Dexamethasone and Surgical-Site Infection.

BACKGROUND: The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection. METHODS: In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours' duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points. RESULTS: A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, -0.9 percentage points; 95.6% confidence interval [CI], -2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group. CONCLUSIONS: Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695.).

Candidate Kidney Protective Strategies for Patients Undergoing Major Abdominal Surgery: A Secondary Analysis of the RELIEF Trial Cohort.

BACKGROUND: Acute kidney injury (AKI) is common after major abdominal surgery. Selection of candidate kidney protective strategies for testing in large trials should be based on robust preliminary evidence. METHODS: A secondary analysis of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial was conducted in adult patients undergoing major abdominal surgery and randomly assigned to a restrictive or liberal perioperative fluid regimen. The primary outcome was maximum AKI stage before hospital discharge. Two multivariable ordinal regression models were developed to test the primary hypothesis that modifiable risk factors associated with increased maximum stage of postoperative AKI could be identified. Each model used a separate approach to variable selection to assess the sensitivity of the findings to modeling approach. For model 1, variable selection was informed by investigator opinion; for model 2, the Least Absolute Shrinkage and Selection Operator (LASSO) technique was used to develop a data-driven model from available variables. RESULTS: Of 2,444 patients analyzed, stage 1, 2, and 3 AKI occurred in 223 (9.1%), 59 (2.4%), and 36 (1.5%) patients, respectively. In multivariable modeling by model 1, administration of a nonsteroidal anti-inflammatory drug or cyclooxygenase-2 inhibitor, intraoperatively only (odds ratio, 1.77 [99% CI, 1.11 to 2.82]), and preoperative day-of-surgery administration of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker compared to no regular use (odds ratio, 1.84 [99% CI, 1.15 to 2.94]) were associated with increased odds for greater maximum stage AKI. These results were unchanged in model 2, with the additional finding of an inverse association between nadir hemoglobin concentration on postoperative day 1 and greater maximum stage AKI. CONCLUSIONS: Avoiding intraoperative nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors is a potential strategy to mitigate the risk for postoperative AKI. The findings strengthen the rationale for a clinical trial comprehensively testing the risk-benefit ratio of these drugs in the perioperative period.

A protocol for a prospective, multicentre observational study to determine if nonanaemic iron deficiency worsens postoperative outcome in patients undergoing elective surgery for resection of colorectal cancer: The NATO study.

BACKGROUND: Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically plausible that "early", or "nonanaemic" iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality. METHODS: We have designed a prospective, observational study to delineate associations between preoperative non-anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health-related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two-day difference in the primary outcome. The study commenced in May 2019. CONCLUSION: The results of this study will provide patients and clinicians with high-quality evidence concerning associations between nonanaemic iron deficiency and patient-centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.

Low tidal volume ventilation for patients undergoing laparoscopic surgery: a secondary analysis of a randomised clinical trial.

BACKGROUND: We recently reported the results for a large randomized controlled trial of low tidal volume ventilation (LTVV) versus conventional tidal volume (CTVV) during major surgery when positive end expiratory pressure (PEEP) was equal between groups. We found no difference in postoperative pulmonary complications (PPCs) in patients who received LTVV. However, in the subgroup of patients undergoing laparoscopic surgery, LTVV was associated with a numerically lower rate of PPCs after surgery. We aimed to further assess the relationship between LTVV versus CTVV during laparoscopic surgery. METHODS: We conducted a post-hoc analysis of this pre-specified subgroup. All patients received volume-controlled ventilation with an applied PEEP of 5 cmH2O and either LTVV (6 mL/kg predicted body weight [PBW]) or CTVV (10 mL/kg PBW). The primary outcome was the incidence of a composite of PPCs within seven days. RESULTS: Three hundred twenty-eight patients (27.2%) underwent laparoscopic surgeries, with 158 (48.2%) randomised to LTVV. Fifty two of 157 patients (33.1%) assigned to LTVV and 72 of 169 (42.6%) assigned to conventional tidal volume developed PPCs within 7 days (unadjusted absolute difference, - 9.48 [95% CI, - 19.86 to 1.05]; p = 0.076). After adjusting for pre-specified confounders, the LTVV group had a lower incidence of the primary outcome than patients receiving CTVV (adjusted absolute difference, - 10.36 [95% CI, - 20.52 to - 0.20]; p = 0.046). CONCLUSION: In this post-hoc analysis of a large, randomised trial of LTVV we found that during laparoscopic surgeries, LTVV was associated with a significantly reduced PPCs compared to CTVV when PEEP was applied equally between both groups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry no: 12614000790640.

