidepressants in juveniles in the real world. This study aimed to compare the effectiveness of antidepressants in youths with MDD. Methods: Youths (

Summary: Background: Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD. Methods: An NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100–400 mg), medium (1 g), and high (at least 2 g). Findings: A total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=−1.76 days (95% confidence intervals (95% CIs): −3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18–1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00–0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00–1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07–0.62) in refractory-stage KD. Interpretation: The NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results. Funding: None.

Abstract Timely performing electrocardiography (ECG) is crucial for early detection of ST-elevation myocardial infarction (STEMI). For shortening door-to-ECG time, a chief complaint-based “cardiac triage” protocol comprising (1) raising alert among medical staff with bedside triage tags, and (2) immediate bedside ECG after focused history-taking was implemented at the emergency department (ED) in a single tertiary referral center. All patients diagnosed with STEMI visiting the ED between November 2017 and January 2020 were retrospectively reviewed to investigate the effectiveness of strategy before and after implantation. Analysis of a total of 117 ED patients with STEMI (pre-intervention group, n = 57; post-intervention group, n = 60) showed significant overall improvements in median door-to-ECG time from 5 to 4 min (p = 0.02), achievement rate of door-to-ECG time 10 min for those with initially underestimated disease severity (from 90 to 10%, p

Abstract Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04–10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29–80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04–4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02–11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02–11.65)], oral atenolol [RR = 0.51 (95% CI 0.20–1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03–25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08–10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma. Trial registration: PROSPERO CRD42020190540.

Developing growth techniques for the manufacture of wide band gap III-nitrides semiconductors is important for the further improvement of optoelectronic applications. A plasma-assisted halide phase vapor epitaxy (PA-HVPE) approach is demonstrated for the manufacture of undoped and In-doped GaN layers at ~600 °C. A dielectric barrier discharge (DBD) plasma source is utilized for the low-temperature activation of ammonia. The use of the plasma source at a growth temperature of ~600 °C increases the growth rate from ~1.2 to ~4–5 µm/h. Furthermore, the possibility for the growth of InGaN at ~600 °C has been studied. Precursors of GaCl and InCl/InCl3 are formed in situ in the reactor by flowing HCl gas over a melt of metallic Ga and In, respectively. The In concentration was low, in the order of a few percent, as the incorporation of In is reduced by plasma due to the activation of chlorine-containing species that etch the relatively poorly bonded In atoms. Nevertheless, the approach of using plasma for ammonia activation is a very promising approach to growing epitaxial III-nitrides at low temperatures.

California faces crisis conditions on its forested landscapes. A century of aggressive logging and fire suppression in combination with conditions exacerbated by climate change have created an ongoing ecological, economic, and public health emergency. Between commercial harvests on California’s working forestlands and the increasing number of acres the state treats each year for fire risk reduction and carbon sequestration, California forests generate millions of tons of woody residues annually—residues that are typically left or burned in the field. State policymakers have turned to biomass electricity generation as a key market for woody biomass in the hope that it can support sustainable forest management activities while also providing low-carbon renewable electricity. However, open questions surrounding the climate and air pollution performance of electricity generation from woody biomass have made it difficult to determine how best to manage the risks and opportunities posed by forest residues. The California Biomass Residue Emissions Characterization (C-BREC) model offers a spatially-explicit life cycle assessment framework to rigorously and transparently establish the climate and air pollution impacts of biopower from forest residues in California under current conditions. The C-BREC model characterizes the variable emissions from different biomass supply chains as well as the counterfactual emissions from prescribed burn, wildfire, and decay avoided by residue mobilization. We find that the life cycle ‘carbon footprint’ of biopower from woody residues generated by recent forest treatments in California ranges widely—from comparable with solar photovoltaic on the low end to comparable with natural gas on the high end. This variation stems largely from the heterogeneity in the fire and decay conditions these residues would encounter if left in the field, with utilization of residue that would otherwise have been burned in place offering the best climate and air quality performance. California’s energy and forest management policies should account for this variation to ensure desired climate benefits are achieved.

