Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. SIGNIFICANCE: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.

Achieving equity: patient demographics and outcomes after surgical and non-surgical procedures in South Australia, 2022.

BACKGROUND: Although modern Australian healthcare systems provide patient-centred care, the ability to predict and prevent suboptimal post-procedural outcomes based on patient demographics at admission may improve health equity. This study aimed to identify patient demographic characteristics that might predict disparities in mortality, readmission, and discharge outcomes after either an operative or non-operative procedural hospital admission. METHODS: This retrospective cohort study included all surgical and non-surgical procedural admissions at three of the four major metropolitan public hospitals in South Australia in 2022. Multivariable logistic regression, with backwards selection, evaluated association between patient demographic characteristics and outcomes up to 90 days post-procedurally. RESULTS: 40 882 admissions were included. Increased likelihood of all-cause, post-procedure mortality in-hospital, at 30 days, and 90 days, were significantly associated with increased age (P < 0.001), increased comorbidity burden (P < 0.001), an emergency admission (P < 0.001), and male sex (P = 0.046, P = 0.03, P < 0.001, respectively). Identification as ATSI (P < 0.001) and being born in Australia (P = 0.03, P = 0.001, respectively) were associated with an increased likelihood of 30-day hospital readmission and decreased likelihood of discharge directly home, as was increased comorbidity burden (P < 0.001) and emergency admission (P < 0.001). Being married (P < 0.001) and male sex (P = 0.003) were predictive of an increased likelihood of discharging directly home; in contrast to increased age (P < 0.001) which was predictive of decreased likelihood of this occurring. CONCLUSIONS: This study characterized several associations between patient demographic factors present on admission and outcomes after surgical and non-surgical procedures, that can be integrated within patient flow pathways through the Australian healthcare system to improve healthcare equity.

One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication.

PURPOSE: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells. EXPERIMENTAL DESIGN: Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. RESULTS: Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells. CONCLUSIONS: Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Opioid prescribing, pain, and hospital stay of general surgery patients with oxycodone allergies in South Australia.

BACKGROUND: The frequency of oxycodone adverse reactions, subsequent opioid prescription, effect on pain and patient care in general surgery patients are not well known. This study aimed to determine prevalence of documented oxycodone allergy and intolerances (independent variables) in a general surgical cohort, and association with prescribing other analgesics (particularly opioids), subjective pain scores, and length of hospital stay (dependent variables). METHODS: This retrospective cohort study included general surgery patients from two South Australian hospitals between April 2020 and March 2022. Multivariable logistic regression evaluated associations between previous oxycodone allergies and intolerances, prescription records, subjective pain scores, and length of hospital stay. RESULTS: Of 12 846 patients, 216 (1.7%) had oxycodone allergies, and 84 (0.7%) oxycodone intolerances. The 216 oxycodone allergy patients had lower odds of receiving oxycodone (OR 0.17, P < 0.001), higher odds of tramadol (OR 3.01, P < 0.001) and tapentadol (OR 2.87, P = 0.001), but 91 (42.3%) still received oxycodone and 19 (8.8%) morphine. The 84 with oxycodone intolerance patients had lower odds of receiving oxycodone (OR 0.23, P < 0.001), higher odds of fentanyl (OR 3.6, P < 0.001) and tramadol (OR 3.35, P < 0.001), but 42 (50%) still received oxycodone. Patients with oxycodone allergies and intolerances had higher odds of elevated subjective pain (OR 1.60, P = 0.013; OR 2.36, P = 0.002, respectively) and longer length of stay (OR 1.36, P = 0.038; OR 2.24, P = 0.002, respectively) than patients without these. CONCLUSIONS: General surgery patients with oxycodone allergies and intolerances are at greater risk of worse postoperative pain and longer length of stay, compared to patients without. Many still receive oxycodone, and other opioids that could cause cross-reactivity.

Surgery's Rosetta Stone: Natural language processing to predict discharge and readmission after general surgery.

