Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis.

AIM: Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19. METHODS: We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events. RESULTS: The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. CONCLUSION: These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Usefulness of Analgesia Nociception Index for guiding intraoperative opioid administration: a systematic review and meta-analysis.

INTRODUCTION: This study primarily aimed at investigating the efficacy of Analgesia Nociception Index (ANI) for guiding intraoperative opioid administration in patients receiving surgery under general anesthesia. EVIDENCE ACQUISITION: The Medline, Embase, Google scholar, and the Cochrane Library databases were searched from inception to April 2022 for randomized controlled trials. The primary outcome was intraoperative opioid administration, while the secondary outcomes included postoperative opioid consumption, pain score, emergency time, risk of nausea/vomiting (PONV), and Postanesthesia Care Unit (PACU) stay. EVIDENCE SYNTHESIS: Six studies including 399 participants (published from 2015 to 2022) focused on non-cardiac surgery, including spine surgery (two trials), breast surgery (two trials), gynecologic surgery (one trial), and laparoscopic cholecystectomy (one trial) were included. Meta-analysis revealed no difference in intraoperative opioid administration with the use of ANI-guided analgesia compared to the control group that used conventional clinical measurements (e.g., heart rate) to guide opioid use [standardized mean difference (SMD)=-0.17, 95% CI: -0.56 to 0.22, P=0.39, I2=72%, six trials, 399 participants]. Gender-based subgroup analysis showed effectiveness of ANI for reducing opioid administration in female patients (SMD=-0.53, P=0.02). There were no differences in postoperative recovery characteristics including pain score [Mean difference (MD): -0.03, P=0.79], opioid consumption (SMD: -0.34, P=0.08), emergence time (MD=1.12, P=0.47), length of stay in the PACU (MD: -0.56, P=0.83), and risk of PONV [risk ratio(RR): 0.75, P=0.46] between the two groups. CONCLUSIONS: Analgesia nociception index-guided analgesia was unable to reduce intraoperative opioid administration compared to monitoring using conventional clinical parameters. Further studies are required to support our findings.

Cancer related fatigue-light therapy: updated meta-analysis of randomised controlled trials.

BACKGROUND: Moderate-to-severe cancer related fatigue occurs in 45% of patients with cancer and interferes with many aspects of quality of life. Although physical exercise has level 1 evidence for improvement of cancer related fatigue, it has a relatively high behavioural demand compared with other non-pharmacological interventions. The aim of this updated meta-analysis was to address the efficacy of light therapy in improving cancer related fatigue in patients with cancer. METHODS: We included randomised controlled trials investigating the efficacy of bright white light (BWL) therapy in ameliorating cancer related fatigue in patients with cancer. This meta-analysis was conducted using a random-effects model. The target outcomes were changes in cancer related fatigue associated with BWL or dim red light (DRL). RESULTS: There were 9 articles with 231 participants included. The main results revealed that daily morning BWL for 30 min was associated with significantly better improvement in fatigue severity compared with DRL (k=5, Hedges' g=-0.414, 95% CI -0.740 to -0.087, p=0.013). The subgroup without psychiatric comorbidities (k=4, Hedges' g=-0.479, 95% CI -0.801 to -0.156, p=0.004) was associated with significantly better improvement in fatigue severity with BWL than with DRL. In contrary, BWL was not associated with significantly different changes in depression severity or quality of life compared with DRL. Finally, BWL was associated with similar acceptability (ie, dropout rate) and safety profile (ie, any discomfort) as those of DRL. CONCLUSIONS: This meta-analysis provides an updated evidence on the rationale for application of BWL in ameliorating cancer related fatigue in patients with different types of cancer. TRIAL REGISTRATION NUMBER: INPLASY202140090.

EZ Clear for simple, rapid, and robust mouse whole organ clearing.

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.

Efficacy of laryngeal mask airway against postoperative pharyngolaryngeal complications following thyroid surgery: a systematic review and meta-analysis of randomized controlled studies.

