Mendelian randomization highlights sleep disturbances mediated the effect of depression on chronic pain.

INTRODUCTION: Depression and chronic pain are significant contributors to the global burden of disease. Previous research has revealed complex relationships between these two conditions, which may be influenced by sleep quality. However, observational studies have limitations, including confounding factors and reverse causation. This study aims to explore the mediating effects of sleep on the relationship between depression and chronic pain using Mendelian randomization (MR). METHODS: We conducted a two-step, two-sample MR study using mediation analysis. We obtained major depressive disorder (MDD) Genome-Wide Association Studdies (GWAS) data from Wray et al.'s GWAS meta-analysis. Phenotypic data related to sleep were collected from the UK Biobank. Chronic pain data were obtained from the Finnish database. RESULTS: MR analysis revealed significant genetic associations between MDD and chronic localized pain [IVW: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.16-1.38, p = 2.52 × 10-7] as well as fibromyalgia (IVW: OR = 2.17, 95% CI = 1.34-3.52, p = .002). Genetic susceptibility for MDD was also associated with insomnia (IVW: OR = 1.10, 95% CI = 1.06-1.13, p = 3.57 × 10-8) and self-reported short sleep duration (IVW: OR = 1.03, 95% CI = 1.00-1.06, p = .047). The mediating effects of insomnia and fibromyalgia on the pathway from depression to chronic regional pain were 1.04 and 1.03, respectively, with mediation proportions of 12.8% and 15.2%. Insomnia mediated the pathway between depression and fibromyalgia with an effect of 1.12, accounting for 15.2% of the total effect. CONCLUSION: This two-step MR analysis strengthens the evidence of genetic predictive associations between depression and chronic pain, highlighting the mediating roles of insomnia and short sleep duration. It further elucidates the specific roles of distinct sleep disorders, differentiating insomnia and short sleep duration from other sleep-related phenotypes.

The impact of preoperative serum lactate dehydrogenase on mortality and morbidity after noncardiac surgery.

Preoperative serum lactate dehydrogenase (LDH) has been reported to be associated with adverse outcomes following thoracic surgery. However, its association with outcomes in noncardiac surgery as a whole has not been investigated. We conducted a retrospective cohort study at West China Hospital, Sichuan University, from 2018 to 2020, including patients undergoing noncardiac surgery. Multivariable logistic regression and propensity score weighting were employed to assess the link between LDH levels and postoperative outcomes. Preoperative LDH was incorporated into four commonly used clinical models, and its discriminative ability, reclassification, and calibration were evaluated in comparison to models without LDH. Among 130,879 patients, higher preoperative LDH levels (cut-off: 220 U/L) were linked to increased in-hospital mortality (4.382% vs. 0.702%; OR 1.856, 95% CI 1.620-2.127, P < 0.001), myocardial injury after noncardiac surgery (MINS) (3.012% vs. 0.537%; OR 1.911, 95% CI 1.643-2.223, P < 0.001), and ICU admission (15.010% vs. 6.414%; OR 1.765, 95% CI 1.642-1.896, P < 0.001). The inverse probability of treatment-weighted estimation supported these results. Additionally, LDH contributed significantly to four surgical prognostic models, enhancing their predictive capability. Our study revealed a significant association between preoperative LDH and in-hospital mortality, MINS, and ICU admission following noncardiac surgery. Moreover, LDH provided supplementary predictive information, extending the utility of commonly used surgical prognostic scores.

Therapeutic Potential of Downregulated Interleukin-6 Signaling for the Treatment of Chronic Pain: A Mendelian Randomization Study.

