Causal inference in perioperative medicine observational research: part 2, advanced methods.

Although RCTs represent the gold standard in clinical research, most clinical questions cannot be answered using this technique, because of ethical considerations, time, and cost. The goal of observational research in clinical medicine is to gain insight into the relationship between a clinical exposure and patient outcome, in the absence of evidence from RCTs. Observational research offers additional benefit when compared with data from RCTs: the conclusions are often more generalisable to a heterogenous population, which may be of greater value to everyday clinical practice. In Part 2 of this methods series, we will introduce the reader to several advanced methods for supporting the case for causality between an exposure and outcome, including: mediation analysis, natural experiments, and joint effects methods.

Causal inference in perioperative medicine observational research: part 1, a graphical introduction.

Graphical models have emerged as a tool to map out the interplay between multiple measured and unmeasured variables, and can help strengthen the case for a causal association between exposures and outcomes in observational studies. In Part 1 of this methods series, we will introduce the reader to graphical models for causal inference in perioperative medicine, and set the framework for Part 2 of the series involving advanced methods for causal inference.

Bleeding After Musculoskeletal Surgery in Hospitals That Switched From Hydroxyethyl Starch to Albumin Following a Food and Drug Administration Warning.

BACKGROUND: While US Food and Drug Administration (FDA) black box warnings are common, their impact on perioperative outcomes is unclear. Hydroxyethyl starch (HES) is associated with increased bleeding and kidney injury in patients with sepsis, leading to an FDA black box warning in 2013. Among patients undergoing musculoskeletal surgery in a subset of hospitals where colloid use changed from HES to albumin following the FDA warning, we examined the rate of major perioperative bleeding post- versus pre-FDA warning. METHODS: The authors of this article used a retrospective, quasi-experimental, repeated cross-sectional, interrupted time series study of patients undergoing musculoskeletal surgery in hospitals within the Premier Healthcare Database, in the year before and year after the 2013 FDA black box warning. We examined patients in 23 "switcher" hospitals (where the percentage of colloid recipients receiving HES exceeded 50% before the FDA warning and decreased by at least 25% in absolute terms after the FDA warning) and patients in 279 "nonswitcher" hospitals. Among patients having surgery in "switcher" and "nonswitcher" hospitals, we determined monthly rates of major perioperative bleeding during the 12 months after the FDA warning, compared to 12 months before the FDA warning. Among patients who received surgery in "switcher" hospitals, we conducted a propensity-weighted segmented regression analysis assessing differences-in-differences (DID), using patients in "nonswitcher" hospitals as a control group. RESULTS: Among 3078 patients treated at "switcher" hospitals (1892 patients treated pre-FDA warning versus 1186 patients treated post-FDA warning), demographic and clinical characteristics were well-balanced. Two hundred fifty-one (13.3%) received albumin pre-FDA warning, and 900 (75.9%) received albumin post-FDA warning. Among patients undergoing surgery in "switcher" hospitals during the pre-FDA warning period, 282 of 1892 (14.9%) experienced major bleeding during the hospitalization, compared to 149 of 1186 (12.6%) following the warning. In segmented regression, the adjusted ratio of slopes for major perioperative bleeding post- versus pre-FDA warning was 0.98 (95% confidence interval [CI], 0.93-1.04). In the DID estimate using "nonswitcher" hospitals as a control group, the ratio of ratios was 0.93 (95% CI, 0.46-1.86), indicating no significant difference. CONCLUSIONS: We identified a subset of hospitals where colloid use for musculoskeletal surgery changed following a 2013 FDA black box warning regarding HES use in sepsis. Among patients undergoing musculoskeletal surgery at these "switcher" hospitals, there was no significant decrease in the rate of major perioperative bleeding following the warning, possibly due to incomplete practice change. Evaluation of the impact of systemic changes in health care may contribute to the understanding of patient outcomes in perioperative medicine.

Seasonality and schizophrenia: a comprehensive overview of the seasonal pattern of hospital admissions and potential drivers.