Feasibility and acceptability of the use of flash glucose monitoring encountered by Indigenous Australians with type 2 diabetes mellitus: initial experiences from a pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is highly prevalent within the Indigenous Australian community. Novel glucose monitoring technology offers an accurate approach to glycaemic management, providing real-time information on glucose levels and trends. The acceptability and feasibilility of this technology in Indigenous Australians with T2DM has not been investigated. OBJECTIVE: This feasibility phenomenological study aims to understand the experiences of Indigenous Australians with T2DM using flash glucose monitoring (FGM). METHODS: Indigenous Australians with T2DM receiving injectable therapy (n = 8) who used FGM (Abbott Freestyle Libre) for 6-months, as part of a clinical trial, participated in semi-structured interviews. Thematic analysis of the interviews was performed using NVivo12 Plus qualitative data analysis software (QSR International). RESULTS: Six major themes emerged: 1) FGM was highly acceptable to the individual; 2) FGM's convenience was its biggest benefit; 3) data from FGM was a tool to modify lifestyle choices; 4) FGM needed to be complemented with health professional support; 5) FGM can be a tool to engage communities in diabetes management; and 6) cost of the device is a barrier to future use. CONCLUSIONS: Indigenous Australians with T2DM had positive experiences with FGM. This study highlights future steps to ensure likelihood of FGM is acceptable and effective within the wider Indigenous Australian community.

The epidemiology of rapid response team activation amongst patients undergoing major gastrointestinal surgery.

BACKGROUND: Clinical deterioration requiring rapid response team (RRT) review is associated with increased morbidity amongst hospitalised patients. The frequency of and association with RRT calls in patients undergoing major gastrointestinal surgery is unknown. Understanding the epidemiology of RRT calls might identify areas for quality improvement in this cohort. OBJECTIVES: The objective of this study is to identify perioperative risks and outcome associations with RRT review following major gastrointestinal surgery. METHODS: We conducted a retrospective cohort study using electronic databases at a large Australian university hospital. We included adult patients admitted for major gastrointestinal surgery between 1 January 2015 and 31 March 2018. RESULTS: Of 7158 patients, 514 (7.4%) required RRT activation postoperatively. After adjustment, variables associated with RRT activation included the following: hemiplegia/paraplegia (odds ratio [OR]: 8.0, 95% confidence interval [CI]: 2.3 to 27.8, p = 0.001), heart failure (OR: 6.9, 95% CI: 3.3 to 14.6, p < 0.001), peripheral vascular disease (OR: 5.3, 95% CI: 2.7 to 10.4, p < 0.001), peptic ulcer disease (OR: 4.2, 95% CI: 2.2 to 8.0, p < 0.001), chronic obstructive pulmonary disease (OR: 4.0, 95% CI: 2.2 to 7.2, p < 0.001), and emergency admission status (OR: 2.6, 95% CI: 2.1 to 3.3, p < 0.001). Following the index operation, 46% of first RRT activations occurred within 24 h of surgery and 61% had occurred within 48 h. The most common triggers for RRT activation were tachycardia, hypotension, and tachypnoea. Postoperative RRT activation was associated with in-hospital mortality (OR: 6.7, 95% CI: 3.8 to 11.8, p < 0.001), critical care admission (incidence rate ratio: 8.18, 95% CI: 5.23 to 12.77, p < 0.001), and longer median length of hospital stay (12 days vs. 2 days, p < 0.001) compared to no RRT activation. CONCLUSION: After major gastrointestinal surgery, one in 14 patients had an RRT activation, almost half within 24 h of surgery. Such activation was independently associated with increased morbidity and mortality. Identified associations may guide more pre-emptive management for those at an increased risk of RRT activation.

Inclusion, characteristics, and outcomes of male and female participants in large international perioperative studies.

