Isopropyl alcohol inhalation versus 5-HT3 antagonists for treatment of nausea: a meta-analysis of randomised controlled trials.

PURPOSE: Nausea is a common and unpleasant sensation for which current therapies such as serotonin (5-HT3) antagonists are often ineffective, while also conferring a risk of potential adverse events. Isopropyl alcohol (IPA) has been proposed as a treatment for nausea. We aimed to compare IPA with 5-HT3 antagonists for the treatment of nausea across all clinical settings. METHODS: MEDLINE, EMBASE, PubMed, CENTRAL and CINAHL were searched from inception to 17 July 2023 for randomised controlled trials (RCTs) comparing inhaled IPA and a 5-HT3 antagonist for treatment of nausea. Severity and duration of nausea, rescue antiemetic use, adverse events and patient satisfaction were the outcomes sought. Risk of bias (RoB) was assessed using Cochrane RoB 2. Random-effects model was used for meta-analysis. Combination of meta-analyses and narrative review was used to synthesise findings. The evidence was appraised using GRADE. RESULTS: From 1242 records, 4 RCTs were included with 382 participants. Participants receiving IPA had a significantly lower mean time to 50% reduction in nausea (MD - 20.06; 95% CI - 26.26, - 13.85). Nausea score reduction at 30 min was significantly greater in the IPA group (MD 21.47; 95% CI 15.47, 27.47). IPA led to significantly reduced requirement for rescue antiemetics (OR 0.60; 95% CI 0.37, 0.95; p = 0.03). IPA led to no significant difference in patient satisfaction when compared with a 5-HT3 antagonist. The overall GRADE assessment of evidence quality ranged from very low to low. CONCLUSION: IPA may provide rapid, effective relief of nausea when compared with 5-HT3 antagonists.

Depression after stoma surgery: a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors. METHODS: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model. REGISTRATION: PROSPERO, CRD42021262345. RESULTS: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2-58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia-Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not. CONCLUSIONS: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period.

The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle.

Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.

Novel imaging tools for investigating the role of immune signalling in the brain.

The importance of neuro-immune interactions in both physiological and pathophysiological states cannot be overstated. As our appreciation for the neuroimmune nature of the brain and spinal cord grows, so does our need to extend the spatial and temporal resolution of our molecular analysis techniques. Current imaging technologies applied to investigate the actions of the neuroimmune system in both health and disease states have been adapted from the fields of immunology and neuroscience. While these classical techniques have provided immense insight into the function of the CNS, they are however, inherently limited. Thus, the development of innovative methods which overcome these limitations are crucial for imaging and quantifying acute and chronic neuroimmune responses. Therefore, this review aims to convey emerging novel and complementary imaging technologies in a form accessible to medical scientists engaging in neuroimmune research.

Surgical Management of Dupuytren Disease: A Systematic Review and Network Meta-analyses.

BACKGROUND: Dupuytren disease is a common fibroproliferative disease that affects the palmar fascia of the hands. Currently, there is limited consensus regarding the optimal therapy for this condition, with treatment decisions based largely on surgeon preference. Therefore, the aim of this study was to determine which treatments are the most effective for Dupuytren disease. METHOD: A systematic review and network meta-analyses were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Medline, EMBASE, and Web of Science were searched for randomized trials comparing treatments for Dupuytren disease in adults. Eligible treatments included open limited fasciectomy, collagenase injection, and percutaneous needle fasciotomy. Study selection, data extraction, and quality appraisal were performed in duplicate. The methodological quality was evaluated with the Cochrane risk-of-bias critical appraisal tool. RESULTS: Eleven randomized clinical trials were included in this study. At short-term (1-12 weeks) and long-term (2-5 years) time points, fasciectomy improved contracture release more than collagenase and needle fasciotomy as inferred by a lower total passive extension deficit. However, there was no difference between the groups regarding the best possible outcome at any time point. Fasciectomy was also superior in terms of recurrence and patient satisfaction compared with collagenase and needle fasciotomy, but only at later time points. There was no difference in skin damage-related and nerve damage-related complications following fasciectomy compared with other modalities. Risk of bias was generally moderate. CONCLUSIONS: Fasciectomy provides superior long-term advantages in terms of patient outcomes when compared with collagenase and needle fasciotomy. Larger trials with better blinding of outcome assessors are needed in the future.

