High-Frequency Spinal Stimulation Suppresses Microglial Kaiso-P2X7 Receptor Axis-Induced Inflammation to Alleviate Neuropathic Pain in Rats.

OBJECTIVE: Neuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last-resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high-frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings. METHODS: We established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single-cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS-mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments. RESULTS: We found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso-P2X7R pathological axis in microglia, promoting long-lasting pain relief. Targeting Kaiso-P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long-lasting pain relief. INTERPRETATION: HF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso-P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024;95:966-983.

Impact of COVID-19 pandemic on hepatocellular carcinoma surveillance in British Columbia, Canada: An interrupted time series study.

We assessed the impact of the COVID-19 pandemic on hepatocellular carcinoma (HCC) surveillance among individuals with HCV diagnosed with cirrhosis in British Columbia (BC), Canada. We used data from the British Columbia Hepatitis Testers Cohort (BC-HTC), including all individuals in the province tested for or diagnosed with HCV from 1 January 1990 to 31 December 2015, to assess HCC surveillance. To analyse the impact of the pandemic on HCC surveillance, we used pre-policy (January 2018 to February 2020) and post-policy (March to December 2020) periods. We conducted interrupted time series (ITS) analysis using a segmented linear regression model and included first-order autocorrelation terms. From January 2018 to December 2020, 6546 HCC screenings were performed among 3429 individuals with HCV and cirrhosis. The ITS model showed an immediate decrease in HCC screenings in March and April 2020, with an overall level change of -71 screenings [95% confidence interval (CI): -105.9, -18.9]. We observed a significant decrease in HCC surveillance among study participants, regardless of HCV treatment status and age group, with the sharpest decrease among untreated HCV patients. A recovery of HCC surveillance followed this decline, reflected in an increasing trend of 7.8 screenings (95% CI: 0.6, 13.5) per month during the post-policy period. There was no level or trend change in the number of individuals diagnosed with HCC. We observed a sharp decline in HCC surveillance among people living with HCV and cirrhosis in BC following the COVID-19 pandemic control measures. HCC screening returned to pre-pandemic levels by mid-2020.

Addition of liposomal bupivacaine to standard bupivacaine versus standard bupivacaine alone in the supraclavicular brachial plexus block: a randomized controlled trial.

BACKGROUND: The analgesic effect of adding liposomal bupivacaine to standard bupivacaine in supraclavicular brachial plexus block is not known. We hypothesized that addition of liposomal bupivacaine would reduce acute postoperative pain compared to standard bupivacaine alone. METHODS: A randomized controlled trial was conducted. Patients and outcome assessors were blinded. Eighty patients undergoing distal radial fracture fixation under regional anesthesia with supraclavicular brachial plexus block were randomized into two groups. The liposomal bupivacaine (LB-BPB) group received 10ml of 0.5% plain bupivacaine immediately followed by 10ml of 1.33% liposomal bupivacaine (n=40). The standard bupivacaine (S-BPB) group received 20ml of 0.5% plain bupivacaine (n=40). The primary outcome was weighted area under curve (AUC) numerical rating scale (NRS) pain score at rest over the first 48 hours after surgery. Secondary outcomes included AUC scores for pain with movement, overall benefit with analgesia score (OBAS) and other functional scores. RESULTS: For the primary outcome, LB-BPB group was associated with statistically significantly lower AUC pain score at rest (0.6 vs 1.4, p-value < 0.001) in the first 48 hours. Of the secondary outcomes, no difference between treatment groups reached statistical significance with the exception of AUC score for pain with movement (2.3 vs 3.7, adjusted p-value < 0.001) and OBAS (1.1 vs 1.7, adjusted p-value = 0.020) in the first 48 hours, as well as NRS pain score at rest (0.5 vs 1.9, adjusted p-value < 0.001) and with movement (2.7 vs 4.9, adjusted p-value < 0.001) on postoperative day (POD) 1. Differences in NRS pain scores on POD2, POD3 and POD4 did not reach the level of statistical significance. There were no statistically significant differences in sensory function. CONCLUSION: Liposomal bupivacaine given via supraclavicular brachial plexus block reduced pain at rest in the early postoperative period.

High-Dose Buprenorphine Initiation: A Scoping Review.