Introduction: While numerous studies have emphasized the pivotal involvement of the Interleukin 6 (IL-6) pathway in the development of chronic pain, the causal nature of this relationship remains uncertain. Methods: In this study, we opted to include genetic variants situated within the locus of the IL-6 receptor (IL-6R) that exhibited associations with C-reactive protein (CRP) levels. CRP serves as a downstream effector in the IL-6 pathway. Utilizing these variants as genetic proxies, we aimed to modulate IL-6 signaling. Employing a two-sample Mendelian randomization (MR) approach, we investigated the potential link between the genetic proxy and seven distinct subtypes of chronic pain, categorized based on their corresponding body locations. Moreover, we examined the relationship between chronic pain and an alternative instrument of IL-6 signaling that was weighted based on s-IL-6R levels. Furthermore, we conducted exploratory analyses to estimate the plausible causal association between CRP, gp130, and the subtypes of chronic pain. Results: Our analysis showed that genetic proxied downregulation of IL-6 signaling, weighted on CRP levels, was linked to a reduced risk of chronic back and knee pain. The sensitivity analyses across various MR methods confirmed the consistency of the findings and showed no evidence of horizontal pleiotropy or heterogeneity. Moreover, the results remained robust with different sets of instrument variables. A genetically increased level of s-IL-6R was also negatively associated with chronic back and knee pain. However, there was no causal relationship between CRP and gp130 with chronic pain. Conclusion: Based on our findings, there is evidence to suggest a potential causal relationship between IL-6 signaling and chronic back and knee pain. Consequently, the downregulation of IL-6 signaling holds promise as a potential therapeutic target for addressing chronic back and knee pain.

Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study.

INTRODUCTION: Migraine, a prevalent headache disorder with unclear mechanisms and limited treatments, may be influenced by dyslipidemia and genetic factors. Statins and emerging lipid-modifying agents show potential but lack evidence for migraine management. Mendelian Randomization analysis offers insights into causal relationships and therapeutic targets. This study aims to explore genetically predicted lipid traits, drug targets, and their association with migraine risk. METHOD: We conducted Mendelian randomization (MR) analyses utilizing genetic variants associated with lipid traits and variants in genes encoding the protein targets of various classes of lipid-lowering drugs. The specific drug classes investigated included HMGCR, PCSK9, NPC1L1, ABCG5/ABCG8, LDLR, LPL, ANGPTL3, APOB, CETP, and APOC3. To determine the effects on migraine risk, we meta-analyzed MR estimates for regional variants using data from two large sample sets. The genetic variants were weighted based on their associations with specific lipid traits, such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Apolipoprotein A1, and Apolipoprotein B. To obtain association weights, we utilized data from lipid genetics consortia. For lipid-modifying drug targets that exhibited suggestive significance, we further employed expression quantitative trait locus (eQTL) data. Additionally, we performed colocalization analysis to assess genetic confounding. RESULT: The use of genetic proxies for HMGCR inhibition demonstrated a significant association with a decreased risk of migraine in the FinnGen dataset (OR = 0.64, 95% CI: 0.46-0.88, p = 0.0006) and a nearly significant association in the Choquet dataset (OR = 0.78, 95% CI: 0.60-1.01, p = 0.06). When pooling the estimates, the overall effect size showed a reduced risk of migraine (OR = 0.73, 95% CI: 0.60-0.89, p = 0.0016). Similarly, genetic mimicry of LPL enhancement was associated with a lower risk of migraine in the FinnGen dataset (OR = 0.82, 95% CI: 0.69-0.96, p = 0.01) and the Choquet dataset (OR = 0.91, 95% CI: 0.83-0.99, p = 0.03). Pooling the estimates showed a consistent effect size (OR = 0.89, 95% CI: 0.83-0.96, p = 0.002). Sensitivity analyses yielded no statistically significant evidence of bias arising from pleiotropy or genetic confounding. CONCLUSION: In the study, it was observed that among the 10 lipid-lowering drug targets investigated, LPL and HMGCR showed significant associations with migraine risk. These findings indicate that LPL and HMGCR have the potential to serve as candidate drug targets for the treatment or prevention of migraines.

Assessment of the prognostic value of preoperative high-sensitive troponin T for myocardial injury and long-term mortality for groups at high risk for cardiovascular events following noncardiac surgery: a retrospective cohort study.