In-hospital survival after pancreatoduodenectomy is greater in high-volume hospitals versus lower-volume hospitals: a meta-analysis.

BACKGROUND: Variation in cut-off values for what is considered a high volume (HV) hospital has made assessments of volume-outcome relationships for pancreaticoduodenectomy (PD) challenging. Accordingly, we performed a systematic review and meta-analysis comparing in-hospital mortality after PD in hospitals above and below HV thresholds of various cut-off values. METHOD: PubMed/MEDLINE, Embase and Cochrane Library were searched to 4 January 2021 for studies comparing in-hospital mortality after PD in hospitals above and below defined HV thresholds. After data extraction, risk of bias was assessed using the Downs and Black checklist. A random-effects model was used for meta-analysis, including meta-regressions. Registration: PROSPERO, CRD42021224432. RESULTS: From 1855 records, 17 observational studies of moderate quality were included. Median HV cut-off was 25 PDs/year (IQR: 20-32). Overall relative risk of in-hospital mortality was 0.37 (95% CI: 0.30, 0.45), that is, 63% less in HV hospitals. All subgroup analyses found an in-hospital survival benefit in performing PDs at HV hospitals. Meta-regressions from included studies found no statistically significant associations between relative risk of in-hospital mortality and region (USA vs. non-USA; p = 0.396); or 25th percentile (p = 0.231), median (p = 0.822) or 75th percentile (p = 0.469) HV cut-off values. Significant inverse relationships were found between PD hospital volume and other outcomes. CONCLUSION: In-hospital survival was significantly greater for patients undergoing PDs at HV hospitals, regardless of HV cut-off value or region. Future research is required to investigate regions where low-volume centres have specialized PD infrastructure and the potential impact on mortality.

Mesh versus non-mesh repair of groin hernias: a rapid review.

BACKGROUND: Mesh is frequently utilized intraoperatively for the repair of groin hernias. However, patients may request non-mesh hernia repairs owing to adverse events reported in other mesh procedures. To inform surgical safety, this study aimed to compare postoperative complications between mesh and non-mesh groin hernia repairs and identify other operative and patient-related risk factors associated with poor postoperative outcomes. METHODS: Ovid MEDLINE and grey literature were searched to 9 June 2021 for studies comparing mesh to non-mesh techniques for primary groin hernia repair. Outcomes of interest were postoperative complications, recurrence of hernia, pain and risk factors associated with poorer surgical outcomes. Methodological quality was appraised using the AMSTAR 2 tool. RESULTS: The systematic search returned 4268 results, which included seven systematic reviews and five registry analyses. Mesh repair techniques resulted in lower hernia recurrence rates, with no difference in chronic pain, seroma, haematoma or wound infection, compared to non-mesh techniques. Risk factors associated with increased risk of hernia recurrence were increased body mass index (BMI), positive smoking status and direct hernia. These were independent of surgical technique. Patients under 40 years of age were at increased risk of postoperative pain. CONCLUSIONS: Surgical repair of primary groin hernias using mesh achieves lower recurrence rates, with no difference in safety outcomes, compared with non-mesh repairs. Additional risk factors associated with increased recurrence include increased BMI, history of smoking and hernia subtype.

Impact of COVID-19, gender, race, specialty and seniority on mental health during surgical training: an international study.