OBJECTIVE: The aim of the study is to review and synthesize the literature on high-dose buprenorphine initiation (>12-mg total dose on day of initiation). METHODS: A scoping review of literature about high-dose buprenorphine initiation was conducted. MEDLINE, Embase, PsycINFO, and Cochrane Central were searched. Randomized controlled trials, prospective and retrospective cohort studies, and case studies/reports published in English before February 13, 2023, were included. RESULTS: Fifteen studies reporting outcomes from 580 high-dose buprenorphine initiations were included. Eight studies were in inpatient settings, 3 in emergency departments, 3 in outpatient settings, and 1 in a first-responder setting. Four studies reported high-dose initiations among individuals exposed to fentanyl. There were no reported events of fatal or nonfatal overdose or respiratory depression, although adverse event reporting was inconsistent in published reports. The most reported side effects with high-dose buprenorphine initiation were nausea or vomiting (n = 17) and precipitated withdrawal (n = 7). The most serious reported adverse event was hypotension requiring oral hydration (n = 2). Most studies reported improvements in subjective or objective withdrawal symptoms. The duration of follow-up ranged from none to 8 months. CONCLUSIONS: High-dose buprenorphine initiation has not been associated with reported cases of overdose or respiratory depression. However, the current literature about high-dose buprenorphine is limited by inconsistent side effect reporting, limited power to detect rare safety events such as respiratory depression, limited follow-up data, and few comparison studies between high-dose and regular initiation protocols. Further prospective data are needed to evaluate the safety and effectiveness of this initiation strategy.

How to optimize the systematic review process using AI tools.

Systematic reviews are a cornerstone for synthesizing the available evidence on a given topic. They simultaneously allow for gaps in the literature to be identified and provide direction for future research. However, due to the ever-increasing volume and complexity of the available literature, traditional methods for conducting systematic reviews are less efficient and more time-consuming. Numerous artificial intelligence (AI) tools are being released with the potential to optimize efficiency in academic writing and assist with various stages of the systematic review process including developing and refining search strategies, screening titles and abstracts for inclusion or exclusion criteria, extracting essential data from studies and summarizing findings. Therefore, in this article we provide an overview of the currently available tools and how they can be incorporated into the systematic review process to improve efficiency and quality of research synthesis. We emphasize that authors must report all AI tools that have been used at each stage to ensure replicability as part of reporting in methods.

Risk of Major Adverse Cardiovascular Events After SARS-CoV-2 Infection in British Columbia: A Population-Based Study.

BACKGROUND: COVID-19 is associated with increased risk of post-acute cardiovascular outcomes. Population-based evidence for long periods of observation is still limited. METHODS: This population-based cohort study was conducted using data (2020-2021) from the British Columbia COVID-19 Cohort. The exposure of interest was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, identified through reverse transcription-polymerase chain reaction (RT-PCR) assay. Individuals who tested positive (exposed) on RT-PCR were matched to negative controls (unexposed) on sex, age, and RT-PCR collection date in a 1:4 ratio. Outcomes of interest were incident major adverse cardiovascular events and acute myocardial infarction, identified more than 30 days after RT-PCR collection date. The association between SARS-CoV-2 infection and cardiovascular risk was assessed through multivariable survival models. Population attributable fractions were computed from Cox models. RESULTS: We included 649,320 individuals: 129,864 exposed and 519,456 unexposed. The median duration of follow-up was 260 days; 1,786 events (0.34%) took place among the unexposed, and 702 (0.54%) in the exposed. The risk of major adverse cardiovascular events was higher in the exposed (adjusted hazard ratio [aHR] 1.34; 95% confidence interval [CI], 1.22-1.46), with greater risk observed in those who were hospitalized (aHR 3.81; 95% CI, 3.12-4.65) or required intensive care unit admission (aHR 6.25; 95% CI, 4.59-8.52) compared with the unexposed group. The fraction of cardiovascular events attributable to SARS-CoV-2 was 7.04% (95% CI, 4.67-9.41%). Comparable results were observed for acute myocardial infarction. CONCLUSIONS: SARS-CoV-2 infection was associated with higher cardiovascular risk, with graded increase across the acute COVID-19 severity, contributing to 7% of incident major adverse cardiovascular events. These findings suggest that long-term monitoring of cardiovascular risk is required in COVID-19 survivors.

Lumbar Epidural versus Caudal Epidural for Postoperative Analgesia After Lower Extremity Osteotomy Surgery in Pediatric Patients with Osteogenesis Imperfecta: A Propensity-Matched Cohort Analysis in a Single-Center Over 9 Years.