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 < 0.05). Nevertheless, hoarseness severity was lower in the LMA group only at postsurgical 48 h [standardized mean difference = - 0.35, p = 0.008, three trials]. Moreover, the risk of emergence cough was lower in patients using LMA than those receiving ETT (RR = 0.14, p = 0.002, two trials). The two groups did not differ in the severity of dysphagia at postoperative 1 h, 24 h, and 48 h. This meta-analysis showed that LMA may be associated with fewer pharyngolaryngeal complications compared to ETT without airway impacts. The limited number of included studies warrants further research to support our findings.

Elevated Surgical Pleth Index at the End of Surgery Is Associated with Postoperative Moderate-to-Severe Pain: A Systematic Review and Meta-Analysis.

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.

Association of peripheral nerve blocks with patient-reported quality of recovery in female patients receiving breast cancer surgery: a systematic review and meta-analysis of randomized controlled studies.

PURPOSE: This systematic review and meta-analysis investigated the impact of peripheral nerve blocks (PNBs) on patient-reported quality of recovery (QoR) following breast cancer surgery. SOURCE: Medline, EMBASE, Cochrane Library, and Google scholar databases were searched for randomized controlled trials (RCTs) comparing the QoR with or without PNBs in patients receiving breast cancer surgery from inception to September 2021. Using a random effects model, the primary outcome was total scores of postoperative QoR scales (i.e., QoR-15 and QoR-40). PRINCIPAL FINDINGS: Eight RCTs (QoR-15, n = 4; QoR-40, n = 4) involving 653 patients published from 2018 to 2021 were included. For the QoR-40 scale, pooled results revealed a significantly higher total score (mean difference [MD], 12.8 [8.2%]; 95% confidence interval [CI], 10.6 to 14.9; I2 = 59%; five RCTs; n = 251) and scores on all subscales, except psychological support, in the PNB group than in controls at 24 hr after surgery. For the QoR-15 scale, pooled results also showed favorable QoR (MD, 7.7 [5.2%]; 95% CI, 4.9 to 10.5; I2 = 75%; four RCTs; n = 402) in the PNB group at 24 hr after surgery. Sensitivity analysis showed no effect on the QoR-40 score and the difference in total QoR-15 score was no longer significant when a single trial was omitted. The use of PNBs was associated with a significantly lower opioid consumption and risk of postoperative nausea and vomiting without significant differences in the pain score between the two groups. CONCLUSION: Our results verified the efficacy of PNBs for enhancing postoperative QoR using two validated patient-reported tools in female patients receiving breast cancer surgery under general anesthesia. STUDY REGISTRATION: PROSPERO (CRD42021272575); first submitted 9 August 2021.

RéSUMé: OBJECTIF: Cette revue systématique et méta-analyse a étudié l'impact des blocs nerveux périphériques (BNP) sur la qualité de récupération (QoR) rapportée par les patientes après une chirurgie du cancer du sein. SOURCES: Les bases de données Medline, EMBASE, Cochrane Library et Google Scholar ont été analysées pour en tirer les études randomisées contrôlées (ERC) comparant la QoR avec ou sans BNP chez les patientes bénéficiant d'une chirurgie de cancer du sein, de leur création jusqu'en septembre 2021. À l'aide d'un modèle à effets aléatoires, le critère d'évaluation principal était les scores totaux sur les échelles de QoR postopératoire (c.-à-d. QoR-15 et QoR-40). CONSTATATIONS PRINCIPALES: Huit ERC (QoR-15, n = 4; QoR-40, n = 4) impliquant 653 patientes publiées de 2018 à 2021 ont été incluses. Pour l'échelle QoR-40, les résultats regroupés ont révélé un score total (différence moyenne [DM], 12,8 [8,2 %]; intervalle de confiance [IC] à 95 %, 10,6 à 14,9; I2 = 59 %; cinq ECR; n = 251) et des scores sur toutes les sous-échelles significativement plus élevés, à l'exception du soutien psychologique, dans le groupe BNP que dans le groupe témoin 24 heures après la chirurgie. Pour l'échelle QoR-15, les résultats groupés ont également montré un QoR favorable (DM, 7,7 [5,2 %]; IC 95 %, 4,9 à 10,5; I2 = 75 %; quatre ECR; n = 402) dans le groupe BNP 24 heures après la chirurgie. L'analyse de sensibilité n'a montré aucun effet sur le score de QoR-40 et la différence dans le score total de QoR-15 n'était plus significative lorsqu'une seule étude était omise. L'utilisation de BNP a été associée à une consommation d'opioïdes significativement plus faible et à un risque de nausées et vomissements postopératoires sans différences significatives dans le score de douleur entre les deux groupes. CONCLUSION: Nos résultats ont confirmé l'efficacité des BNP pour améliorer la QoR postopératoire à l'aide de deux outils validés rapportés par les patientes recevant une chirurgie du cancer du sein sous anesthésie générale. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021272575); soumis pour la première fois le 9 août 2021.