BACKGROUND: We compared baseline characteristics and outcomes and evaluated the subgroup effects of randomised interventions by sex in males and females in large international perioperative trials. METHODS: Nine randomised trials and two cohort studies recruiting adult patients, conducted between 1995 and 2020, were included. Baseline characteristics and outcomes common to six or more studies were evaluated. Regression models included terms for sex, study, and an interaction between the two. Comparing outcomes without adjustment for baseline characteristics represents the 'total effect' of sex on the outcome. RESULTS: Of 54 626 participants, 58% were male and 42% were female. Females were less likely to have ASA physical status ≥3 (56% vs 64%), to smoke (15% vs 23%), have coronary artery disease (21% vs 32%), or undergo vascular surgery (10% vs 23%). The pooled incidence of death was 1.6% in females and 1.8% in males (risk ratio [RR] 0.92; 95% confidence interval [CI]: 0.81-1.05; P=0.20), of myocardial infarction was 4.2% vs 4.5% (RR 0.92; 95% CI: 0.81-1.03; P=0.10), of stroke was 0.5% vs 0.6% (RR 1.03; 95% CI: 0.79-1.35; P=0.81), and of surgical site infection was 8.6% vs 8.3% (RR 1.03; 95% CI: 0.79-1.35; P=0.70). Treatment effects of three interventions demonstrated statistically significant effect modification by sex. CONCLUSIONS: Females were in the minority in all included studies. They were healthier than males, but outcomes were comparable. Further research is needed to understand the reasons for this discrepancy. CLINICAL TRIAL REGISTRATION: International Registry of Meta-Research (UID: IRMR_000011; 5 January 2021).

Postoperative anaemia and patient-centred outcomes after major abdominal surgery: a retrospective cohort study.

BACKGROUND: Compared with anaemia before surgery, the underlying pathogenesis and implications of postoperative anaemia are largely unknown. METHODS: This retrospective cohort study analysed prospective data obtained from 2983 adult patients across 47 centres enrolled in a clinical trial evaluating restrictive and liberal intravenous fluids. The primary endpoint was persistent disability or death up to 90 days after surgery. Secondary endpoints included major septic complications, hospital stay, and patient quality of recovery using a 15-item quality of recovery (QoR-15) score, hospital re-admissions, and disability-free survival up to 12 months after surgery. Anaemia and disability were defined according to the WHO definitions. Multivariable regression was used to adjust for baseline risk and surgery. RESULTS: A total of 2983 patients met inclusion criteria for this study, of which 78.5% (95% confidence interval [CI], 76.7-80.1%) had postoperative anaemia. Patients with postoperative anaemia had a higher adjusted risk of death or disability up to 90 days after surgery when compared with those without anaemia: 18.2% vs 9.2% (risk ratio [RR]=1.51; 95% CI, 1.10-2.07, P=0.011); lower QoR-15 scores on Day 3 and Day 30, 105 (95% CI, 87-119) vs 114 (95% CI, 99-128; P<0.001), and 130 (95% CI, 112-140) vs 139 (95% CI, 121-144; P<0.011), respectively; higher adjusted risk of a composite of mortality/septic complications, 2.01 (95% CI, 1.55-42.67; P<0.001); unplanned admission to ICU (RR=2.65; 95% CI, 1.65-4.23; P<0.001); and longer median (inter-quartile range [IQR]) hospital stays, 6.6 (4.4-12.4) vs 3.7 (2.5-6.5) days (P<0.001). CONCLUSIONS: Postoperative anaemia is common and is independently associated with poor outcomes after surgery. Optimal prevention and treatment strategies need to be investigated. CLINICAL TRIAL REGISTRATION: NCT04978285 (ClinicalTrials.gov).

Exploring patient acceptability of a short-stay care pathway in hospital post arthroplasty: A theory-informed qualitative study.