Background: Few studies explored the association between high-sensitive cardiac troponin T (hs-cTnT) and long-term mortality for patients after surgery. This study was conducted to assess the association of hs-cTnT with long-term mortality and to investigate the extent to which this association is mediated via myocardial injury after noncardiac surgery (MINS). Methods: This retrospective cohort study included all patients with hs-cTnT measurements who underwent non-cardiac surgery at Sichuan University West China Hospital. Data were collected from February 2018 and November 2020, with follow-up through February 2022. The primary outcome was all-cause mortality within 1 year. As secondary outcomes, MINS, length of hospital stay (LOS), and ICU admission were analyzed. Results: The cohort included 7,156 patients (4,299 [60.1%] men; 61.0 [49.0-71.0] years). Among 7,156 patients, there were 2,151 (30.05%) with elevated hs-cTnT(>14 ng/L). After more than 1 year of follow-up, more than 91.8% of mortality information was available. During one-year follow-up after surgery, there were 308 deaths (14.8%) with a preoperative hs-cTnT >14 ng/L, compared with 192 deaths (3.9%) with a preoperative hs-cTnT <=14 ng/L(adjusted hazard ratio [aHR] 1.93, 95% CI 1.58-2.36; p < 0.001). Elevated preoperative hs-cTnT was also associated with several other adverse outcomes (MINS: adjusted odds ratio [aOR] 3.01; 95% CI, 2.46-3.69; p < 0.001; LOS: aOR 1.48, 95%CI 1.34-1.641; p < 0.001; ICU admission: aOR 1.52, 95%CI 1.31-1.76; p < 0.001). MINS explained approximately 33.6% of the variance in mortality due to preoperative hs-cTnT levels. Conclusion: Preoperative elevated hs-cTnT concentrations have a significant association with long-term mortality after noncardiac surgery, one-third of which may by accounted for by MINS.

Assessment of prognostic value of preoperative neutrophil-to-lymphocyte ratio for postoperative mortality and morbidity.

Background: The preoperative elevated neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with poorer outcomes after cancer and cardiovascular surgeries. It is unclear, however, if the predictive value is particular or if it may be applied to other types of surgery. We aimed to assess the prognostic value of preoperative NLR levels for morbidity and mortality after various surgery and determine an optimal threshold for NLR. Methods: We conducted a cohort analysis on patients receiving surgery at Sichuan University West China Hospital between 2018 and 2020. Multivariable piecewise regression analysis were used to determine the optimal cutoff value of NLR. Subgroup analysis were performed to verify the correlation. Sensitivity analysis was used to explore the effect of different thresholds. Results: We obtained data from 136,347 patients. The optimal cutoff of NLR was determined as 3.6 [95% CI (3.0, 4.1)] by piecewise regression method. After multivariable adjustment, preoperative high NLR remained significantly associated with increased in-hospital mortality (aOR, 2.19; 95% CI, 1.90-2.52; p < 0.001) and ICU admission after surgery (aOR, 1.69; 95% CI, 1.59-1.79; p < 0.001). Subgroup analyses confirmed the predictive value of high NLR in multiple surgical subgroups, including general, orthopedic, neurosurgical, and thoracic surgery subgroups, otorhinolaryngology, head and neck surgery, and burn plastic surgery. A NLR threshold of 3.6 gave excellent predictive value, whether employed alone or added in an extended model. Conclusions: In conclusion, the association of elevated NLR with higher mortality and ICU admission can be extended to a wider range of procedures. NLR threshold of 3.6 could provide good prognostic value for the prognostic model.

Association of Preoperative Neutrophil-to-Lymphocyte Ratio with Postoperative Acute Kidney Injury and Mortality Following Major Noncardiac Surgeries.