Schizophrenia is a severe neuropsychiatric disorder with heterogeneous aetiology mostly affecting younger people and causing immense disability. Seasonal patterns may be observed in schizophrenia hospital admissions with possible association with changing climatic parameters and socio-demographic characteristics. This study critically reviewed studies that have assessed seasonal variations of hospital admissions for schizophrenia and/or explored an association with climate parameters and/or other potential factors. Following PRISMA guidelines, a systematic literature search was conducted using electronic databases (e.g. MEDLINE, Science Direct, PsycINFO, Pub Med) from inception to February 29, 2020. Thirty five papers were identified, of which only six (17.1%) examined evidence for a seasonal pattern or monthly excess of hospital admissions and the remaining twenty nine (82.9%) assessed climatic and socio-demographic attributes relating to the seasonal pattern or increased hospitalisation for schizophrenia. While most studies reported a summer peak in hospital admission rates, other studies reported a winter peak. Most of the evidence indicated that higher temperatures (> 28 °C) were positively correlated with schizophrenia admission rates. The individual effects of other climatic parameters (e.g. relative humidity, rainfall, atmospheric pressure, sunlight) were less frequently assessed. Males, people of 21-60 years old, and those married were more vulnerable to climatic variability specifically to higher temperatures. Further studies using large sample sizes, analysis of a wide range of interacting environmental variables and sophisticated statistical approaches are needed to better understand the underlying mechanisms involved. This will also provide more reliable statistical evidence that will help in the prevention and better management of cases.

Effects of Intraoperative Fluid Management on Postoperative Outcomes: A Hospital Registry Study.

OBJECTIVE: Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients. BACKGROUND: Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery. METHODS: This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors. RESULTS: A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6-7 mL/kg/hr or 1 L of fluid for a 3-hour case. CONCLUSIONS: Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay.

Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications.

BACKGROUND: Duration of action increases with repeated administration of neuromuscular-blocking agents, and intraoperative use of high doses of neuromuscular-blocking agent may affect respiratory safety. METHODS: In a hospital-based registry study on 48,499 patients who received intermediate-acting neuromuscular-blocking agents, the authors tested the primary hypothesis that neuromuscular-blocking agents are dose dependently associated with the risk of postoperative respiratory complications. In the secondary analysis, the authors evaluated the association between neostigmine dose given for reversal of neuromuscular-blocking agents and respiratory complications. Post hoc, the authors evaluated the effects of appropriate neostigmine reversal (neostigmine ≤ 60 µg/kg after recovery of train-of-four count of 2) on respiratory complications. The authors controlled for patient-, anesthesia-, and surgical complexity-related risk factors. RESULTS: High doses of neuromuscular-blocking agents were associated with an increased risk of postoperative respiratory complications (n = 644) compared with low doses (n = 205) (odds ratio [OR], 1.28; 95% CI, 1.04 to 1.57). Neostigmine was associated with a dose-dependent increase in the risk of postoperative respiratory complications (OR, 1.51; 95% CI, 1.25 to 1.83). Post hoc analysis revealed that appropriate neostigmine reversal eliminated the dose-dependent association between neuromuscular-blocking agents and respiratory complications (for neuromuscular-blocking agent effects with appropriate reversal: OR, 0.98; 95% CI, 0.63 to 1.52). CONCLUSIONS: The use of neuromuscular-blocking agents was dose dependently associated with increased risk of postoperative respiratory complications. Neostigmine reversal was also associated with a dose-dependent increase in the risk of respiratory complications. However, the exploratory data analysis suggests that the proper use of neostigmine guided by neuromuscular transmission monitoring results can help eliminate postoperative respiratory complications associated with the use of neuromuscular-blocking agents.

DSM-IV "criterion A" schizophrenia symptoms across ethnically different populations: evidence for differing psychotic symptom content or structural organization?

There is significant variation in the expression of schizophrenia across ethnically different populations, and the optimal structural and diagnostic representation of schizophrenia are contested. We contrasted both lifetime frequencies of DSM-IV criterion A (the core symptom criterion of the internationally recognized DSM classification system) symptoms and types/content of delusions and hallucinations in transethnic schizophrenia populations from Australia (n = 776), India (n = 504) and Sarawak, Malaysia (n = 259), to elucidate clinical heterogeneity. Differences in both criterion A symptom composition and symptom content were apparent. Indian individuals with schizophrenia reported negative symptoms more frequently than other sites, whereas individuals from Sarawak reported disorganized symptoms more frequently. Delusions of control and thought broadcast, insertion, or withdrawal were less frequent in Sarawak than Australia. Curiously, a subgroup of 20 Indian individuals with schizophrenia reported no lifetime delusions or hallucinations. These findings potentially challenge the long-held view in psychiatry that schizophrenia is fundamentally similar across cultural groups, with differences in only the content of psychotic symptoms, but equivalence in structural form.