BACKGROUND: Superior patient outcomes rely on surgical training being optimized. Accordingly, we conducted an international, prospective, cross-sectional study determining relative impacts of COVID-19, gender, race, specialty and seniority on mental health of surgical trainees. METHOD: Trainees across Australia, New Zealand and UK enrolled in surgical training accredited by the Royal Australasian College of Surgeons or Royal College of Surgeons were included. Outcomes included the short version of the Perceived Stress Scale, Oxford Happiness Questionnaire short scale, Patient Health Questionnaire-2 and the effect on individual stress levels of training experiences affected by COVID-19. Predictors included trainee characteristics and local COVID-19 prevalence. Multivariable linear regression analyses were conducted to assess association between outcomes and predictors. RESULTS: Two hundred and five surgical trainees were included. Increased stress was associated with number of COVID-19 patients treated (P = 0.0127), female gender (P = 0.0293), minority race (P = 0.0012), less seniority (P = 0.001), and greater COVID-19 prevalence (P = 0.0122). Lower happiness was associated with training country (P = 0.0026), minority race (P = 0.0258) and more seniority (P < 0.0001). Greater depression was associated with more seniority (P < 0.0001). Greater COVID-19 prevalence was associated with greater reported loss of training opportunities (P = 0.0038), poor working conditions (P = 0.0079), personal protective equipment availability (P = 0.0008), relocation to areas of little experience (P < 0.0001), difficulties with career progression (P = 0.0172), loss of supervision (P = 0.0211), difficulties with pay (P = 0.0034), and difficulties with leave (P = 0.0002). CONCLUSION: This is the first study to specifically describe the relative impacts of COVID-19 community prevalence, gender, race, surgical specialty and level of seniority on stress, happiness and depression of surgical trainees on an international scale.

Telehealth in surgery: an umbrella review.

BACKGROUND: Telehealth use has increased worldwide during the COVID-19 pandemic. However, hands-on requirements of surgical care may have resulted in slower implementation. This umbrella review (review of systematic reviews) evaluated the perceptions, safety and implementation of telehealth services in surgery, and telehealth usage in Australia between 2020 and 2021. METHODS: PubMed was searched from 2015 to 2021 for systematic reviews evaluating real-time telehealth modalities in surgery. Outcomes of interest were patient and provider satisfaction, safety, and barriers and facilitators associated with its use. Study quality was appraised using the AMSTAR 2 tool. A working group of surgeons provided insights into the clinical relevance to telehealth in surgical practice of the evidence collated. RESULTS: From 2025 identified studies, 17 were included, which were of low to moderate risk of bias. Patient and provider satisfaction with telehealth was high. Time savings, decreased healthcare resource use and lower costs were reported as key advantages of the service. Inability to perform comprehensive examinations was noted as the primary barrier. In Australia, peak telehealth usage coincided with the introduction of temporary telehealth services and increased lockdown measures. CONCLUSIONS: Patients and providers are broadly satisfied with telehealth and its benefits. Barriers may be overcome via multidisciplinary collaboration. Telehealth may benefit surgical care long-term if implemented correctly both during and after the COVID-19 pandemic.

Gastrointestinal recovery after surgery: protocol for a systematic review.

INTRODUCTION: Gastrointestinal recovery after surgery is of worldwide significance. Postoperative gastrointestinal dysfunction is multifaceted and known to represent a major source of postoperative morbidity, however, its significance to postoperative care across all surgical procedures is unknown. The complexity of postoperative gastrointestinal recovery is poorly defined within gastrointestinal surgery, and even less so outside this field. To inform the clinical care of surgical patients worldwide, this systematic review and meta-analysis will aim to characterise the duration of postoperative gastrointestinal recovery that can be expected across all surgical procedures and determine the associations between factors that may affect this. METHODS AND ANALYSIS: MEDLINE, Embase, Cochrane Library and CINAHL will be searched for studies reporting the time to first postoperative passage of stool after any surgical procedure. We will screen records, extract data and assess risk of bias in duplicate. Forest plots will be constructed for time to postoperative gastrointestinal recovery, as assessed by various outcome measures. Because of potential heterogeneity, a random-effects model will be used throughout the meta-analysis. Funnel plots will be used to test for publication bias. Meta-regressions will be undertaken where the outcome is the mean time to first postoperative passage of stool, with potential predictors and confounders being patient characteristics, postoperative outcomes and surgical factors. ETHICS AND DISSEMINATION: This study will not involve human or animal subjects and, thus, does not require ethics approval. The outcomes will be disseminated via publication in peer-reviewed scientific journal(s) and presentations at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42021256210.