BACKGROUND: Acute kidney injury (AKI) is a major complication that occurs following an operation. Therefore, there is an increasing need to discover new predictors of AKI. We hypothesized that the preoperative neutrophil-to-lymphocyte ratio (NLR) was associated with postoperative AKI and in-hospital mortality following noncardiac surgery. METHODS: This is a retrospective observational study of patients who underwent noncardiac surgery at Sichuan University West China Hospital from 2018 to 2020. Multivariable logistic regression was performed as the major analytic method. In addition, sensitivity and subgroup analyses were performed to validate the results. RESULTS: A total of 44,065 patients were included in this study. The prevalence of postoperative AKI was 5.62%, and the in-hospital mortality was 1.58%. Multivariable analysis demonstrated that NLR ≥ 5 was independently associated with the development of postoperative AKI (OR 1.42, 1.24-1.73; P < 0.001) and in-hospital mortality (OR 2.03, 1.63-2.52; P < 0.001). Similar results were achieved when propensity-score matching was performed for patients with NLR ≥ 5 and < 5 on the baseline. In stratified analysis, the associations remained persistent in most subgroups. For the sensitivity analysis, we took NLR as a continuous variable and demonstrated the potential linear relationship between NLR and postoperative AKI and mortality. CONCLUSIONS: Our results indicated that preoperative NLR is associated with the prevalence of postoperative AKI and in-hospital mortality that occur after major noncardiac surgery. These findings suggest that NLR has the potential to be a significant correlation biomarker associated with perioperative risk assessment of patients undergoing noncardiac surgeries.

Distinctions between Fournier's gangrene and lower extremity necrotising fasciitis: microbiology and factors affecting mortality.

OBJECTIVES: In this study, we aimed to illustrate distinctions between Fournier's gangrene (FG) and lower extremity necrotising fasciitis (NF) and screen out possible risk factors of poor prognosis for each cohort. METHODS: The medical records of qualified patients with NF admitted to the Second People's Hospital of Yibin from January 2016 to June 2021 were retrospectively reviewed. All participants were anatomically categorised into FG and lower extremity NF groups, and their baseline data and microbiological results were compared. Further comparisons of critical parameters were conducted between survivors and nonsurvivors within each group. RESULTS: A total of 49 patients were included in the study with a median age of 58 years, and overall mortality was 20.4%. There were 18 patients with FG and 31 patients with lower extremity NF. A microbiology distinction was found-the predominance of gram-negative infection in FG and gram-positive infection in lower extremity NF. High Fournier's gangrene severity index scores (greater than 7), advanced age, procalcitonin and D-dimer value were identified as risk factors for FG, and the presentation of sepsis was an alarming indicator for lower extremity NF. CONCLUSIONS: The distinction of microbiology might provide advice for appropriate antibacterial administrations. In addition, with practical prognostic predicting tools, clinicians might be able to identify patients at increased risk and intervene promptly to avoid unfavourable outcomes.

Preoperative serum alpha-hydroxybutyrate dehydrogenase level as a predictor of postoperative mortality and morbidity after noncardiac surgery: A propensity-adjusted analysis.

BACKGROUND: Preoperative serum alpha-hydroxybutyrate dehydrogenase is reportedly associated with myocardial infarction. Myocardial injury after noncardiac surgery is independently associated with postoperative mortality. However, the association between preoperative alpha-hydroxybutyrate dehydrogenase and outcomes after noncardiac surgery has not been researched. We aimed to assess the association between preoperative serum alpha-hydroxybutyrate dehydrogenase levels and mortality and morbidity after noncardiac surgery. METHODS: We conducted a retrospective cohort study on patients undergoing noncardiac surgery from 2018 to 2020 in Sichuan University West China Hospital. After multivariate adjustment, the alpha-hydroxybutyrate dehydrogenase level was verified to be associated with postoperative outcomes by logistic regression analyses and propensity score weighting methods. RESULTS: We obtained data from 130,880 patients. An elevated preoperative serum alpha-hydroxybutyrate dehydrogenase level was associated with increasing mortality (odds ratio 1.244, 1.190-1.300; P < .001), myocardial injury after noncardiac surgery (odds ratio 1.198, 1.141-1.257; P < .001), and intensive care unit admission (odds ratio 1.138, 1.111-1.166; P < .001) in logistic regression analyses. The covariate balancing generalized propensity score methodology demonstrated similar results. After classifying alpha-hydroxybutyrate dehydrogenase as a binary variable with a cut-off value of 182, we found that mortality, myocardial injury after noncardiac surgery, and intensive care unit admission >24 hours were significantly higher in the elevated alpha-hydroxybutyrate dehydrogenase group (5.458% vs 0.737%; odds ratio 1.771, 1.533-2.046; P < .001), (3.598% vs 0.572%; odds ratio 1.636, 1.393-1.922; P < .001), and (18.182% vs 6.442%; odds ratio 1.430, 1.327-1.542; P < .001), respectively. Similarly, the inverse-probability-of-treatment weighted estimation demonstrated similar results. CONCLUSION: Our results suggest that the preoperative serum alpha-hydroxybutyrate dehydrogenase level was associated with in-hospital mortality, myocardial injury after noncardiac surgery, and intensive care unit admission after noncardiac surgery.