INTRODUCTION: Arthroplasty is an effective, yet costly, surgical procedure for end-stage osteoarthritis. Shorter stays in hospital are being piloted in Australia. In some countries, short stay is established practice, associated with improving perioperative care and enhanced recovery after surgery practices. Exploring the acceptability to patients of a short stay care pathway in hospital postarthroplasty is important for informing health policy, adoption and potential scalability of this model of care. METHODS: Consecutive patients at one site, at least 3 months post total joint arthroplasty, were invited to participate in theory-informed semi-structured qualitative interviews. The Theoretical Framework of Acceptability (TFA) informed development of the interview guide. Interview data were analysed using the Framework Method. RESULTS: Eighteen patients were invited. Fifteen consented to be contacted and were interviewed. Short-stay post arthroplasty was highly acceptable to patients who had the supports necessary to recover safely at home. Key findings were as follows: flexibility of short-stay care pathway was essential and valued; prior beliefs and expectations informed acceptability; and the absence of out-of-pocket expenses had an incentivizing effect, but was not the primary reason for patients choosing this care pathway. Further themes analysed within the TFA constructs highlighted nuances of acceptability relating to this model of care. CONCLUSIONS: A short stay in hospital post arthroplasty appeared to be acceptable to patients who had experienced this care pathway. Our thematic findings identified aspects of the short-stay care pathway that enhanced acceptability and some aspects that limited acceptability. These findings can inform refinement of the short-stay care pathway. PATIENT OR PUBLIC CONTRIBUTION: Patients/people with lived experience were not involved in the study design or conduct of this preliminary work; as this short-stay model of care was recently introduced, only a small group of patients was eligible to participate in this study. This study is the first step towards understanding the experiences of patients about a short-stay model of care post arthroplasty. The findings will help inform future patient and public involvement in expanding the programme.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

Intra-operative ventilator mechanical power as a predictor of postoperative pulmonary complications in surgical patients: A secondary analysis of a randomised clinical trial.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P < 0.001) and acute respiratory failure (OR 1.40, 95% CI, 1.21 to 1.61; P < 0.001). CONCLUSION: In patients receiving ventilation during major noncardiothoracic, nonintracranial surgery, exposure to a higher mechanical power was independently associated with an increased risk of PPCs and acute respiratory failure. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry no: 12614000790640.

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery.

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).

In Vivo Molding of Airway Stents.

Like ready-to-wear clothing, medical devices come in a fixed set of sizes. While this may accommodate a large fraction of the patient population, others must either experience suboptimal results due to poor sizing or must do without the device. Although techniques have been proposed to fabricate patient-specific devices in advance of a procedure, this process is expensive and time consuming. An alternative solution that provides every patient with a tailored fit is to create devices that can be customized to the patient's anatomy as they are delivered. This paper reports an in vivo molding process in which a soft flexible photocurable stent is delivered into the trachea or bronchi over a UV-transparent balloon. The balloon is expanded such that the stent conforms to the varying cross-sectional shape of the airways. UV light is then delivered through the balloon curing the stent into its expanded conformal shape. The potential of this method is demonstrated using phantom, ex vivo and in vivo experiments. This approach can produce stents providing equivalent airway support to those made from standard materials while providing a customized fit.

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis.

Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.

Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology.

Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na+ and K+ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

Accuracy of the Clinical Frailty Scale for perioperative frailty screening: a prospective observational study.

PURPOSE: Perioperative frailty increases postoperative complications, mortality, and new functional dependence. Despite this, routine perioperative frailty screening is not widespread. We aimed to assess the accuracy of the Clinical Frailty Scale (CFS) as a screening tool prior to anesthesia, and to determine which health domains are affected by frailty. METHODS: In a prospective, single-centre observational study, we enrolled 218 patients aged ≥ 65 yr undergoing elective and emergency surgery. The screening performance of the CFS was compared with the Edmonton Frail Scale, including the effect in individual frailty domains, and outcomes including discharge location and mortality. RESULTS: The median [interquartile range] age of the enrolled subjects was 74 [69-80] yr and 24% of the patients were frail. The CFS and Edmonton scales were highly correlated (Spearman correlation coefficient, 0.81; 95% confidence interval [CI], 0.77 to 0.86), and in substantial agreement (kappa coefficient, 0.76; 95% CI, 0.70 to 0.81), with an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.86 to 0.94) indicating excellent discrimination for the CFS in predicting frailty status based on the Edmonton scale. Frail patients had higher 30-day mortality (odds ratio, 5.26; 95% CI, 1.28 to 21.62), and were less likely to be discharged home. Frail patients had poorer health throughout frailty domains, including functional dependence (42% of frail vs 4% of non-frail patients; P < 0.001), malnutrition (48% vs 19%, P < 0.001), and poor physical performance (47% vs 7%, P < 0.001). CONCLUSION: The CFS is a valid and accurate tool to screen for perioperative frailty, which encompasses the spectrum of health-related domains.