Purpose: Although pediatric epidural analgesia is a well-established technique used perioperatively. It is unclear whether a lumbar or caudal epidural is suitable for osteogenesis imperfecta (OI) patients, which may be associated with brittle bones and spine deformity. We conducted a retrospective study to investigate and compare the efficacy of the two continuous epidural techniques in pediatric patients undergoing lower extremity osteotomy surgery using a propensity score-matched analysis (PSMA). Patients and Methods: A total of 274 patients were included. Patients' age, weight, and height were adjusted using PSMA. 90 patients were matched for further analysis, with 45 patients in the lumbar epidural group (Group L) and 45 patients in the caudal epidural group (Group C). Pain scores were categorized into three grades: mild (0-3), moderate (4-6), and severe (7-10), and compared between the two groups. Additionally, operation time, operation site, blood loss, scoliosis, oral analgesic medications, and catheter or nerve-related complications were compared. Results: There were no significant differences in operation time, operation site, scoliosis, and blood loss between the two groups. The percentage of moderate to severe pain during movement was significantly higher in Group L than in Group C, with 37.5% versus 17.5% on the second-day post-operation (P=0.039). However, no statistically significant difference was observed on other days. Additionally, there was no significant difference in oral medication consumption and complications between the two groups. Conclusion: Both lumbar and caudal epidural analgesia can be effectively used postoperatively, and a caudal epidural should be considered where performing a lumbar epidural is challenging in OI pediatric patients.

Osteogenesis imperfecta (OI) is a rare genetic disorder that affects the body's connective tissues, particularly the bones and ligaments. It is caused by abnormalities in type I collagen, which leads to skeletal fragility known as "brittle bones". This fragility can cause various issues, including an increased risk of fractures from minor trauma, limb deformities, and unusual fractures such as vertebral compressions. OI patients may also experience spinal manifestations such as scoliosis and kyphosis. Lumbar epidural analgesia has been found to be effective in providing pain relief for surgeries that involve the lower extremities. Additionally, caudal epidural analgesia has also demonstrated its effectiveness in providing postoperative analgesia for surgeries that affect the lower limbs. However, there is still debate about the safety of epidural analgesia in patients with skeletal dysplasias, especially those with OI. Despite this uncertainty, our center, which was supported by the Rare Diseases Public Welfare Organization, has successfully used epidural analgesia since 2015 in the southern part of China for OI surgeries. We conducted a retrospective study to share our experiences of nine years of practice and compare lumbar epidural with caudal epidural using a propensity score matching to balance basic demographics. We also compared the presence of scoliosis. Our findings suggest that both lumbar and caudal epidural analgesia can be safely used in OI patients. In cases where lumbar punctures may pose challenges due to potential spine deformities, the caudal route can be an alternative.

Intrinsic and extrinsic actions of human neural progenitors with SUFU inhibition promote tissue repair and functional recovery from severe spinal cord injury.

Neural progenitor cells (NPCs) derived from human pluripotent stem cells(hPSCs) provide major cell sources for repairing damaged neural circuitry and enabling axonal regeneration after spinal cord injury (SCI). However, the injury niche and inadequate intrinsic factors in the adult spinal cord restrict the therapeutic potential of transplanted NPCs. The Sonic Hedgehog protein (Shh) has crucial roles in neurodevelopment by promoting the formation of motorneurons and oligodendrocytes as well as its recently described neuroprotective features in response to the injury, indicating its essential role in neural homeostasis and tissue repair. In this study, we demonstrate that elevated SHH signaling in hNPCs by inhibiting its negative regulator, SUFU, enhanced cell survival and promoted robust neuronal differentiation with extensive axonal outgrowth, counteracting the harmful effects of the injured niche. Importantly, SUFU inhibition in NPCs exert non-cell autonomous effects on promoting survival and neurogenesis of endogenous cells and modulating the microenvironment by reducing suppressive barriers around lesion sites. The combined beneficial effects of SUFU inhibition in hNPCs resulted in the effective reconstruction of neuronal connectivity with the host and corticospinal regeneration, significantly improving neurobehavioral recovery in recipient animals. These results demonstrate that SUFU inhibition confers hNPCs with potent therapeutic potential to overcome extrinsic and intrinsic barriers in transplantation treatments for SCI.

Interventions to prevent and treat delirium: An umbrella review of randomized controlled trials.