Enigmatic fossil plants with three-dimensional, arborescent-growth architecture from the earliest Carboniferous of New Brunswick, Canada.

The evolution of arborescence in Devonian plants, followed by their architectural radiation in the Carboniferous, is a transition fundamental to Earth-system processes and ecological development. However, this evolutionary transition in trees is based on preserved trunks, of which only a few known specimens possess crowns. We describe Mississippian-aged (Tournaisian) trees with a unique three-dimensional crown morphology from New Brunswick, Canada. The trees were preserved by earthquake-induced, catastrophic burial of lake-margin vegetation. The tree architecture consists of an unbranched, 16-cm-diameter trunk with compound leaves arranged in spirals of ∼13 and compressed into ∼14 cm of vertical trunk length. Compound leaves in the upper ∼0.75 m of the trunk measure >1.75 m in length and preserve alternately arranged secondary laterals beginning at 0.5 m from the trunk; the area below the trunk bears only persistent leaf bases. The principal specimen lacks either apical or basal sections, although an apex is preserved in another. Apically, the leaves become less relaxed toward horizontal and are borne straight at an acute angle at the crown. The compact leaf organization and leaf length created a crown volume of >20-30 m3. This growth strategy likely maximized light interception and reduced resource competition from groundcover. From their growth morphology, canopy size, and volume, we propose that these fossils represent the earliest evidence of arborescent subcanopy-tiering. Moreover, although systematically unresolved, this specimen shows that Early Carboniferous vegetation was more complex than realized, signaling that it was a time of experimental, possibly transitional and varied, growth architectures.

Comparing preoperative fasting and ultrasound-measured intravascular volume status in elective surgery, enhanced recovery patients versus inpatient, urgent surgery patients and the ability of IVC collapsibility to predict post-induction hypotension.

Hypotension following induction of general anaesthesia has been shown to result in increased complications and mortality postoperatively. Patients admitted to the hospital undergoing urgent surgery are often fasted from fluids for significant periods compared to elective patients subject to Enhanced Recovery After Surgery protocols despite guidelines stating that a two-hour fast is sufficient. The aim of this prospective, observational study was to compare fasting times and intravascular volume status between elective surgery patients subject to enhanced recovery protocols and inpatient, urgent surgery patients and to assess differences in the incidence of post-induction hypotension. Fasting data was obtained by questionnaire in the preoperative area in addition to inferior vena cava collapsibility index, a non-invasive measure of intravascular volume. Blood pressure readings and drug administration for the ten minutes following induction were obtained from patients' charts. Inpatients undergoing urgent surgery were fasted significantly longer than enhanced recovery patients and had lower intravascular volume. However, no difference was found in the incidence of post-induction hypotension.

Venous Excess Ultrasound (VExUS Grading to Assess Perioperative Fluid Status for Noncardiac Surgeries: a Prospective Observational Pilot Study.