BACKGROUND: This study aimed to examine the accuracy with which multiple natural language processing artificial intelligence models could predict discharge and readmissions after general surgery. METHODS: Natural language processing models were derived and validated to predict discharge within the next 48 hours and 7 days and readmission within 30 days (based on daily ward round notes and discharge summaries, respectively) for general surgery inpatients at 2 South Australian hospitals. Natural language processing models included logistic regression, artificial neural networks, and Bidirectional Encoder Representations from Transformers. RESULTS: For discharge prediction analyses, 14,690 admissions were included. For readmission prediction analyses, 12,457 patients were included. For prediction of discharge within 48 hours, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.86 and 0.86 for Bidirectional Encoder Representations from Transformers, 0.82 and 0.81 for logistic regression, and 0.82 and 0.81 for artificial neural networks. For prediction of discharge within 7 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.82 and 0.81 for Bidirectional Encoder Representations from Transformers, 0.75 and 0.72 for logistic regression, and 0.68 and 0.67 for artificial neural networks. For readmission prediction within 30 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.55 and 0.59 for Bidirectional Encoder Representations from Transformers and 0.77 and 0.62 for logistic regression. CONCLUSION: Modern natural language processing models, particularly Bidirectional Encoder Representations from Transformers, can effectively and accurately identify general surgery patients who will be discharged in the next 48 hours. However, these approaches are less capable of identifying general surgery patients who will be discharged within the next 7 days or who will experience readmission within 30 days of discharge.

Sociocultural and Demographic Factors Predict Readmissions for General Surgery Patients.

INTRODUCTION: Readmission is a poor outcome for both patients and healthcare systems. The association of certain sociocultural and demographic characteristics with likelihood of readmission is uncertain in general surgical patients. METHOD: A multi-centre retrospective cohort study of consecutive unique individuals who survived to discharge during general surgical admissions was conducted. Sociocultural and demographic variables were evaluated alongside clinical parameters (considered both as raw values and their proportion of change in the 1-2 days prior to admission) for their association with 7 and 30 days readmission using logistic regression. RESULTS: There were 12,701 individuals included, with 304 (2.4%) individuals readmitted within 7 days, and 921 (7.3%) readmitted within 30 days. When incorporating absolute values of clinical parameters in the model, age was the only variable significantly associated with 7-day readmission, and primary language and presence of religion were the only variables significantly associated with 30-day readmission. When incorporating change in clinical parameters between the 1-2 days prior to discharge, primary language and religion were predictive of 30-day readmission. When controlling for changes in clinical parameters, only higher comorbidity burden (represented by higher Charlson comorbidity index score) was associated with increased likelihood of 30-day readmission. CONCLUSIONS: Sociocultural and demographic patient factors such as primary language, presence of religion, age, and comorbidity burden predict the likelihood of 7 and 30-day hospital readmission after general surgery. These findings support early implementation a postoperative care model that integrates all biopsychosocial domains across multiple disciplines of healthcare.

Vital signs and medical emergency response (MER) activation predict in-hospital mortality in general surgery patients: a study of 15 969 admissions.

BACKGROUND: The applicability of the vital signs prompting medical emergency response (MER) activation has not previously been examined specifically in a large general surgical cohort. This study aimed to characterize the distribution, and predictive performance, of four vital signs selected based on Australian guidelines (oxygen saturation, respiratory rate, systolic blood pressure and heart rate); with those of the MER activation criteria. METHODS: A retrospective cohort study was conducted including patients admitted under general surgical services of two hospitals in South Australia over 2 years. Likelihood ratios for patients meeting MER activation criteria, or a vital sign in the most extreme 1% for general surgery inpatients (<0.5th percentile or > 99.5th percentile), were calculated to predict in-hospital mortality. RESULTS: 15 969 inpatient admissions were included comprising 2 254 617 total vital sign observations. The 0.5th and 99.5th centile for heart rate was 48 and 133, systolic blood pressure 85 and 184, respiratory rate 10 and 31, and oxygen saturations 89% and 100%, respectively. MER activation criteria with the highest positive likelihood ratio for in-hospital mortality were heart rate ≤ 39 (37.65, 95% CI 27.71-49.51), respiratory rate ≥ 31 (15.79, 95% CI 12.82-19.07), and respiratory rate ≤ 7 (10.53, 95% CI 6.79-14.84). These MER activation criteria likelihood ratios were similar to those derived when applying a threshold of the most extreme 1% of vital signs. CONCLUSIONS: This study demonstrated that vital signs within Australian guidelines, and escalation to MER activation, appropriately predict in-hospital mortality in a large cohort of patients admitted to general surgical services in South Australia.

The Adelaide Score: An artificial intelligence measure of readiness for discharge after general surgery.