Impact of Opioid-Free Anesthesia on Analgesia and Recovery Following Bariatric Surgery: a Meta-Analysis of Randomized Controlled Studies.

This meta-analysis aimed at exploring the impact of opioid-free anesthesia (OFA) on pain score and opioid consumption in patients undergoing bariatric surgery (BS). Literature search identified eight eligible trials. Forest plot revealed a significantly lower pain score (mean difference (MD) = - 0.96, p = 0.0002; 318 patients), but not morphine consumption (MD = - 5.85 mg, p = 0.1; 318 patients) at postoperative 24 h in patients with OFA than in those without. Pooled analysis also showed a lower pain score (p = 0.002), morphine consumption (p = 0.0003) in the postanesthetic care unit, and risk of postoperative nausea/vomiting (p = 0.0003) in the OFA group compared to the controls. In conclusion, this meta-analysis demonstrated that opioid-free anesthesia improved pain outcomes immediately and at 24 h after surgery without a beneficial impact on opioid consumption at postoperative 24 h. KEY POINTS: • Roles of opioid-free anesthesia (OFA) in bariatric surgery (BS) were investigated. • Outcomes included postoperative pain score, opioid use, and nausea/vomiting risk. • OFA was associated with lower 24-h pain score but not opioid consumption. • Lower pain score and opioid consumption were noted in the postanesthetic care unit. • OFA correlated with a lower risk of postoperative nausea/vomiting.

Analgesic Efficacy of Gabapentin and Pregabalin in Patients Undergoing Laparoscopic Bariatric Surgeries: a Systematic Review and Meta-analysis.

This meta-analysis investigated the effect of oral gabapentinoids (i.e., pregabalin and gabapentin) on analgesic consumption (i.e., primary outcome) and pain relief (i.e., secondary outcome) in patients following bariatric surgery. Analysis of five eligible trials published between 2010 and 2019 including 363 participants receiving gabapentinoids revealed a significantly lower morphine consumption [mean difference (MD) = - 15.1 mg, p = 0.004; evidence certainty: low] and risk of nausea/vomiting [risk ratio (RR) = 0.49, p = 0.002; evidence certainty: high] at postoperative 6-24 h. There was also a lower pain score at postoperative 0-4 h (MD = - 1.41, p < 0.00001; evidence certainty: low) and 6-12 h (MD = - 0.9, p = 0.007; evidence certainty: low) compared with controls, while pain severity at postoperative 24 h was comparable between two groups. In summary, preoperative oral gabapentinoids optimized postoperative pain outcomes and reduced risk of nausea/vomiting following bariatric surgery.

Angiogenesis, Osseointegration, and Antibacterial Applications of Polyelectrolyte Multilayer Coatings Incorporated With Silver/Strontium Containing Mesoporous Bioactive Glass on 316L Stainless Steel.

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.

Extracorporeal Shock Wave Therapy Shows Superiority Over Injections for Pain Relief and Grip Strength Recovery in Lateral Epicondylitis: A Systematic Review and Network Meta-analysis.