Thoracolumbar interfascial plane block for postoperative analgesia in spine surgery: A systematic review and meta-analysis.

INTRODUCTION: Thoracolumbar interfascial plane (TLIP) block has been discussed widely in spine surgery. The aim of our study is to evaluate analgesic efficacy and safety of TLIP block in spine surgery. METHOD: We performed a quantitative systematic review. Randomized controlled trials that compared TLIP block to non-block care or wound infiltration for patients undergoing spine surgery and took the pain or morphine consumption as a primary or secondary outcome were included. The primary outcome was cumulative opioid consumption during 0-24-hour. Secondary outcomes included postoperative pain intensity, rescue analgesia requirement, and adverse events. RESULT: 9 randomized controlled trials with 539 patients were included for analysis. Compared with non-block care, TLIP block was effective to decrease the opioid consumption (WMD -16.00; 95%CI -19.19, -12.81; p<0.001; I2 = 71.6%) for the first 24 hours after the surgery. TLIP block significantly reduced postoperative pain intensity at rest or movement at various time points compared with non-block care, and reduced rescue analgesia requirement ((RR 0.47; 95%CI 0.30, 0.74; p = 0.001; I2 = 0.0%) and postoperative nausea and vomiting (RR 0.58; 95%CI 0.39, 0.86; p = 0.006; I2 = 25.1%). Besides, TLIP block is superior to wound infiltration in terms of opioid consumption (WMD -17.23, 95%CI -21.62, -12.86; p<0.001; I2 = 63.8%), and the postoperative pain intensity at rest was comparable between TLIP block and wound infiltration. CONCLUSION: TLIP block improved analgesic efficacy in spine surgery compared with non-block care. Furthermore, current literature supported the TLIP block was superior to wound infiltration in terms of opioid consumption.

Erector spinae plane block for postoperative analgesia in spine surgery: a systematic review and meta-analysis.

PURPOSE: Although in recent years some randomized controlled trails (RCTs) have explored the analgesic effect of erector spinae plane block (ESPB) in spine surgery, their results are controversial. Our study aimed to examine the analgesic effect of preoperative ESPB in spine surgery by a meta-analysis of RCTs. METHODS: The articles of RCTs that compared preoperative ESPB with no block in terms of the analgesic effect in adult patients following spine surgery were eligible for inclusion. The primary outcome was the pain scores reported by Visual Analog Scale or Numerical Rating Scale of pain at different time intervals in 48 h after surgery. The secondary outcomes included postoperative opioid consumption, rescue analgesia requirement, opioid-related side effects and complications associated with ESPB. RESULTS: Twelve studies involving 828 patients were eligible for our study. Compared with no block, ESPB had a significant effect on reducing postoperative pain scores at rest and at movement at different time intervals except at movement at 48 h. ESPB significantly decreased opioid consumption in 24 h after surgery (SMD - 1.834; 95%CI - 2.752, - 0.915; p < 0.001; I2 = 89.0%), and reduced the incidence of rescue analgesia (RR 0.333; 95%CI 0.261, 0.425; p < 0.001; I2 = 0%) and postoperative nausea and vomiting (RR 0.380; 95%CI 0.272, 0.530; p < 0.001; I2 = 9.0%). Complications associated with ESPB were not reported in the included studies. CONCLUSION: Our meta-analysis demonstrates that ESPB is effective in decreasing postoperative pain intensity and postoperative opioid consumption in spine surgery. Therefore, for the management of postoperative pain following spine surgery, preoperative ESPB is a good choice.

The Effect of Ketamine on Acute and Chronic Wound Pain in Patients Undergoing Breast Surgery: A Meta-Analysis and Systematic Review.