Objectives: Perioperative fluid administration impacts the rate of complications following surgery. VExUS grading system is a standardized point of care ultrasound (POCUS)-based, comprehensive method to assess volume status. VExUS could serve as a tool to guide fluid management, if validated perioperatively. The primary aim was to assess the success rate of obtaining required windows for VExUS grading , as well as the feasibility within a perioperative setting among noncardiac surgery. Further, this study describes the incidence of perioperative venous congestion and associations with 30-day postoperative complications. Methods: This observational study was conducted in non-critically ill adults undergoing noncardiac surgery. Patients were scanned preoperatively, in the post anesthesia care unit (PACU), and 24 hours postoperatively for venous congestion. Researchers retrospectively captured 30-day complications for multivariate analyses. Results: The cohort included 69 participants. Ninety-one percent of scans over all timepoints were successfully completed. Pre-operatively, 57 (83%) scans were Grade 0, and 11 (16%) were Grade 1. Venous congestion was observed in 29 (44%) patients in the PACU (n=66). 22 (33%) patients were Grade 1, while 7 (11%) were Grade 2. At 24 hours (n=63), 31 patients (49%) had venous congestion: 20 (32%) Grade 1 and 11 (17%) Grade 2. Of the pre-operative Grade 0, 28 (50%) had at least one postoperative scan with venous congestion. No patients were Grade 3 at any timepoint. The 30-day complication rate was 32% (n=22). Eleven (16%) patients developed acute kidney injury (AKI). There was no statistically significant association between VExUS grading and all-cause complications or AKI. Conclusion: This study demonstrates that perioperative VExUS scoring is a feasible tool among a variety of noncardiac surgeries. We highlight that venous congestion is common and increases postoperatively within non-ICU populations. Larger studies are needed to assess the relationship between VExUS grading and postoperative complications.

Refining clinical phenotypes by contrasting ethnically different populations with schizophrenia from Australia, India and Sarawak.

We contrasted demographic and clinical characteristics in transethnic schizophrenia populations from Australia (n=821), India (n=520) and Sarawak, Malaysia (n=298) and proposed cultural explanations for identified site differences. From these we aimed to identify candidate variables free from significant cultural confounding that are hence suitable for inclusion in genetic analyses. We observed five phenomena: (1) more individuals were living alone in Australia than India or Sarawak; (2) drug use was lower in India than Australia or Sarawak; (3) duration of untreated psychosis (DUP) was longer in India than Australia or Sarawak; (4) the rate of schizoaffective disorder was lower in India than Australia or Sarawak; and (5) age at psychosis onset (AAO) was older in Sarawak than Australia or India. We suggest that site differences for living arrangements, drug use and DUP are culturally confounded. The schizoaffective site difference likely results from measurement bias. The AAO site difference, however, has no obvious cultural or measurement bias explanation. Therefore, this may be an ideal candidate for use in genetic studies, given that genetic variants affecting AAO have already been proposed.

Significant relationship between lifetime alcohol use disorders and suicide attempts in an Australian schizophrenia sample.

OBJECTIVE: Suicide and attempted suicide are common in individuals with schizophrenia, and evidence exists for a link between substance use disorders and suicidality in this disorder. However, alcohol has not been consistently implicated. We examined the relationship between substance use disorders and suicide attempts in schizophrenia. METHODS: We recruited a schizophrenia sample in Australia (n = 821) for genetic analyses. We analysed demographic and clinical variables, including substance use disorders, and their relationship to suicide attempts using generalised equation modelling. RESULTS: A significant association was identified between lifetime alcohol abuse/dependence and suicide attempts (OR = 1.66; 95% CI, 1.23 to 2.24; p = 0.001) after adjustment for potential confounders, but not between cannabis abuse/dependence and suicide attempts, nor between other illicit drug abuse/dependence and suicide attempts. Polysubstance abuse/dependence was also not implicated. CONCLUSIONS: These results suggest that the presence of alcohol abuse/dependence may be a risk factor for suicide attempts in individuals with schizophrenia, independent of comorbid substance abuse/dependence.

Perioperative colloid choice and bleeding in patients undergoing musculoskeletal surgery: An observational administrative database study.

BACKGROUND: The synthetic colloid hydroxyethyl starch (HES) received a black box warning, issued by the US Food and Drug Administration (FDA) in June 2013, in patients with sepsis, due to increased risk of bleeding, renal injury, and death. Risks of HES in populations undergoing noncardiac surgery are unclear. Here, we examine the association of colloid choice - human-derived albumin versus HES - with bleeding in musculoskeletal surgery. METHODS: Inpatient musculoskeletal surgical patients who received colloids on the day of surgery were included during a time period before the FDA warning on HES using the Premier Healthcare database. The exposure was type of colloids administered on the day of surgery: HES versus albumin. The primary outcome was major perioperative bleeding, measured on the 1st postoperative day through hospital discharge. The secondary outcomes included acute renal failure and postoperative length of stay >75th percentile. RESULTS: We identified 41,211 patients who received albumin (n = 12,803) and HES (n = 28,408) on the day of surgery. The propensity-weighted multivariable analysis demonstrated a reduced risk of major perioperative bleeding on the day after surgery following treatment with albumin versus HES (relative risk: 0.89 [95% confidence interval, 0.84-0.93]). No significant differences were observed in the secondary outcomes. CONCLUSION: When compared with albumin, treatment with HES on the day of musculoskeletal surgery was associated with an increased risk of major perioperative bleeding on subsequent days. Given that HES continues to be used as a colloid in multiple patient populations worldwide, further studies examining the safety of HES versus albumin solutions are needed.