Abstract Gallium oxide is a promising semiconductor with great potential for efficient power electronics due to its ultra-wide band gap and high breakdown electric field. Optimization of halide vapor phase epitaxy growth of heteroepitaxial $$\upbeta$$ β -Ga2O3 layers is demonstrated using a simulation model to predict the distribution of the ratio of gallium to oxygen precursors inside the reactor chamber. The best structural quality is obtained for layers grown at 825–850 °C and with a III/VI precursor ratio of 0.2. Although the structural and optical properties are similar, the surface morphology is more deteriorated for the $$\upbeta$$ β -Ga2O3 layers grown on 5 degree off-axis sapphire substrates compared to on-axis samples even for optimized process parameters. Cathodoluminescence with a peak at 3.3 eV is typical for unintentionally doped n-type $$\upbeta$$ β -Ga2O3 and shows the appearance of additional emissions in blue and green region at ~ 3.0, ~ 2.8, ~ 2.6 and ~ 2.4 eV, especially when the growth temperatures is lowered to 800–825 °C. Estimation of the band gap energy to ~ 4.65 eV from absorption indicates a high density of vacancy defects.

The main causes for failure in implant surgery are prolonged exposure of implants or wound and tissue ischemia. Bacterial infection caused by the surrounding medical environment and equipment is also a major risk factor. The medical risk would be greatly reduced if we could develop an implant coating to guide tissue growth and promote antibacterial activity. Mesoporous bioactive glasses are mainly silicates with good osteoinductivity and have been used in medical dentistry and orthopedics for several decades. Strontium ions and silver ions could plausibly be incorporated into bioactive glass to achieve the required function. Strontium ions are trace elements in human bone that have been proposed to promote osseointegration and angiogenesis. Silver ions can cause bacterial apoptosis through surface charge imbalance after bonding to the cell membrane. In this study, functional polyelectrolyte multilayer (PEM) coatings were adhered to 316L stainless steel (SS) by spin coating. The multilayer film was composed of biocompatible and biodegradable collagen as a positively charged layer, γ-polyglutamic acid (γ-PGA) as a negatively charged layer. Chitosan was incorporated to the 11th positively charged layer as a stabilizing barrier. Spray pyrolysis prepared mesoporous bioactive glass incorporated with silver and strontium (AgSrMBG) was added to each negatively charged layer. The PEM/AgSrMBG coating was well hydrophilic with a contact angle of 37.09°, hardness of 0.29 ± 0.09 GPa, Young’s modulus of 5.35 ± 1.55 GPa, and roughness of 374.78 ± 22.27 nm, as observed through nano-indention and white light interferometry. The coating’s antibacterial activity was sustained for 1 month through the inhibition zone test, and was biocompatible with rat bone marrow mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs), as observed in the MTT assay. There was more hydroxyapatite precipitation on the PEM/AgSrMBG surface after being soaked in simulated body fluid (SBF), as observed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). In both in vitro and in vivo tests, the PEM/AgSrMBG coating promoted angiogenesis, osseointegration, and antibacterial activity due to the sustained release of silver and strontium ions.

Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Background: Allergic diseases are frequently observed in children with Kawasaki disease (KD). However, the evidence supporting the association between KD and allergies has been conflicting. The objective of the current study is to examine the association between KD and allergic diseases.Methods: We conducted an electronic search using PubMed, Embase, and the Cochrane through 24 July 2021. The inclusion criteria consisted of studies that examined the prevalence of allergic diseases in children with a previous diagnosis of KD and in a comparison group. We pooled studies by using a random effects model. The effects of KD on the subsequent risk of allergic diseases were expressed as odds ratio (OR) with 95% confidence intervals (CI).Results: We included a total of four studies that assessed the effect of KD on asthma, allergic rhinitis, and atopic dermatitis vs. non-KD children (KD individuals for asthma, four studies, n = 8,474; allergic rhinitis, four studies, n = 8,474; atopic dermatitis, three studies, n = 8,330). The overall prevalence of asthma, allergic rhinitis, and atopic dermatitis was 9.12, 27.63, and 6.55% among patients with previous KD. The meta-analysis showed a significantly increased risk of asthma (OR:1.437, CI: 1.067–1.937) and allergic rhinitis (OR: 1.726, CI: 1.291–2.307) in patients with KD, compared with the control groups. However, patients with KD did not have a significantly different level of risk of atopic dermatitis (OR: 1.243, 95% CI: 0.857–1.802).Conclusion: This meta-analysis supports that individuals with KD are more likely to have asthma and allergic rhinitis compared to controls.

The development of growth processes for the synthesis of high-quality epitaxial layers is one of the requirements for utilizing the ultrawide band gap semiconductor Ga2O3 for high-voltage, high-power electronics. A halide vapor phase epitaxy (HVPE) process used to grow β-Ga2O3 layer was optimized by modifying the gas inlet, resulting in improved growth uniformity. A conventional tube acting as an inlet for the Ga precursor GaCl gas was replaced with a shower head with four outlets at 45 degrees to the horizontal axis of the reactor. The modification was performed based on numerical calculations of the three-dimensional distribution of gases inside the growth chamber with different designs of the GaCl precursor inlet. It was shown that variation in the Ga/O ratio over the substrate holder was ~10% for a shower head compared with ~40% for a tube. In addition, growth with a tube leads to the film thickness varying by a factor of ~4 depending on the position on the holder, whereas when using a shower head, the thickness of the grown Ga2O3 layers became much more uniform with a total spread of just ~30% over the entire substrate holder.

Despite acceptance of the surgical pleth index (SPI) for monitoring the intraoperative balance between noxious stimulation and anti-nociception under general anesthesia, its efficacy for predicting postoperative moderate-to-severe pain remains unclear. We searched electronic databases (e.g., Google Scholar, MEDLINE, Cochrane Library, and EMBASE) to identify articles focusing on associations of SPI at the end of surgery with immediate moderate-to-severe pain in the postanesthesia care unit from inception to 7 July 2022. A total of six observational studies involving 756 adults published between 2016 and 2020 were eligible for quantitative syntheses. Pooled results revealed higher values of SPI in patients with moderate-to-severe pain than those without (mean difference: 7.82, 95% CI: 3.69 to 11.95, p = 0.002, I2 = 46%). In addition, an elevated SPI at the end of surgery was able to predict moderate-to-severe pain with a sensitivity of 0.71 (95% confidence interval (CI): 0.65–0.77; I2 = 29.01%) and a specificity of 0.58 (95% CI: 0.39–0.74; I2 = 79.31%). The overall accuracy based on the summary receiver operating characteristic (sROC) curve was 0.72. In conclusion, this meta-analysis highlighted the feasibility of the surgical pleth index to predict postoperative moderate-to-severe pain immediately after surgery. Our results from a limited number of studies warrant further investigations for verification.

Background: Patients with end-stage kidney disease (ESKD), have been associated with higher risk of developing depression. Erythropoietin (EPO), frequently used for the treatment of anemia in ESKD patients, has been shown to have neuroprotective and antidepressant effects. In this study, we examined whether EPO treatment changed the risk of depression in ESKD patients. Methods: In a nationwide population-based cohort in Taiwan from 1998 to 2013, patients with a diagnosis of ESKD on maintenance dialysis and aged greater than 18 years were classified into EPO treatment group or non-EPO treatment group. All patients were followed up until the diagnosis of depressive disorder or the end of the study period. Results: In this cohort (13,067 patients in the EPO and 67,258 patients in the non-EPO group), 5569 patients were diagnosed as depressive disorder in the follow-up period. We found the risk of depression in EPO group was not significantly different from that in non-EPO group (adjusted hazard ratio = 0.98, 95% confidence interval 0.92–1.04, p = 0.499) after adjusting for sex, age, certification year of catastrophic illness for ESKD, physical co-morbidities, and use of benzodiazepines. Conclusion: In summary, using the nationwide reimbursement data in Taiwan, we found that EPO treatment in ESKD patients was not associated with their general risk of developing depression.

We examined the cardiovascular safety, acceptability, and trajectory of the antidepressant effects of psilocybin after single- or two-dose administration. Four major electronic databases were systematically searched. Data were pooled using a multivariate random-effects meta-analysis. Primary outcomes were changes in depressive symptoms. Secondary outcomes were cardiovascular safety and acceptability. Ten studies were included. The estimated effect sizes (standardized mean difference (SMD) with 95% confidence intervals) for psilocybin were −0.75 (−1.15 to −0.35) on day 1, −1.74 (−2.15 to −1.32) at 1 week, −1.35 (−1.77 to −0.93) at 1 month, −0.91 (−1.31 to −0.51) at 3 months, and −1.12 (−1.56 to −0.68) at 6 months. Higher doses and two sessions of psilocybin treatment were significantly associated with superior antidepressant effects. The all-cause discontinuation and heart rate after psilocybin administration were comparable to placebo; meanwhile, psilocybin increased systolic and diastolic blood pressure by 19.00 mmHg and 8.66 mmHg, respectively. There were no significant differences between SMD derived from placebo-controlled trials compared to those from pre–post changes and SMD in randomized controlled trials (RCTs) compared to those in non-RCTs. The present study demonstrates that single- or two-dose psilocybin administration has rapid and sustained antidepressant effects for up to 6 months, with favorable cardiovascular safety and acceptability.

Copyright © 2020 Harris. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Curcumin is a polyphenol with strong antioxidant and anti-inflammatory effects that has been shown to be effective in ameliorating cognitive decline in animal studies. However, its clinical effectiveness is inconclusive, and relevant gastrointestinal adverse events (AEs) have been reported. The aim of this meta-analysis was to summarize the existing evidence from randomized controlled trials (RCTs) of effects of curcumin on overall cognitive function, individual cognitive domains, and gastrointestinal AE. The study includes 8 RCTs and 389 participants. A random-effects model was used for the meta-analysis. Compared with the placebo group, the curcumin group was associated with an improvement in working memory (Hedges’ g = 0.396, 95% confidence interval (CI) = 0.078 to 0.714, p = 0.015) and a borderline benefit in processing speed (Hedges’ g = 0.303, 95% CI = −0.013 to 0.619, p = 0.06). In the domains of language, episodic memory/visual learning, verbal memory, cognitive flexibility/problem solving, and overall cognitive function, no significant difference existed for the comparison between the curcumin and placebo groups. The curcumin group had a significantly higher risk of gastrointestinal AEs than the placebo group (odds ratio = 3.019, 95% CI = 1.118 to 8.150, p = 0.029). In the future, the effects of curcumin on working memory, processing speed, and gastrointestinal AE should be further investigated.

Routine monitoring of lithium levels is common clinical practice. This is because the lithium prediction strategies available developed by previous studies are still limited due to insufficient prediction performance. Thus, we used machine learning approaches to predict lithium concentration in a large real-world dataset. Real-world data from multicenter electronic medical records were used in different machine learning algorithms to predict: (1) whether the serum level was 0.6–1.2 mmol/L or 0.0–0.6 mmol/L (binary prediction), and (2) its concentration value (continuous prediction). We developed models from 1505 samples through 5-fold cross-validation and used 204 independent samples to test their performance by evaluating their accuracy. Moreover, we ranked the most important clinical features in different models and reconstructed three reduced models with fewer clinical features. For binary and continuous predictions, the average accuracy of these models was 0.70–0.73 and 0.68–0.75, respectively. Seven features were listed as important features related to serum lithium levels of 0.6–1.2 mmol/L or higher lithium concentration, namely older age, lower systolic blood pressure, higher daily and last doses of lithium prescription, concomitant psychotropic drugs with valproic acid and -pine drugs, and comorbid substance-related disorders. After reducing the features in the three new predictive models, the binary or continuous models still had an average accuracy of 0.67–0.74. Machine learning processes complex clinical data and provides a potential tool for predicting lithium concentration. This may help in clinical decision-making and reduce the frequency of serum level monitoring.

Personality disorders (PDs) are grouped into clusters A, B, and C. However, whether the three clusters of PDs have differences in comorbid mental disorders or gender distribution is still lacking sufficient evidence. We aim to investigate the distribution pattern across the three clusters of PDs with a population-based cohort study. This study used the Taiwan national database between 1995 and 2013 to examine the data of patients with cluster A PDs, cluster B PDs, or cluster C PDs. We compared the differences of psychiatric comorbidities classified in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition across the three clusters of PDs. Moreover, we formed gender subgroups of the three PDs to observe the discrepancy between male and female. Among the 9845 patients, those with cluster A PDs had the highest proportion of neurodevelopmental disorders, schizophrenia and neurocognitive disorders, those with cluster B PDs demonstrated the largest percentage of bipolar disorders, trauma and stressor disorders, feeding and eating disorders, and substance and addictive disorders, and those with cluster C PDs had the greatest proportion of depressive disorders, anxiety disorders, obsessive–compulsive disorders, somatic symptom disorders, and sleep–wake disorders. The gender subgroups revealed significant male predominance in neurodevelopmental disorders and female predominance in sleep–wake disorders across all three clusters of PDs. Our findings support that some psychiatric comorbidities are more prevalent in specified cluster PDs and that gender differences exist across the three clusters of PDs. These results are an important reference for clinicians who are developing services that target real-world patients with PDs.

The application of transcranial direct current stimulation (tDCS) to targeted cortices has been found to improve in skill acquisition; however, these beneficial effects remained unclear in fine and complicated skill. The aim of the current meta-analysis was to investigate the association between tDCS application and the efficacy of surgical performance during surgical skill training. We included randomized controlled trials (RCTs) investigating the efficacy of tDCS in enhancing surgical skill acquisition. This meta-analysis was conducted under a random-effect model. Six RCTs with 198 participants were included. The main result revealed that tDCS was associated with significantly better improvement in surgical performance than the sham control (Hedges’ g = 0.659, 95% confidence intervals (95%CIs) = 0.383 to 0.935, p < 0.001). The subgroups of tDCS over the bilateral prefrontal cortex (Hedges’ g = 0.900, 95%CIs = 0.419 to 1.382, p < 0.001) and the primary motor cortex (Hedges’ g = 0.599, 95%CIs = 0.245 to 0.953, p = 0.001) were both associated with significantly better improvements in surgical performance. The tDCS application was not associated with significant differences in error scores or rates of local discomfort compared with a sham control. This meta-analysis supported the rationale for the tDCS application in surgical training programs to improve surgical skill acquisition.

Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neurodevelopmental disorder, and its dysregulation of gene expression involves microRNAs (miRNAs). The purpose of this study was to identify potential miRNAs biomarkers and then use these biomarkers to establish a diagnostic panel for ADHD.Design and methods: RNA samples from white blood cells (WBCs) of five ADHD patients and five healthy controls were combined to create one pooled patient library and one control library. We identified 20 candidate miRNAs with the next-generation sequencing (NGS) technique (Illumina). Blood samples were then collected from a Training Set (68 patients and 54 controls) and a Testing Set (20 patients and 20 controls) to identify the expression profiles of these miRNAs with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate both the specificity and sensitivity of the probability score yielded by the support vector machine (SVM) model.Results: We identified 13 miRNAs as potential ADHD biomarkers. The ΔCt values of these miRNAs in the Training Set were integrated to create a biomarker model using the SVM algorithm, which demonstrated good validity in differentiating ADHD patients from control subjects (sensitivity: 86.8%, specificity: 88.9%, AUC: 0.94, p < 0.001). The results of the blind testing showed that 85% of the subjects in the Testing Set were correctly classified using the SVM model alignment (AUC: 0.91, p < 0.001). The discriminative validity is not influenced by patients' age or gender, indicating both the robustness and the reliability of the SVM classification model.Conclusion: As measured in peripheral blood, miRNA-based biomarkers can aid in the differentiation of ADHD in clinical settings. Additional studies are needed in the future to clarify the ADHD-associated gene functions and biological mechanisms modulated by miRNAs.

In the original published version of the article, Valerie Vancollie was mistakenly omitted from the list of members of the International Mouse Phenotyping Consortium. In addition, recognition of funding from Wellcome Trust grant WT098051 was mistakenly omitted from the Acknowledgements.The errors have been corrected in both the PDF and HTML versions of the paper.

This paper investigates and compares the impacts of metal-gate work-function variation (WFV) on III-V heterojunction tunnel FET (HTFET), homojunction TFET, and FinFET devices using a novel Voronoi method to capture the realistic metal-gate grain patterns for Technology Computer Aided Design atomistic simulations. Due to the broken-gap nature, HTFET shows significantly steeper subthreshold slope and higher susceptibility to WFV near OFF state. For ON current variation, both the HTFET and homojunction TFET show better immunity to WFV than the III-V FinFET. Device design using source-side underlap to mitigate the impact of WFV on HTFET is also assessed.