Antagonising TLR4-TRIF signalling before or after a low-dose alcohol binge during adolescence prevents alcohol drinking but not seeking behaviour in adulthood.

Adolescents frequently engage in risky behaviours such as binge drinking. Binge drinking, in turn, perturbs neurodevelopment reinforcing reward seeking behaviour in adulthood. Current animal models are limited in their portrayal of this behaviour and the assessment of neuroimmune involvement (specifically the role of Toll-like receptor 4 (TLR4)). Therefore, the aims of this project were to develop a more relevant animal model of adolescent alcohol exposure and to characterise its effects on TLR4 signalling and alcohol-related behaviours later life. Balb/c mice received a short (P22-P25), low dose alcohol binge during in early adolescence, and underwent tests to investigate anxiety (elevated plus maze), alcohol seeking (conditioned place preference) and binge drinking behaviour (drinking in the dark) in adulthood. Four doses of alcohol during adolescence increased alcohol-induced conditioned place preference and alcohol intake in adulthood. However, this model did not affect basal elevated plus maze performance. Subsequent analysis of nucleus accumbal mRNA, revealed increased expression of TLR4-related mRNAs in mice who received alcohol during adolescence. To further elucidate the role of TLR4, (+)-Naltrexone, a biased TLR4 antagonist was administered 30 min before or after the adolescent binge paradigm. When tested in adulthood, (+)-Naltrexone treated mice exhibited reduced alcohol intake however, alcohol seeking and anxiety behaviour was unaltered. This study highlights that even a small amount of alcohol, when given during a critical neurodevelopmental period, can potentiate alcohol-related behaviours and TLR4 activation later in life. Interestingly, attenuation of TLR4 before or after adolescent alcohol exposure reduced only binge alcohol intake in adulthood.

Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy.

Drug addiction and dependence have proven to be difficult psychiatric disorders to treat. The limited efficacy of neuronally acting medications, such as acamprosate and naltrexone, highlights the need to identify novel targets. Recent research has underscored the importance of the neuroimmune system in many behavioural manifestations of drug addiction. In this review, we propose that our appreciation for complex phenotypes such as drug addiction and dependence will come with a greater understanding that these disorders are the result of intricate, interconnected signalling pathways that are, if only partially, determined at the receptor level. The idea of receptor heteromerisation and receptor mosaics will be introduced to explain cross talk between the receptors and signalling molecules implicated in neuroimmune signalling pathways.

Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction.

Opioids have historically, and continue to be, an integral component of pain management. However, despite pharmacokinetic and dynamic optimization over the past 100 years, opioids continue to produce many undesirable side effects such as tolerance, reward, and dependence. As such, opioids are liable for addiction. Traditionally, opioid addiction was viewed as a solely neuronal process, and while substantial headway has been made into understanding the molecular and cellular mechanisms mediating this process, research has however, been relatively ambivalent to how the rest of the central nervous system (CNS) responds to opioids. Evidence over the past 20 years has clearly demonstrated the importance of the immunocompetent cells of the CNS (glia) in many aspects of opioid pharmacology. Particular focus has been placed on microglia and astrocytes, who in response to opioids, become activated and release inflammatory mediators. Importantly, the mechanism underlying immune activation is beginning to be elucidated. Evidence suggests an innate immune pattern-recognition receptor (toll-like receptor 4) as an integral component underlying opioid-induced glial activation. The subsequent proinflammatory response may be viewed akin to neurotransmission creating a process termed central immune signaling. Translationally, we are beginning to appreciate the importance of central immune signaling as it contributes to many behavioral actions of addiction including reward, withdrawal, and craving. As such, the aim of this chapter is to review and integrate the neuronal and central immune signaling perspective of addiction.