INTRODUCTION: Perioperative use of ketamine has been discussed widely in many kinds of surgery. The aim of our study was to evaluate the short-term and long-term benefits and safety of ketamine after breast surgery. METHOD: We performed a quantitative systematic review. We included randomized controlled trials that compared intravenous administration of ketamine to a placebo control group, or compared bupivacaine in combination with ketamine to bupivacaine alone in thoracic paravertebral blocks or pectoral blocks among patients undergoing breast surgery. The primary outcome was postoperative pain intensity. Secondary outcomes included cumulative opioid consumption during the 0- to 24-hour postoperative period, the effect on postmastectomy pain syndrome, the effect on postoperative depression, and the adverse events associated with the use of ketamine. RESULTS: Thirteen randomized controlled trials with 1,182 patients were included for analysis. Compared with placebo, intravenous ketamine was effective in reducing wound pain intensity during the first 6 hours after surgery (weighted mean difference [WMD] -0.83; 95% confidence interval [CI] -1.65, -0.01; P = 0.048) and during the first 24 hours after surgery (WMD -0.65; 95% CI -0.95, -0.35; P < 0.001), and in decreasing opioid consumption (WMD -4.14; 95% CI -8.00, -0.29; P = 0.035) during the first 24 hours after surgery, without increasing the risks for gastrointestinal and central nervous system adverse events. Adding ketamine to bupivacaine in thoracic paravertebral blocks was also effective in reducing postoperative wound pain during the first 6 hours after surgery (WMD -0.59; 95% CI, -1.06, -0.12; P = 0.014) and during the first 24 hours after surgery (WMD -0.90; 95% CI -1.27, -0.53; P < 0.001), and in decreasing opioid consumption (WMD - 4.59; 95% CI -5.76, -3.42; P < 0.001) during the first 24 hours after surgery. Perioperative use of ketamine was associated with improved postoperative depression symptoms (standardized mean difference -0.80; 95% CI - 1.34, -0.27; P = 0.003) and less incidence of postmastectomy pain syndrome (relative risk 0.79; 95% CI 0.63, 0.99; P = 0.043). CONCLUSION: Ketamine is an effective and safe multimodal analgesic in patients undergoing breast surgery, administered both intravenously and when added to bupivacaine in paravertebral blocks. In addition, ketamine showed a long-term benefit for preventing postoperative depression and postmastectomy pain syndrome.

Effect of perioperative intravenous lidocaine for patients undergoing spine surgery: A meta-analysis and systematic review.

BACKGROUND: Perioperative intravenous lidocaine has been reported to have analgesic and opioid-sparing effects in many kinds of surgery. Several studies have evaluated its use in the settings of spine surgery. The aim of the study is to examine the effect of intravenous lidocaine in patients undergoing spine surgery. METHODS: We performed a quantitative systematic review. Databases of PubMed, Medline, Embase database and Cochrane library were investigated for eligible literatures from their establishments to June, 2019. Articles of randomized controlled trials that compared intravenous lidocaine to a control group in patients undergoing spine surgery were included. The primary outcome was postoperative pain intensity. Secondary outcomes included postoperative opioid consumption and the length of hospital stay. RESULT: Four randomized controlled trials with 275 patients were included in the study. postoperative pain compared with control was reduced at 6 hours after surgery (WMD -0.50, 95%CI, -0.76 to -0.25, P < .001), at 24 hours after surgery (WMD -0.50, 95%CI, -0.70 to -0.29, P < .001) and at 48 hours after surgery (WMD -0.57, 95%CI, -0.96 to -0.17, P = .005). The effect of intravenous lidocaine on postoperative opioid consumption compared with control revealed a significant effect (WMD -15.36, 95%CI, -21.40 to -9.33 mg intravenous morphine equivalents, P < .001). CONCLUSION: This quantitative analysis of randomized controlled trials demonstrated that the perioperative intravenous lidocaine was effective for reducing postoperative opioid consumption and pain in patients undergoing spine surgery. The intravenous lidocaine should be considered as an effective adjunct to improve analgesic outcomes in patients undergoing spine surgery. However, the quantity of the studies was very low, more research is needed.