CTLA-4 single-nucleotide polymorphisms in a Caucasian population with schizophrenia.

Associations between a single-nucleotide polymorphism (SNP) in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene and schizophrenia in a Korean population have been previously described. The current study investigated whether a similar link occurs in a Caucasian population with schizophrenia. One hundred and twenty-two age- and sex-matched pairs of people with DSM-III-R diagnosis of schizophrenia and healthy controls were included in this study. Three previously described SNPs (from the promoter, exon 1 and 3' UTR) of the CTLA4 gene were analysed. In the entire sample, we detected no allelic or genotypic association for any of the three SNPs. Given documented gender differences in incidence of schizophrenia, we conducted separate analyses of male and female participants. In males, both the promoter region SNP (-318C/T) and the 3' UTR SNP demonstrated nominally significant association with schizophrenia. The 3' UTR SNP remained significant following correction for multiple testing (permuted P=0.046). In addition, all possible haplogenotypes showed significant association with disease in males with two--both containing the 3' UTR SNP--remaining significant following correction for the genotypic tests of all SNPs and haplogenotypes in males. These results suggest a role for the 3' UTR SNP and/or variants in high linkage disequilibrium with this SNP in the pathogenesis of schizophrenia.

Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.

Importance: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. Objective: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. Design, Setting, and Participants: This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Main Outcomes and Measures: Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. Results: The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Conclusions and Relevance: Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.

Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses.

We previously demonstrated that olfactory cultures from individuals with schizophrenia had increased cell proliferation compared to cultures from healthy controls. The aims of this study were to (a) replicate this observation in a new group of individuals with schizophrenia, (b) examine the specificity of these findings by including individuals with bipolar I disorder and (c) explore gene expression differences that may underlie cell cycle differences in these diseases. Compared to controls (n = 10), there was significantly more mitosis in schizophrenia patient cultures (n = 8) and significantly more cell death in the bipolar I disorder patient cultures (n = 8). Microarray data showed alterations to the cell cycle and phosphatidylinositol signalling pathways in schizophrenia and bipolar I disorder, respectively. Whilst caution is required in the interpretation of the array results, the study provides evidence indicating that cell proliferation and cell death in olfactory neuroepithelial cultures is differentially altered in schizophrenia and bipolar disorder.

Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines.

INTRODUCTION: The aim of this study was to investigate whether there is an increased susceptibility to apoptosis in cultured fibroblasts from patients with schizophrenia. METHOD: Dermal fibroblasts were collected and cultured from three groups: patients with schizophrenia, patients with non-schizophrenic psychosis, and healthy comparison subjects. Susceptibility to apoptosis was measured at the level of degradation product (proportion of cells in the sub-G0 cell cycle fraction in which apoptotic bodies accumulate), pro-apoptotic effector (activated caspase-3), and molecular regulators (P53, Bax and Bcl-2). Cell lines were studied under both basal culture and cycloheximide (an apoptotic inducer) exposure conditions. RESULTS: Consistent with increased susceptibility to apoptosis, the proportion of sub-G0 cells under basal conditions was significantly larger in the schizophrenia group, compared to the non-schizophrenic psychosis group. However when apoptosis was stimulated with cycloheximide, the schizophrenia group showed an attenuated caspase-3 response. The pattern of correlations between regulators, caspase-3 and the proportion of sub-G0 cells was different in the schizophrenia group, consistent with group-specific apoptotic pathway dysregulation. CONCLUSION: The study demonstrated anomalous apoptotic mechanisms in schizophrenia, which appear not to affect non-schizophrenia psychosis patients. The detection of these anomalies in fibroblasts suggests that altered apoptosis may be observable in all somatic cell types in schizophrenia.