PURPOSE: To examine the efficacy of extracorporeal shock wave therapy (ESWT) and injection therapies by synthesizing direct and indirect evidence for all pairs of competing therapies for lateral epicondylitis. METHODS: PubMed, EMBASE, and Web of Science databases were searched for all appropriate randomized controlled trials (RCTs), assessing the effect of ESWT or injection therapies. The primary outcome was short-term (≤3 months) and medium-term (>3 months but ≤12 months) pain, while the secondary outcomes were grip strength and patient-reported outcome measures. All outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs) and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities to determine a hierarchy of treatments. Sensitivity analysis was performed to eliminate potential therapeutic effects of normal saline (NS) and exclude trials that included patients with acute lateral epicondylitis (LE). RESULTS: 40 RCTs were included to evaluate ESWT and five different injection therapies, including corticosteroids (CSs), autologous whole blood, platelet-rich plasma (PRP), botulinum toxin A (BoNT-A), and dextrose prolotherapy (DPT). DPT (-.78 [-1.34 to -.21]), ESWT (.57 [-.89 to -.25]), PRP (-.48 [-.85 to -.11]), and BoNT-A (-.43 [-.84 to -.02]) outperformed placebo for short-term pain relief; ESWT (-.44 [-.85 to -.04]) outperformed placebo for medium-term pain relief. DPT was ranked as the most optimal short-term and medium-term pain reliever (SUCRA, 87.3% and 98.6%, respectively). ESWT was ranked as the most optimal short-term and medium-term grip strength recovery (SUCRA; 79.4% and 86.4%, respectively). CONCLUSIONS: DPT and ESWT were the best two treatment options for pain control and ESWT was the best treatment option for grip strength recovery. CSs were not recommended for the treatment of LE. More evidence is required to confirm the superiority in pain control of DPT among all these treatment options on LE. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I randomized controlled trials.

Efficacy of non-invasive brain stimulation interventions in reducing smoking frequency in patients with nicotine dependence: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Nicotine is a highly addictive substance in tobacco products that dysregulates several neurotransmitters in the brain and impairs executive function. Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising treatments for nicotine dependence. We investigated the efficacy and acceptability of NIBS in managing smoking cessation through a systematic review and network meta-analysis (NMA). METHODS: We conducted a systematic review to identify randomized controlled trials (RCTs) that investigated the efficacy of NIBS for smoking cessation. All pairwise meta-analyses and NMA procedures were conducted using random-effects and frequentist models. The co-primary outcomes were (1) the change in number of cigarettes smoked per day (change in frequency of smoking) in patients with nicotine dependence after NIBS and (2) acceptability (the dropout rate). The effect sizes for co-primary outcomes of change in frequency of smoking and acceptability were assessed according to standardized mean difference (SMD) and odds ratio, respectively. RESULTS: Twelve RCTs with 710 participants (mean age: 44.2 years, 31.2% female) were included. Compared with the sham control, 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) was associated with the largest changes in smoking frequency [SMD = -1.22, 95% confidence interval (95% CI) = -1.77 to -0.66]. The 2-mA bifrontal tDCS (SMD = -0.97, 95% CI = -1.32 to -0.62) and 10-Hz deep rTMS over the bilateral DLPFC with cue provocation (SMD = -0.77, 95% CI = -1.20 to -0.34) were associated with a significantly larger decrease in smoking frequency versus the sham. None of the investigated NIBSs was associated with dropout rates significantly different from those of the sham control groups. CONCLUSION: Prefrontal non-invasive brain stimulation interventions appear to reduce the number of cigarettes smoked with good acceptability.

Association of preoperative prognostic nutritional index with risk of postoperative delirium: A systematic review and meta-analysis.

Study objective: To assess the association between prognostic nutritional index (PNI) and risk of postoperative delirium (POD) in adult patients. Methods: MEDLINE, 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. Results: Analysis 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, I 2 = 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, I 2 = 71%) and Model 3 (OR: 1.68, 95% CI: 1.26-2.23, p < 0.0001, I 2 = 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. Conclusion: Our results demonstrated a negative association between PNI and POD, which warrant further large-scale studies for validation. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022323809.

The Effect of Curcumin Differs on Individual Cognitive Domains across Different Patient Populations: A Systematic Review and Meta-Analysis.

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.