BACKGROUND: This study aimed to examine the performance of machine learning algorithms for the prediction of discharge within 12 and 24 h to produce a measure of readiness for discharge after general surgery. METHODS: Consecutive general surgery patients at two tertiary hospitals, over a 2-year period, were included. Observation and laboratory parameter data were stratified into training, testing and validation datasets. Random forest, XGBoost and logistic regression models were evaluated. Each ward round note time was taken as a different event. Primary outcome was classification accuracy of the algorithmic model able to predict discharge within the next 12 h on the validation data set. RESULTS: 42 572 ward round note timings were included from 8826 general surgery patients. Discharge occurred within 12 h for 8800 times (20.7%), and within 24 h for 9885 (23.2%). For predicting discharge within 12 h, model classification accuracies for derivation and validation data sets were: 0.84 and 0.85 random forest, 0.84 and 0.83 XGBoost, 0.80 and 0.81 logistic regression. For predicting discharge within 24 h, model classification accuracies for derivation and validation data sets were: 0.83 and 0.84 random forest, 0.82 and 0.81 XGBoost, 0.78 and 0.79 logistic regression. Algorithms generated a continuous number between 0 and 1 (or 0 and 100), representing readiness for discharge after general surgery. CONCLUSIONS: A derived artificial intelligence measure (the Adelaide Score) successfully predicts discharge within the next 12 and 24 h in general surgery patients. This may be useful for both treating teams and allied health staff within surgical systems.

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.

Potentially avoidable mortality after endoscopic retrograde cholangiopancreatography in Australia: an 8-year qualitative analysis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a commonly performed procedure worldwide. The aim of this study was to examine cases of mortality after ERCP to identify clinical incidents that are potentially preventable, to improve patient safety. METHODS: The Australian and New Zealand Audit of Surgical Mortality provides an independent and externally peer-reviewed audit of surgical mortality pertaining to potentially avoidable issues. A retrospective review of prospectively collected data within this database was performed for the 8-year audit period from 1 January 2009 to 31 December 2016. Clinical incidents were identified by assessors through first- or second-line review, and thematically coded into periprocedural stages. These themes were then qualitatively analysed. RESULTS: There were 58 potentially avoidable deaths following ERCP, with 85 clinical incidents. Preprocedural incidents were most common (n = 37), followed by postprocedural (n = 32) and then intraprocedural (n = 8). Communication issues occurred across the periprocedural period (n = 8). Preprocedural incidents included delay to procedure, inadequate resuscitative management, decision to perform procedure and inadequate assessment. Intraprocedural incidents comprised technical factors and inadequate support. Postprocedural incidents involved inappropriate treatment, delay in definitive surgical treatment or in recognizing complications, inappropriate second-line intervention and inadequate assessment. Communication incidents comprised inadequate documentation, failure to escalate care and poor inter-clinician communication. CONCLUSION: Causes of mortality following ERCP are wide-ranging, and reviewing clinical incidents associated with potentially avoidable mortality can serve to inform and educate practitioners. In collating a subset of cases in which procedure-related mortality was deemed avoidable, a series of cautionary tales about ERCP is presented that may provide cues to practitioners on improving patient safety and inform future surgical practice.

Is four years enough? An audit of post-hepatectomy surveillance for liver metastases.

BACKGROUND: Optimal timing and modality of surveillance post hepatectomy for colorectal cancer liver metastases (CLM) has not been established. Recommendations vary between countries and surgical units. Individual clinicians do not always adhere to guidelines. METHODS: Using a prospectively collected database of consecutive hepatectomy patients at The Queen Elizabeth Hospital in Adelaide, Australia, CLM patients were reviewed for evidence of recurrent disease (20 February 1996-30 June 2018). Timing and modality of disease detection was analysed. Follow up was until 30 June 2020 or death. RESULTS: 244 patients underwent hepatectomy for CLM during the study period. 139 patients (57%) experienced recurrence post initial hepatectomy (mean time 13.2 months; range 0.6-84.7). For all hepatic recurrences (n = 172), majority of disease was detected in the first seven months post hepatectomy (55%) and by four years, 97.7% of recurrent disease was detected. 51 patients underwent curative repeat hepatectomy after recurrence was detected. Nearly all disease was detected via surveillance CT (160/172; 93%); 12 patients presented with clinical symptoms. CONCLUSION: Hepatectomy patients are likely to experience recurrent disease and clinicians must ensure a robust surveillance plan is in place. We recommend a triple-phase CT at 6, 12, 18, 24, 36 and 48 months.

Predictors of interhospital transfer delays in acute surgical patient deaths in Australia: a retrospective study.

BACKGROUND: Interhospital transfers in Australia facilitate access to acute surgical services, however transfer delays can occur. The aims of this study were to examine Australian mortality audit data on acute surgical patients who were transferred after presenting with a surgical emergency, and to identify modifiable predictors of transfer delay. METHODS: Surgical admissions between 1 January 2001 and 18 August 2020 were retrospectively extracted from the Australian and New Zealand Audit of Surgical Mortality database. Relevant factors and themes of interest were collated. Results were presented as odds ratios (OR) and 95% confidence intervals (CI), with statistical significance defined as P <0.05. RESULTS: After exclusion, a final 8270 cases were analysed. Non-modifiable predictors identified were female gender (OR 1.34, 95% CI 1.05-1.70, P = 0.0184), comorbidities (OR 1.50, 95% CI 1.40-161, P <0.0001) and major non-trauma non-vascular specialty (OR 1.54 to 7.77, depending on specialty, P < 0.05). Modifiable predictors were inadequate clinical assessment (OR 49.48, 95% CI 32.91-74.38, P <0.0001), poor communication (OR 6.62, 95% CI 3.70-11.85, P <0.0001) and multiple transfers (OR 6.30, OR 95% 4.31-9.21, P <0.0001). Age, lack of bed and after-hours transfer did not predict transfer delays. Metropolitan transfers was protective against transfer delays (OR 0.64, 95% CI 0.47-0.86, P = 0.0035). CONCLUSION: In the view of the receiving surgeon or assessor, all transfer delays potentially contributed to patient deaths, and may have been preventable. Strategies directed at modifiable factors could minimize delays. Increased surgical services in non-metropolitan regions could reduce need for transfer. Prospective data is required to examine if the same predictors are observed in surgical patients who survive.

Psychopathological networks: Theory, methods and practice.

In recent years, network approaches to psychopathology have sparked much debate and have had a significant impact on how mental disorders are perceived in the field of clinical psychology. However, there are many important challenges in moving from theory to empirical research and clinical practice and vice versa. Therefore, in this article, we bring together different points of view on psychological networks by methodologists and clinicians to give a critical overview on these challenges, and to present an agenda for addressing these challenges. In contrast to previous reviews, we especially focus on methodological issues related to temporal networks. This includes topics such as selecting and assessing the quality of the nodes in the network, distinguishing between- and within-person effects in networks, relating items that are measured at different time scales, and dealing with changes in network structures. These issues are not only important for researchers using network models on empirical data, but also for clinicians, who are increasingly likely to encounter (person-specific) networks in the consulting room.

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.

Exercise-induced muscle damage: mechanism, assessment and nutritional factors to accelerate recovery.

There have been a multitude of reviews written on exercise-induced muscle damage (EIMD) and recovery. EIMD is a complex area of study as there are a host of factors such as sex, age, nutrition, fitness level, genetics and familiarity with exercise task, which influence the magnitude of performance decrement and the time course of recovery following EIMD. In addition, many reviews on recovery from exercise have ranged from the impact of nutritional strategies and recovery modalities, to complex mechanistic examination of various immune and endocrine signaling molecules. No one review can adequately address this broad array of study. Thus, in this present review, we aim to examine EIMD emanating from both endurance exercise and resistance exercise training in recreational and competitive athletes and shed light on nutritional strategies that can enhance and accelerate recovery following EIMD. In addition, the evaluation of EIMD and recovery from exercise is often complicated and conclusions often depend of the specific mode of assessment. As such, the focus of this review is also directed at the available techniques used to assess EIMD.

The Theory Crisis in Psychology: How to Move Forward.

Meehl argued in 1978 that theories in psychology come and go, with little cumulative progress. We believe that this assessment still holds, as also evidenced by increasingly common claims that psychology is facing a "theory crisis" and that psychologists should invest more in theory building. In this article, we argue that the root cause of the theory crisis is that developing good psychological theories is extremely difficult and that understanding the reasons why it is so difficult is crucial for moving forward in the theory crisis. We discuss three key reasons based on philosophy of science for why developing good psychological theories is so hard: the relative lack of robust phenomena that impose constraints on possible theories, problems of validity of psychological constructs, and obstacles to discovering causal relationships between psychological variables. We conclude with recommendations on how to move past the theory crisis.

The levels problem in psychopathology.

Psychiatric disorders are studied at multiple levels, but there is no agreement on how these levels are related to each other, or how they should be understood in the first place. In this paper, I provide an account of levels and their relationships that is suited for psychopathology, drawing from recent debates in philosophy of science. Instead of metaphysical issues, the focus is on delivering an understanding of levels that is relevant and useful for scientific practice. I also defend a pragmatic approach to the question of reduction, arguing that even in-principle reductionists should embrace pluralism in practice. Finally, I discuss the benefits and challenges in integrating explanations and models of different levels.