Delirium is a common condition across different settings and populations. The interventions for preventing and managing this condition are still poorly known. The aim of this umbrella review is to synthesize and grade all preventative and therapeutic interventions for delirium. We searched five databases from database inception up to March 15th, 2023 and we included meta-analyses of randomized controlled trials (RCTs) to decrease the risk of/the severity of delirium. From 1959 records after deduplication, we included 59 systematic reviews with meta-analyses, providing 110 meta-analytic estimates across populations, interventions, outcomes, settings, and age groups (485 unique RCTs, 172,045 participants). In surgery setting, for preventing delirium, high GRADE evidence supported dexmedetomidine (RR=0.53; 95%CI: 0.46-0.67, k=13, N=3988) and comprehensive geriatric assessment (OR=0.46; 95%CI=0.32-0.67, k=3, N=496) in older adults, dexmedetomidine in adults (RR=0.33, 95%CI=0.24-0.45, k=7, N=1974), A2-adrenergic agonists after induction of anesthesia (OR= 0.28, 95%CI= 0.19-0.40, k=10, N=669) in children. High certainty evidence did not support melatonergic agents in older adults for delirium prevention. Moderate certainty supported the effect of dexmedetomidine in adults and children (k=4), various non-pharmacological interventions in adults and older people (k=4), second-generation antipsychotics in adults and mixed age groups (k=3), EEG-guided anesthesia in adults (k=2), mixed pharmacological interventions (k=1), five other specific pharmacological interventions in children (k=1 each). In conclusion, our work indicates that effective treatments to prevent delirium differ across populations, settings, and age groups. Results inform future guidelines to prevent or treat delirium, accounting for safety and costs of interventions. More research is needed in non-surgical settings.

Impact of the COVID-19 Pandemic on Hepatitis C Treatment Initiation in British Columbia, Canada: An Interrupted Time Series Study.

We investigated the impacts of the COVID-19 pandemic on hepatitis C (HCV) treatment initiation, including by birth cohort and injection drug use status, in British Columbia (BC), Canada. Using population data from the BC COVID-19 Cohort, we conducted interrupted time series analyses, estimating changes in HCV treatment initiation following the introduction of pandemic-related policies in March 2020. The study included a pre-policy period (April 2018 to March 2020) and three follow-up periods (April to December 2020, January to December 2021, and January to December 2022). The level of HCV treatment initiation decreased by 26% in April 2020 (rate ratio 0.74, 95% confidence interval [CI] 0.60 to 0.91). Overall, no statistically significant difference in HCV treatment initiation occurred over the 2020 and 2021 post-policy periods, and an increase of 34.4% (95% CI 0.6 to 75.8) occurred in 2022 (equating to 321 additional people initiating treatment), relative to expectation. Decreases in HCV treatment initiation occurred in 2020 for people born between 1965 and 1974 (25.5%) and people who inject drugs (24.5%), relative to expectation. In summary, the pandemic was associated with short-term disruptions in HCV treatment initiation in BC, which were greater for people born 1965 to 1974 and people who inject drugs.

Treatment of HCV with direct-acting antivirals on reducing mortality related to extrahepatic manifestations: a large population-based study in British Columbia, Canada.

Background: HCV infection is associated with mortality due to extrahepatic manifestations (EHM). Sustained virologic response (SVR) following direct-acting antiviral (DAA) therapy has been linked to decreased all-cause and liver-related mortality. However, evidence regarding the impact of DAA on EHM-related deaths is lacking. This study aimed to assess the impact of DAA and SVR on EHM-related mortality. Methods: The British Columbia Hepatitis Testers Cohort comprises ∼1.7 million people tested for HCV between 1990 and 2015 and is linked with administrative health data. Among individuals diagnosed with HCV by 12/31/2020, those who received at least one DAA treatment were matched to those who never received treatment by the year of their first HCV RNA positive date. We compared three groups: treated & SVR, treated & no-SVR, and untreated; and generated EHM mortality rates and incidence curves. To account for differences in baseline characteristics, we used inverse probability of treatment weights (IPTW). IPTW-weighted multivariable cause-specific Cox regression models were adjusted for competing risk and confounders. Findings: Study population included 12,815 treated (12,287 SVR, 528 no-SVR) and 12,815 untreated individuals (median follow-up 3.4 years, IQR 2.9). The untreated group had the highest EHM mortality rate (30.9 per 1000 person-years [PY], 95% CI 29.2-32.8), followed by the treated & no-SVR group (21.2 per 1000 PY, 95% CI 14.9-30.1), while the treated & SVR group had the lowest EHM mortality rate (7.9 per 1000 PY, 95% CI 7.1-8.7). In the multivariable model, EHM mortality in the treated & SVR group was significantly decreased (adjusted cause-specific hazard ratio [acsHR] 0.20, 95% CI 0.18-0.23). The treated & SVR group had significant reductions in mortality related to each of the EHMs (78-84%). Interpretation: Treatment of HCV with DAA was associated with significant reductions in EHM-related mortality. These findings emphasize the critical importance of timely diagnosis and treatment of HCV to prevent deaths associated with EHM, and have important implications for clinical practice and public health. Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-348216, PJT-156066, and PHE-337680]. DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and Doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC).