RéSUMé: OBJECTIF: La fragilité périopératoire augmente les complications postopératoires, la mortalité et une nouvelle dépendance fonctionnelle. Le dépistage de routine de la fragilité périopératoire n'est cependant pas une pratique répandue. Nous avions pour objectif d'évaluer la précision de l'échelle de mesure de fragilité CFS (pour Clinical Frailty Scale) comme outil de dépistage préanesthésique et de déterminer quels domaines de la santé étaient affectés par la fragilité. MéTHODE: Nous avons recruté 218 patients âgés de plus de 65 ans et subissant une chirurgie non urgente ou urgente dans notre étude observationnelle prospective et monocentrique. Les résultats du dépistage de la CFS ont été comparés à l'échelle de fragilité d'Edmonton (Edmonton Frail Scale), y compris en ce qui a trait à l'effet de la fragilité sur les domaines individuels de fragilité et aux résultats tels que la destination au congé et la mortalité. RéSULTATS: L'âge médian [écart interquartile] des patients recrutés était de 74 [69­80] ans et 24 % des patients étaient fragiles. Les échelles CFS et d'Edmonton avaient une forte corrélation (coefficient de corrélation de Spearman, 0,81; intervalle de confiance [IC] 95 %, 0,77 à 0,86) et étaient en accord substantiel (coefficient kappa, 0,76; IC 95 %, 0,70 à 0,81), avec une surface sous la courbe de fonction d'efficacité de l'observateur de 0,91 (IC 95 %, 0,86 à 0,94), indiquant une discrimination excellente de la CFS pour prédire l'état de fragilité fondé sur l'échelle d'Edmonton. Les patients fragiles souffraient d'une mortalité à 30 jours plus élevée (rapport de cotes, 5,26; IC 95 %, 1,28 à 21,62) et il était moins probable qu'ils reçoivent leur congé de l'hôpital à la maison. Les patients fragiles étaient en moins bonne santé dans tous les domaines de fragilité, notamment en dépendance fonctionnelle (42 % des patients fragiles vs 4 % des patients non fragiles; P < 0,001), en malnutrition (48 % vs 19 %, P < 0,001) et en mauvaise performance physique (47 % vs 7 %, P < 0,001). CONCLUSION: L'échelle CFS constitue un outil valable et précis pour dépister la fragilité périopératoire, qui englobe l'éventail des domaines liés à la santé.

Effect of Intraoperative Low Tidal Volume vs Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery: A Randomized Clinical Trial.

Importance: In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear. Objective: To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications. Design, Setting, and Participants: Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019. Interventions: Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H2O. Main Outcomes and Measures: The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or noninvasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality. Results: Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, -1.3% [95% CI, -6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11]; P = .64). There were no significant differences in any of the secondary outcomes. Conclusions and Relevance: Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days. Trial Registration: ANZCTR Identifier: ACTRN12614000790640.

12-month randomised controlled trial of ginseng extract for moderate COPD.

BACKGROUND: Panax ginseng (ginseng) is a therapeutic herb which might be beneficial in COPD. The study investigated if ginseng, compared with placebo, is effective and safe for people with moderate COPD. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial compared 24 weeks of ginseng capsules (100 mg twice daily) with placebo. Participants were followed up for a further 24 weeks. Participants were aged 40 years and over and had airflow limitation in the moderate (Global Initiative for Chronic Obstructive Lung Disease 2) COPD range. The coprimary endpoints were the St George's Respiratory Questionnaire, the COPD Assessment Test and the Short Form Health Survey. Secondary outcomes included lung function, exacerbation rate and use of relief medication. FINDINGS: 168 participants were randomised 1:1 from five centres in Australia and China. Baseline characteristics were balanced between groups. There were no significant differences between ginseng and placebo, with overall results improving in both groups. Ginseng seemed safe for, and well tolerated by, people with COPD. INTERPRETATION: There was no significant difference in improvement in health-related quality of life (primary outcome) between the ginseng and placebo groups. TRIAL REGISTRATION NUMBER: ACTRN12610000768099.