Psilocybin for End-of-Life Anxiety Symptoms: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically examine the effectiveness and tolerability of psilocybin for treating end-of-life anxiety symptoms. METHODS: The Medline, Embase, CENTRAL, and PsycINFO databases were searched up to November 25, 2020. We enrolled clinical trials investigating psilocybin for treating end-of-life anxiety symptoms. Meta-analysis was conducted using random-effects model. RESULTS: Overall, five studies were included, revealing that psilocybin was superior to the placebo in treating state anxiety at 1 day (Hedges' g, -0.70; 95% confidence interval, -1.01 to -0.39) and 2 weeks (-1.03; -1.47 to -0.60) after treatment. Psilocybin was more effective than placebo in treating trait anxiety at 1 day (-0.71; -1.15 to -0.26), 2 weeks (-1.08; -1.80 to -0.36), and 6 months (-0.84; -1.37 to -0.30) after treatment. Psilocybin was associated with transient elevation in systolic (19.00; 13.58-24.41 mm Hg) and diastolic (8.66; 5.18-12.15 mm Hg) blood pressure compared with placebo. The differences between psilocybin and placebo groups with regard to allcause discontinuation, serious adverse events, and heart rates were nonsignificant. CONCLUSION: Psilocybin-assisted therapy could ameliorate end-of-life anxiety symptoms without serious adverse events. Because of the small sample sizes of the included studies and high heterogeneity on long-term outcomes, future randomized controlled trials with large sample sizes are needed.

Prevalence and Outcomes of Major Psychiatric Disorders Preceding Index Surgery for Degenerative Thoracic/Lumbar Spine Disease.

The relationship between preexisting major psychiatric disorders and outcomes of spine surgery for degenerative thoracic/lumbar disease remains unclear. A 5% subset of inpatients was randomly selected from the Taiwan National Health Insurance Research Database. A total of 10,109 inpatients aged 18 years or over with degenerative thoracic/lumbar disease and underwent spine surgery met inclusion criteria. Major psychiatric disorders diagnosed by psychiatrists preceding index surgery, including anxiety disorder, depression disorder, bipolar disorder, schizophrenia and dementia, were identified. The prevalence of psychiatric disorders, and their differential risks on in-hospital and post-discharge outcomes were examined. 10.4% had major psychiatric disorders, of which depression (6.6%) and anxiety (4.9%) were most common. Logistic regression revealed increased risks of ventilator use in depression (OR = 1.62, 95% CI = 1.04-2.54, p < 0.05), extended hospitalization length in bipolar (OR = 1.77, 95% CI = 1.08-2.89, p < 0.05), and higher rehabilitation utilization in depression (OR = 1.25, 95% CI = 1.06-1.47, p < 0.01) and bipolar (OR = 1.69, 95% CI = 1.04-2.76, p < 0.05). Those patients with anxiety had a decreased risk of longer hospitalization duration (OR = 0.77, 95% CI = 0.60-0.98, p < 0.05), while those with dementia and schizophrenia had no change in risks. Preoperative recognition of major psychiatric disorders for risk and treatment assessment is suggested as people with preexisting depression or bipolar disorder have worse outcomes after spine surgery.

Efficacy of induction regimens for cryptococcal meningitis in HIV-infected adults: a systematic review and network meta-analysis.

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.

Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type.

Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Here, we report the generation and characterization of two new mouse models to study the role of MMACHC in vivo. CRISPR/Cas9 genome editing was used to develop a Mmachc floxed allele (Mmachcflox/flox), which we validated as a conditional null. For a gain-of-function approach, we generated a transgenic mouse line that over-expresses functional Mmachc (Mmachc-OE+/tg) capable of rescuing Mmachc homozygous mutant lethality. Surprisingly, our data also suggest that these mice may exhibit a partially penetrant maternal-effect rescue, which might have implications for in utero therapeutic interventions to treat cblC. Both the Mmachcflox/flox and Mmachc-OE+/tg mouse models will be valuable resources for understanding the biological roles of MMACHC in a variety of tissue contexts and allow for deeper understanding of the pathophysiology of cblC.