Association of hepatitis B virus treatment with all-cause and liver-related mortality among individuals with HBV and cirrhosis: a population-based cohort study.

Background: We evaluated the association of hepatitis B virus (HBV) treatment with all-cause, and liver-related mortality among individuals with HBV and cirrhosis in British Columbia (BC), Canada. Methods: This analysis included people diagnosed with HBV and had cirrhosis in the BC Hepatitis Testers Cohort, including data on all individuals diagnosed with HBV from 1990 to 2015 in BC and integrated with healthcare administrative data. We followed people with cirrhosis from the first cirrhosis diagnosis date until death or December 31, 2020. We compared all-cause and liver related mortality between those who received treatment and those who did not. HBV treatment was considered a time-varying variable. We performed multivariable Cox proportional hazards model and competing risk regression models to assess the association of HBV treatment with all causes, and liver-related mortality respectively using inverse probability of treatment weighted population. Findings: Among 4962 individuals with HBV and cirrhosis, 48.1% received HBV treatment. Treated individuals had a median follow-up of 2.97 years, compared to 2.87 years for untreated individuals. The treated group was older (median age 57 vs 54 years), had higher proportion of treated of males [1802 (75.50%) vs 1766 (68.8%)], from urban area [2318 (97.2%) vs 2355 (91.8%)], and from East and South Asian ethnicity [1506 (63.1%) vs 709 (27.5%)] compared to untreated group. Untreated people experienced higher all-cause mortality (115.47 vs. 35.72 per 1000 person-years) and liver-related mortality (49.86 vs. 11.39 per 1000 person-years). Multivariable models showed that HBV treatment significantly lowered the risk of all-cause mortality (adjusted hazard ratio (aHR) 0.74; 95% CI: 0.65, 0.84) and liver-related mortality (adjusted subdistribution hazard ratio (asHR) 0.72; 95% CI: 0.58, 0.89) compared to untreated individuals. Among untreated individuals with HBV, those with HCV coinfection had a higher risk of both all-cause and liver-related mortality (aHR 1.57; 95% CI: 1.22, 2.04, and asHR 1.60; 95% CI: 1.25, 2.05, respectively). Interpretation: HBV treatment was associated with a significant reduction in all-cause and liver-related mortality among individuals with cirrhosis. The findings highlight the need for treatment among individuals with HBV related cirrhosis especially those with coinfection with hepatitis C virus. Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-142832, PJT-156066, and SC1 -178736]. JDM has received doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and doctoral fellowship from the CanHepC. CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC).

Physical activity, suicidal ideation, suicide attempt and death among individuals with mental or other medical disorders: A systematic review of observational studies.

A growing body of research has demonstrated the potential role for physical activity as an intervention across mental and other medical disorders. However, the association between physical activity and suicidal ideation, attempts, and deaths has not been systematically appraised in clinical samples. We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, EMBASE, and PsycINFO for observational studies investigating the influence of physical activity on suicidal behavior up to December 6, 2023. Of 116 eligible full-text studies, seven (n = 141691) were included. Depression was the most frequently studied mental condition (43%, k = 3), followed by chronic pain as the most common other medical condition (29%, k = 2). Two case-control studies examined suicide attempts and found an association between physical activity and a reduced frequency of such attempts. However, in studies examining suicidal ideation (k = 3) or suicide deaths (k = 2), no consistent associations with physical activity were observed. Overall, our systematic review found that physical activity may be linked to a lower frequency of suicide attempts in non-prospective studies involving individuals with mental disorders.

Effects of antipsychotic treatment on cardio-cerebrovascular related mortality in schizophrenia: A subanalysis of a systematic review and meta-analysis with meta-regression of moderators.

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes.