Tertiary lymphoid structures and B cells: An intratumoral immunity cycle.

The generation of anti-tumor immunity in the draining lymph nodes is known as the cancer immunity cycle. Accumulating evidence supports the occurrence of such a cycle at tumor sites in the context of chronic inflammation. Here, we review the role of tertiary lymphoid structures (TLS) in the generation of T and B cell immunities, focusing on the impact of B cells that undergo full maturation, resulting in the generation of plasma cells (PCs) producing high-affinity IgG and IgA antibodies. In this context, we propose that antibodies binding to tumor cells induce macrophage or natural killer (NK)-cell-dependent apoptosis. Subsequently, released antigen-antibody complexes are internalized and processed by dendritic cells (DCs), amplifying antigen presentation to T cells. Immune complexes may also be fixed by follicular DCs (FDCs) in TLS, thereby increasing memory B cell responses. This amplification loop creates an intra-tumoral immunity cycle, capable of increasing sensitivity of tumors to immunotherapy even in cancers with low mutational burden.

Activation of B cells in Tertiary Lymphoid Structures in cancer: Anti-tumor or anti-self?

Whereas T cells in the tumor microenvironment have been the main focus as cancer controlling cells and targets of immunotherapies, B cells have recently gained strong attention. Being associated to Tertiary Lymphoid Structures (TLS) located at the vicinity of tumor nests, the fate of B cell depends on TLS maturity. In immature TLS they may evolve as regulatory B cells producing immunosuppressive cytokines and promote tumor growth. In mature TLS with a germinal center, B cells are selected, amplified, undergo affinity maturation and isotypic switching, resulting in plasma cell generation and production of anti-tumor antibodies. In that case, they are associated with longer patient's survival and therapeutic response to immunotherapy. Identification of tumor specific, or tumor overexpressed, antigens recognized by "in situ" produced antibodies and their discrimination from self-antigens induced by ICI treatments is a major challenge to develop novel antibody-based immunotherapies.

B cells are associated with survival and immunotherapy response in sarcoma.

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

Mortality following noncardiac surgery assessed by the Saint Louis University Score (SLUScore) for hypotension: a retrospective observational cohort study.

BACKGROUND: The Saint Louis University Score (SLUScore) was developed to quantify intraoperative blood pressure trajectories and their associated risk for adverse outcomes. This study examines the prevalence and severity of intraoperative hypotension described by the SLUScore and its relationship with 30-day mortality in surgical subtypes. METHODS: This retrospective analysis of perioperative data included surgical cases performed between January 1, 2010, and December 31, 2020. The SLUScore is calculated from cumulative time-periods for which the mean arterial pressure is below a range of hypotensive thresholds. After calculating the SLUScore for each surgical procedure, we quantified the prevalence and severity of intraoperative hypotension for each surgical procedure and the association between intraoperative hypotension and 30-day mortality. We used binary logistic regression to quantify the potential contribution of intraoperative hypotension to mortality. RESULTS: We analysed 490 982 cases (57.7% female; mean age 57 yr); 33.2% of cases had a SLUScore>0, a median SLUScore of 13 (inter-quartile range [IQR] 7-21), with 1.19% average mortality. The SLUScore was associated with mortality in 12/14 surgical groups. The increases in the odds ratio for death within 30 days of surgery per SLUScore increment were: all surgery types 3.5% (95% confidence interval [95% CI] 3.2-3.9); abdominal/transplant surgery 6% (95% CI 1.5-10.7); thoracic surgery1.5% (95% CI 1-3.3); vascular surgery 3.01% (95% CI 1.9-4.05); spine/neurosurgery 1.1% (95% CI 0.1-2.1); orthopaedic surgery 1.4% (95% CI 0.7-2.2); gynaecological surgery 6.3% (95% CI 2.5-10.1); genitourinary surgery 4.84% (95% CI 3.5-6.15); gastrointestinal surgery 5.2% (95% CI 3.9-6.4); gastroendoscopy 5.5% (95% CI 4.4-6.7); general surgery 6.3% (95% CI 5.5-7.1); ear, nose, and throat surgery 1.6% (95% CI 0-3.27); and cardiac electrophysiology (including pacemaker procedures) 6.6% (95% CI 1.1-12.4). CONCLUSIONS: The SLUScore was independently, but variably, associated with 30-day mortality after noncardiac surgery.

Standardized Pathology Screening of Mature Tertiary Lymphoid Structures in Cancers.

Mature tertiary lymphoid structures (mTLSs) are organized lymphoid structures containing B lymphocytes admixed to CD23+ follicular dendritic cells. Their presence has been linked to improved survival and sensitivity to immune checkpoint inhibitors in several cancers, emerging as a promising pancancer biomarker. However, the requirements for any biomarker are clear methodology, proven feasibility, and reliability. In 357 patients' samples, we studied tertiary lymphoid structures (TLSs) parameters using multiplex immunofluorescence (mIF), hematoxylin-eosin-saffron (HES) staining, double CD20/CD23 staining, and single CD23 immunohistochemistry. The cohort included carcinomas (n = 211) and sarcomas (n = 146), gathering biopsies (n = 170), and surgical specimens (n = 187). mTLSs were defined as TLSs containing either a visible germinal center on HES staining or CD23+ follicular dendritic cells. Focusing on 40 TLSs assessed using mIF, double CD20/CD23 staining was less sensitive than mIF to assess maturity in 27.5% (n = 11/40) but was rescued by single CD23 staining in 90.9% (n = 10/11). In 97 patients, several samples (n = 240) were reviewed to characterize TLS distribution. The likelihood of finding TLSs in surgical material was 6.1 higher than in biopsy and 2.0 higher in primary samples than in metastasis after adjustment with a type of sample. Interrater agreement rates over 4 examiners were 0.65 (Fleiss kappa, 95% CI [0.46, 0.90]) for the presence of TLS and 0.90 for maturity (95% CI [0.83, 0.99]). In this study, we propose a standardized method to screen mTLSs in cancer samples using HES staining and immunohistochemistry that can be applied to all specimens.

Antenatal corticosteroids and perinatal outcome in late fetal growth restriction: analysis of prospective cohort.

OBJECTIVE: To evaluate the role of antenatal administration of corticosteroids for fetal lung maturation on the short-term perinatal outcome of pregnancy complicated by late fetal growth restriction (FGR). METHODS: This cohort study was a secondary analysis of a multicenter prospective observational study, the TRUFFLE-2 feasibility study, conducted between 2017 and 2018 in 33 European perinatal centers. The study included women with a singleton pregnancy from 32 + 0 to 36 + 6 weeks of gestation with a fetus considered at risk for FGR, defined as estimated fetal weight (EFW) and/or fetal abdominal circumference < 10th percentile, or umbilicocerebral ratio (UCR) ≥ 95th percentile or a drop of more than 40 percentile points in abdominal circumference measurement from the 20-week scan. For the purposes of the current study, we identified women who received a single course of steroids to improve fetal lung maturation before delivery. Each exposed pregnancy was matched with one that did not receive antenatal corticosteroids (ACS) (control), based on gestational age at delivery and birth weight. The primary adverse outcome was a composite of abnormal condition at birth, major neonatal morbidity or perinatal death. RESULTS: A total of 86 pregnancies that received ACS were matched to 86 controls. The two groups were similar with respect to gestational age (33.1 vs 33.3 weeks), EFW (1673 vs 1634 g) and UCR (0.68 vs 0.62) at inclusion, and gestational age at delivery (35.5 vs 35.9 weeks) and birth weight (1925 vs 1948 g). No significant differences were observed between the exposed and non-exposed groups in the incidence of composite adverse outcome (28% vs 24%; P = 0.73) or any of its elements. CONCLUSION: The present data do not show a beneficial effect of steroids on short-term outcome of fetuses with late FGR. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. MATERIALS AND METHODS: Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. RESULTS: Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. CONCLUSION: SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Intraoperative hypotension is associated with persistent acute kidney disease after noncardiac surgery: a multicentre cohort study.

BACKGROUND: Whilst intraoperative hypotension is associated with postoperative acute kidney injury (AKI), the link between intraoperative hypotension and acute kidney disease (AKD), defined as continuing renal dysfunction for up to 3 months after exposure, has not yet been studied. METHODS: We conducted a retrospective multicentre cohort study using data from noncardiac, non-obstetric surgery extracted from a US electronic health records database. Primary outcome was the association between intraoperative hypotension, at three MAP thresholds (≤75, ≤65, and ≤55 mm Hg), and the following two AKD subtypes: (i) persistent (initial AKI incidence within 7 days of surgery, with continuation between 8 and 90 days post-surgery) and (ii) delayed (renal impairment without AKI within 7 days, with AKI occurring between 8 and 90 days post-surgery). Secondary outcomes included healthcare resource utilisation for patients with either AKD subtype or no AKD. RESULTS: A total of 112 912 surgeries qualified for the study. We observed a rate of 2.2% for delayed AKD and 0.6% for persistent AKD. Intraoperative hypotension was significantly associated with persistent AKD at MAP ≤55 mm Hg (hazard ratio 1.1; 95% confidence interval: 1.38-1.22; P<0.004). However, IOH was not significantly associated with delayed AKD across any of the MAP thresholds. Patients with delayed or persistent AKD had higher healthcare resource utilisation across both hospital and intensive care admissions, compared with patients with no AKD. CONCLUSIONS: Intraoperative hypotension is associated with persistent but not delayed acute kidney disease. Both types of acute kidney disease appear to be associated with increased healthcare utilisation. Correction of intraoperative hypotension is a potential opportunity to decrease postoperative kidney injury and associated costs.

Therapeutic Targeting of the Colorectal Tumor Stroma.

Colorectal tumors have been classified based on histologic factors, genetic factors, and consensus molecular subtypes, all of which affect the tumor microenvironment. Elements of the tumor microenvironment serve as therapeutic targets and might be used as prognostic factors. For example, immune checkpoint inhibitors are used to treat tumors with microsatellite instability, and anti-angiogenic agents may be used in combination with other drugs to slow or inhibit tumor growth. We review the features of the colorectal tumor stroma that are associated with patient outcomes and discuss potential therapeutic agents that target these features.

NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML.

Neural cell adhesion molecule 1 (NCAM1; CD56) is expressed in up to 20% of acute myeloid leukemia (AML) patients. NCAM1 is widely used as a marker of minimal residual disease; however, the biological function of NCAM1 in AML remains elusive. In this study, we investigated the impact of NCAM1 expression on leukemogenesis, drug resistance, and its role as a biomarker to guide therapy. Beside t(8;21) leukemia, NCAM1 expression was found in most molecular AML subgroups at highly heterogeneous expression levels. Using complementary genetic strategies, we demonstrated an essential role of NCAM1 in the regulation of cell survival and stress resistance. Perturbation of NCAM1 induced cell death or differentiation and sensitized leukemic blasts toward genotoxic agents in vitro and in vivo. Furthermore, Ncam1 was highly expressed in leukemic progenitor cells in a murine leukemia model, and genetic depletion of Ncam1 prolonged disease latency and significantly reduced leukemia-initiating cells upon serial transplantation. To further analyze the mechanism of the NCAM1-associated phenotype, we performed phosphoproteomics and transcriptomics in different AML cell lines. NCAM1 expression strongly associated with constitutive activation of the MAPK-signaling pathway, regulation of apoptosis, or glycolysis. Pharmacological inhibition of MEK1/2 specifically inhibited proliferation and sensitized NCAM1+ AML cells to chemotherapy. In summary, our data demonstrate that aberrant expression of NCAM1 is involved in the maintenance of leukemic stem cells and confers stress resistance, likely due to activation of the MAPK pathway. Targeting MEK1/2 sensitizes AML blasts to genotoxic agents, indicating a role for NCAM1 as a biomarker to guide AML treatment.

Fetal cerebral blood-flow redistribution: analysis of Doppler reference charts and association of different thresholds with adverse perinatal outcome.

OBJECTIVES: First, to compare published Doppler reference charts of the ratios of flow in the fetal middle cerebral and umbilical arteries (i.e. the cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR)). Second, to assess the association of thresholds of CPR and UCR based on these charts with short-term composite adverse perinatal outcome in a cohort of pregnancies considered to be at risk of late preterm fetal growth restriction. METHODS: Studies presenting reference charts for CPR or UCR were searched for in PubMed. Formulae for plotting the median and the 10th percentile (for CPR) or the 90th percentile (for UCR) against gestational age were extracted from the publication or calculated from the published tables. Data from a prospective European multicenter observational cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks' gestation, in which fetal arterial Doppler measurements were collected longitudinally, were used to compare the different charts. Specifically, the association of UCR and CPR thresholds (CPR < 10th percentile or UCR ≥ 90th percentile and multiples of the median (MoM) values) with composite adverse perinatal outcome was analyzed. The association was also compared between chart-based thresholds and absolute thresholds. Composite adverse perinatal outcome comprised both abnormal condition at birth and major neonatal morbidity. RESULTS: Ten studies presenting reference charts for CPR or UCR were retrieved. There were large differences between the charts in the 10th and 90th percentile values of CPR and UCR, respectively, while median values were more similar. In the gestational-age range of 28-36 weeks, there was no relationship between UCR or CPR and gestational age. From the prospective observational study, 856 pregnancies at risk of late-onset preterm fetal growth restriction were included in the analysis. The association of abnormal UCR or CPR with composite adverse perinatal outcome was similar for percentile thresholds or MoM values, as calculated from the charts, and for absolute thresholds, both on univariable analysis and after adjustment for gestational age at measurement, estimated fetal weight MoM and pre-eclampsia. The adjusted odds ratio for composite adverse perinatal outcome was 3.3 (95% CI, 1.7-6.4) for an absolute UCR threshold of ≥ 0.9 or an absolute CPR threshold of < 1.11 (corresponding to ≥ 1.75 MoM), and 1.6 (95% CI, 0.9-2.9) for an absolute UCR threshold of ≥ 0.7 to < 0.9 or an absolute CPR threshold of ≥ 1.11 to < 1.43 (corresponding to ≥ 1.25 to < 1.75 MoM). CONCLUSIONS: In the gestational-age range of 32 to 36 weeks, adjustment of CPR or UCR for gestational age is not necessary when assessing the risk of adverse outcome in pregnancies at risk of fetal growth restriction. The adoption of absolute CPR or UCR thresholds, independent of reference charts, is feasible and makes clinical assessment simpler than if using percentiles or other gestational-age normalized units. The high variability in percentile threshold values among the commonly used UCR and CPR reference charts hinders reliable diagnosis and clinical management of late preterm fetal growth restriction. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Intraoperative Hypotension Is Associated With Adverse Clinical Outcomes After Noncardiac Surgery.

BACKGROUND: Intraoperative hypotension (IOH) occurs frequently during surgery and may be associated with organ ischemia; however, few multicenter studies report data regarding its associations with adverse postoperative outcomes across varying hemodynamic thresholds. Additionally, no study has evaluated the association between IOH exposure and adverse outcomes among patients by various age groups. METHODS: A multicenter retrospective cohort study was conducted between 2008 and 2017 using intraoperative blood pressure data from the US electronic health records database to examine postoperative outcomes. IOH was assessed in 368,222 noncardiac surgical procedures using 5 methods: (a) absolute maximum decrease in mean arterial pressure (MAP) during surgery, (b) time under each absolute threshold, (c) total area under each threshold, (d) time-weighted average MAP under each threshold, and (e) cumulative time under the prespecified relative MAP thresholds. MAP thresholds were defined by absolute limits (≤75, ≤65, ≤55 mm Hg) and by relative limits (20% and 40% lower than baseline). The primary outcome was major adverse cardiac or cerebrovascular events; secondary outcomes were all-cause 30- and 90-day mortality, 30-day acute myocardial injury, and 30-day acute ischemic stroke. Residual confounding was minimized by controlling for observable patient and surgical factors. In addition, we stratified patients into age subgroups (18-40, 41-50, 51-60, 61-70, 71-80, >80) to investigate how the association between hypotension and the likelihood of major adverse cardiac or cerebrovascular events and acute kidney injury differs in these age subgroups. RESULTS: IOH was common with at least 1 reading of MAP ≤75 mm Hg occurring in 39.5% (145,743) of cases; ≤65 mm Hg in 19.3% (70,938) of cases, and ≤55 mm Hg in 7.5% (27,473) of cases. IOH was significantly associated with the primary outcome for all age groups. For an absolute maximum decrease, the estimated odds of a major adverse cardiac or cerebrovascular events in the 30-day postsurgery was increased by 12% (95% confidence interval [CI], 11-14) for ≤75 mm Hg; 17.0% (95% CI, 15-19) for ≤65 mm Hg; and by 26.0% (95% CI, 22-29) for ≤55 mm Hg. CONCLUSIONS: IOH during noncardiac surgery is common and associated with increased 30-day major adverse cardiac or cerebrovascular events. This observation is magnified with increasing hypotension severity. The potentially avoidable nature of the hazard, and the extent of the exposed population, makes hypotension in the operating room a serious public health issue that should not be ignored for any age group.

Postoperative Hypotension and Adverse Clinical Outcomes in Patients Without Intraoperative Hypotension, After Noncardiac Surgery.

BACKGROUND: Postoperative hypotension (POH) is associated with major adverse events. However, little is known about the association of blood pressure thresholds and outcomes in postoperative patients without intraoperative hypotension (IOH) on the general-care ward. We evaluated the association of POH with major adverse cardiac or cerebrovascular events (MACCE) in patients without IOH. METHODS: This retrospective analysis included 67,968 noncardiac patient-procedures (2008-2017) for patients discharged to the ward with postoperative mean arterial pressure (MAP) readings, managed for ≥48 hours postsurgery, with no evidence of IOH. The primary outcome was 30-day MACCE evaluated by postoperative MAP thresholds: ≤75, ≤65, and ≤55 mm Hg (POH defined as a single measurement below threshold). Secondary outcomes included all-cause mortality (30-/90-day), 30-day acute myocardial infarction, 30-day acute ischemic stroke, 30-day readmission, 7-day acute kidney injury, and 30-day readmission. Associations between POH and adverse events were also evaluated in a cohort (#2) of 16,034 patient-procedures with IOH (intraoperative MAP ≤65 mm Hg). RESULTS: In patients without IOH, exposure to POH was not associated with MACCE at any investigated MAP threshold (P < .016 was considered significant: ≤75 mm Hg, hazard ratio [HR] 1.18 [98.4% confidence interval {CI} 0.99-1.39], P = .023; ≤65 mm Hg, HR 1.18 [0.99-1.41], P = .028; ≤55 mm Hg, HR 1.23 [0.90-1.71], P = .121); however, associations were observed at all MAP thresholds for secondary outcomes of acute kidney injury and 30-day readmission, for 30-/90-day mortality for MAP ≤65 mm Hg, and 90-day mortality for MAP ≤55 mm Hg, compared to those without POH. No associations were detected between POH and secondary outcomes of acute ischemic stroke or acute myocardial infarction at any MAP threshold. No interaction between POH and IOH was found when we evaluated the association of POH on outcomes in the data set including all patients, regardless of IOH status (P values for interaction terms nonsignificant). When the interaction term was utilized, the association between POH without IOH and MACCE was significant for MAP ≤75 mm Hg (HR 1.20 [1.01-1.41]) and MAP ≤65 mm Hg (HR 1.21 [1.02-1.45]), but not MAP ≤55 mm Hg. Cohort #2 (POH with IOH) showed largely similar results for MACCE: not significant for MAP ≤75 and ≤65 mm Hg, but significant for MAP ≤55 mm Hg (HR 1.53 [1.05-2.22], P = .006). CONCLUSIONS: POH in patients without IOH was not associated with MACCE at any MAP investigated. No interaction was identified between POH and IOH. Large prospective randomized trials are necessary to develop better evidence and inform clinicians the value of postoperative blood pressure management.

Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology.

MOTIVATION: The composition and density of immune cells in the tumor microenvironment (TME) profoundly influence tumor progression and success of anti-cancer therapies. Flow cytometry, immunohistochemistry staining or single-cell sequencing are often unavailable such that we rely on computational methods to estimate the immune-cell composition from bulk RNA-sequencing (RNA-seq) data. Various methods have been proposed recently, yet their capabilities and limitations have not been evaluated systematically. A general guideline leading the research community through cell type deconvolution is missing. RESULTS: We developed a systematic approach for benchmarking such computational methods and assessed the accuracy of tools at estimating nine different immune- and stromal cells from bulk RNA-seq samples. We used a single-cell RNA-seq dataset of ∼11 000 cells from the TME to simulate bulk samples of known cell type proportions, and validated the results using independent, publicly available gold-standard estimates. This allowed us to analyze and condense the results of more than a hundred thousand predictions to provide an exhaustive evaluation across seven computational methods over nine cell types and ∼1800 samples from five simulated and real-world datasets. We demonstrate that computational deconvolution performs at high accuracy for well-defined cell-type signatures and propose how fuzzy cell-type signatures can be improved. We suggest that future efforts should be dedicated to refining cell population definitions and finding reliable signatures. AVAILABILITY AND IMPLEMENTATION: A snakemake pipeline to reproduce the benchmark is available at https://github.com/grst/immune_deconvolution_benchmark. An R package allows the community to perform integrated deconvolution using different methods (https://grst.github.io/immunedeconv). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Reporting Quality of Discrete Event Simulations in Healthcare-Results From a Generic Reporting Checklist.

OBJECTIVES: The aims of this study were to formulate a generic reporting checklist for healthcare-related discrete event simulation (DES) studies and to critically appraise the existing studies. METHODS: Based on the principles of accessibility and generality, assessment items were derived from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR)-Society for Medical Decision Making (SMDM) Task Force reports. The resulting checklist was applied to all 211 DES studies identified in a previous review. The proportion of fulfilled checklist items served as an indicator of reporting quality. A logistic regression was conducted to investigate whether study characteristics (eg, publication before or after the publication of the ISPOR-SMDM reports) increased the likelihood of fulfilling more than the mean number of items fulfilled by the appraised DES studies. RESULTS: An 18-item checklist was formulated covering model conceptualization, parameterization and uncertainty assessment, validation, generalizability, and stakeholder involvement. The reporting quality of the DES models fluctuated around the mean of 63.7% (SD 11.0%) over the period studied. A modest nonsignificant improvement in reporting quality was found after the publication of the ISPOR-SMDM reports (64.5% vs 62.9%). Items with the lowest performance were related to predictive validation (2.8% of studies), cross validation (8.5%), face validity assessment (26.5%), and stakeholder involvement (27.5%). Models applied to health economic evaluation (HEE), country under study, and industry sponsorship were significantly associated with the odds of achieving above-average reporting quality. CONCLUSIONS: The checklist is applicable across various model-based analyses beyond HEEs. Adherence to the ISPOR-SMDM guidelines should be improved, particularly regarding model validation.

Magnesium sulphate for fetal neuroprotection at imminent risk for preterm delivery: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Ordinary meta-analyses indicate that magnesium sulphate (MgSO4 ) treatment in women at imminent risk for preterm delivery decreases the offspring's risk of cerebral palsy (CP). However, repetitive testing of cumulative data calls for statistical caution, e.g. by trial sequential analysis (TSA), for which there are previously insufficient samples to draw a firm conclusion. Recently, a randomised controlled trial (RCT) provided additional data that potentially increased the sample size such that a new TSA might detect a statistically significant effect. OBJECTIVES: To assess the possible fetal neuroprotective effect of MgSO4 for women at imminent risk for preterm delivery in an updated systematic review with meta-analysis and TSA. SEARCH STRATEGY: We searched MEDLINE, Embase, Cochrane and ClinicalTrials.gov on 8 October 2019. The search strategy clustered terms describing the MgSO4 intervention and preterm delivery. SELECTION CRITERIA: RCTs. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed-effects models. A TSA was applied to the primary outcome, CP. The quality of the evidence was assessed using GRADE. The protocol was registered in PROSPERO (registration: CRD42019151441). MAIN RESULTS: We identified six eligible trials (5917 women). MgSO4 intervention in women at imminent risk for preterm birth decreased the offspring's CP risk (meta-analysis RR 0.68, 95% CI 0.54-0.85; TSA RR 0.69, 95% CI 0.48-0.97). CONCLUSIONS: This systematic review with meta-analysis and TSA shows conclusively that MgSO4 , when given to women at imminent risk for preterm delivery, decreases the offspring's CP risk. TWEETABLE ABSTRACT: Antenatal magnesium sulphate decreases the risk of cerebral palsy in children born preterm.

Antenatal magnesium sulphate for the prevention of cerebral palsy in infants born preterm: a double-blind, randomised, placebo-controlled, multi-centre trial.

OBJECTIVE: To study the effect of antenatal magnesium sulphate (MgSO4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis. DESIGN: Double-blind, randomised, placebo-controlled, multi-centre trial. SETTING: Fourteen Danish obstetric departments. POPULATION: In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children. METHODS: Women were randomised to receive either a loading dose of 5 g MgSO4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire. MAIN OUTCOME MEASURE: The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP. RESULTS: The crude rates of moderate to severe CP in the MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65). CONCLUSIONS: Antenatal MgSO4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis. TWEETABLE ABSTRACT: Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation.

Postoperative hypotension in patients discharged to the intensive care unit after non-cardiac surgery is associated with adverse clinical outcomes.

BACKGROUND: The postoperative period is critical for a patient's recovery, and postoperative hypotension, specifically, is associated with adverse clinical outcomes and significant harm to the patient. However, little is known about the association between postoperative hypotension in patients in the intensive care unit (ICU) after non-cardiac surgery, and morbidity and mortality, specifically among patients who did not experience intraoperative hypotension. The goal of this study was to assess the impact of postoperative hypotension at various absolute hemodynamic thresholds (≤ 75, ≤ 65 and ≤ 55 mmHg), in the absence of intraoperative hypotension (≤ 65 mmHg), on outcomes among patients in the ICU following non-cardiac surgery. METHODS: This multi-center retrospective cohort study included specific patient procedures from Optum® healthcare database for patients without intraoperative hypotension (MAP ≤ 65 mmHg) discharged to the ICU for ≥ 48 h after non-cardiac surgery with valid mean arterial pressure (MAP) readings. A total of 3185 procedures were included in the final cohort, and the association between postoperative hypotension and the primary outcome, 30-day major adverse cardiac or cerebrovascular events, was assessed. Secondary outcomes examined included all-cause 30- and 90-day mortality, 30-day acute myocardial infarction, 30-day acute ischemic stroke, 7-day acute kidney injury stage II/III and 7-day continuous renal replacement therapy/dialysis. RESULTS: Postoperative hypotension in the ICU was associated with an increased risk of 30-day major adverse cardiac or cerebrovascular events at MAP ≤ 65 mmHg (hazard ratio [HR] 1.52; 98.4% confidence interval [CI] 1.17-1.96) and ≤ 55 mmHg (HR 2.02, 98.4% CI 1.50-2.72). Mean arterial pressures of ≤ 65 mmHg and ≤ 55 mmHg were also associated with higher 30-day mortality (MAP ≤ 65 mmHg, [HR 1.56, 98.4% CI 1.22-2.00]; MAP ≤ 55 mmHg, [HR 1.97, 98.4% CI 1.48-2.60]) and 90-day mortality (MAP ≤ 65 mmHg, [HR 1.49, 98.4% CI 1.20-1.87]; MAP ≤ 55 mmHg, [HR 1.78, 98.4% CI 1.38-2.31]). Furthermore, we found an association between postoperative hypotension with MAP ≤ 55 mmHg and acute kidney injury stage II/III (HR 1.68, 98.4% CI 1.02-2.77). No associations were seen between postoperative hypotension and 30-day readmissions, 30-day acute myocardial infarction, 30-day acute ischemic stroke and 7-day continuous renal replacement therapy/dialysis for any MAP threshold. CONCLUSIONS: Postoperative hypotension in critical care patients with MAP ≤ 65 mmHg is associated with adverse events even without experiencing intraoperative hypotension.

Computerized fetal heart rate analysis in early preterm fetal growth restriction.

OBJECTIVE: To assess the value of computerized cardiotocography (cCTG) with calculation of fetal heart rate (FHR) short-term variability (STV) in early preterm fetal growth restriction (FGR) for prevention of fetal death and neonatal asphyxia, neonatal morbidity, and 2-year neurodevelopmental impairment. METHODS: This was a retrospective cohort study of all women who were admitted to the Amsterdam University Medical Center-AMC between 2003 and 2015 due to FGR and/or pre-eclampsia, and who were delivered by prelabor Cesarean section, or had a fetal death, before 32 weeks' gestation. STV of all available cCTG registrations during the 5 days preceding fetal death or delivery was calculated retrospectively, and FHR decelerations were classified visually as absent, 1-2/h or recurrent (> 2/h). Adverse outcome endpoints were defined as fetal death, neonatal asphyxia at birth (including fetal death), neonatal death, major neonatal morbidity and 2-year neurodevelopmental outcome. A simulation analysis was performed to assess the incidence of adverse outcome using two thresholds for cCTG: (1) highly abnormal (STV < 2.6 ms before 29 weeks and < 3.0 ms thereafter, and/or recurrent FHR decelerations); and (2) moderately abnormal (STV < 3.5 ms before 29 weeks and < 4.0 ms thereafter, and/or recurrent FHR decelerations). Three management strategies were assessed using a strict schedule for the frequency of cCTG recordings: (1) cCTG without use of fetal arterial Doppler; (2) cCTG with additional fetal arterial Doppler after 29 weeks; and (3) cCTG with additional fetal arterial Doppler after 27 weeks. RESULTS: Included were 367 pregnancies (3295 cCTG recordings), of which 20 resulted in fetal death and 347 were delivered by Cesarean section before the onset of labor. Cesarean delivery was indicated by fetal condition in 94% of cases and by maternal condition in 6%. Median gestational age at delivery was 30 (interquartile range (IQR), 28-31) weeks and median birth weight was 900 (IQR, 740-1090) g. Six cases of fetal death were not anticipated by standard practice using visual assessment of CTG. A last highly abnormal cCTG was associated with fetal death and with neonatal asphyxia (including fetal death; n = 99), but not with major neonatal morbidity and 2-year neurodevelopmental outcome. Moderately abnormal cCTG had no significant association with any endpoint. Simulation analysis showed that a strategy that combined cCTG results with umbilicocerebral ratio or umbilical absent or reversed end-diastolic flow could detect all fetal deaths. CONCLUSIONS: Computerized CTG in combination with fetal arterial Doppler, with a strict protocol for the frequency of recordings, is likely to be more effective than visual CTG assessment for preventing fetal death in early preterm FGR. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials.

OBJECTIVE: To explore the effect on perinatal outcome of different fetal monitoring strategies for early-onset fetal growth restriction (FGR). METHODS: This was a cohort analysis of individual participant data from two European multicenter trials of fetal monitoring methods for FGR: the Growth Restriction Intervention Study (GRIT) and the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE). All women from GRIT (n = 238) and TRUFFLE (n = 503) who were randomized between 26 and 32 weeks' gestation were included. The women were grouped according to intervention and monitoring method: immediate delivery (GRIT) or delayed delivery with monitoring by conventional cardiotocography (CTG) (GRIT), computerized CTG (cCTG) only (GRIT and TRUFFLE) or cCTG and ductus venosus (DV) Doppler (TRUFFLE). The primary outcome was survival without neurodevelopmental impairment at 2 years of age. RESULTS: Gestational age at delivery and birth weight were similar in both studies. Fetal death rate was similar between the GRIT and TRUFFLE groups, but neonatal and late death were more frequent in GRIT (18% vs 6%; P < 0.01). The rate of survival without impairment at 2 years was lowest in pregnancies that underwent immediate delivery (70% (95% CI, 61-78%)) or delayed delivery with monitoring by CTG (69% (95% CI, 57-82%)), increased in those monitored using cCTG only in both GRIT (80% (95% CI, 68-91%)) and TRUFFLE (77% (95% CI, 70-84%)), and was highest in pregnancies monitored using cCTG and DV Doppler (84% (95% CI, 80-89%)) (P < 0.01 for trend). CONCLUSIONS: This analysis supports the hypothesis that the optimal method for fetal monitoring in pregnancies complicated by early-onset FGR is a combination of cCTG and DV Doppler assessment. TRIAL REGISTRATION: GRIT ISRCTN41358726 and TRUFFLE ISRCTN56204499. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Análisis comparativo de los resultados a los 2 años de edad en los ensayos GRIT y TRUFFLE OBJETIVO: Examinar el efecto sobre el resultado perinatal de diferentes estrategias de monitoreo del feto para la restricción del crecimiento fetal (RCF) de inicio precoz. MÉTODOS: Este estudio realizó un análisis de cohortes de datos de participantes individuales en dos ensayos multicéntricos europeos de métodos de monitoreo fetal para la RCF: el Estudio de Intervención en la Restricción del Crecimiento (GRIT, por sus siglas en inglés) y el Ensayo Europeo de Flujo Umbilical y Fetal (TRUFFLE, por sus siglas en inglés). Se incluyeron todas las mujeres de GRIT (n = 238) y de TRUFFLE (n = 503) que habían sido asignadas al azar entre 26 y 32 semanas de gestación. Las mujeres se agruparon según el método de intervención y monitoreo: parto inmediato (GRIT) o parto diferido con monitoreo mediante cardiotocografía convencional (CTG) (GRIT), solo CTG digital (cCTG, por sus siglas en inglés) (GRIT y TRUFFLE) o cCTG y Doppler del conducto de Arancio (DV) (TRUFFLE). La medida de resultado primaria fue la supervivencia sin deterioro del desarrollo neurológico a los dos años de edad. RESULTADOS: La edad gestacional al momento del parto y el peso al nacer fueron similares en ambos estudios. La tasa de mortalidad fetal fue similar entre los grupos de GRIT y TRUFFLE, pero la muerte neonatal y tardía fue más frecuente en el grupo de GRIT (18% vs 6%; P < 0,01). La tasa de supervivencia sin deterioro a los dos años fue más baja en los embarazos que se sometieron a un parto inmediato (70% (IC 95%, 61-78%)) o a un parto tardío con monitoreo mediante CTG (69% (IC 95%, 57-82%)), más alta en los monitoreados solo mediante cCTG en GRIT (80% (IC 95%, 68-91%)) y TRUFFLE (77% (IC 95%, 70-84%)), y mayor aun en los embarazos monitoreados mediante cCTG y Doppler DV (84% (IC 95%, 80-89%)) (P < 0,01 para tendencia). CONCLUSIONES: Este análisis apoya la hipótesis de que el método óptimo para el monitoreo fetal en los embarazos complicados por RCF de inicio precoz es una combinación de cCTG y evaluación Doppler DV. INSCRIPCIÓN DEL ENSAYO: GRIT ISRCTN41358726 y TRUFFLE ISRCTN56204499. © 2019 Los autores. Ultrasonido en Obstetricia y Ginecología publicado por John Wiley & Sons Ltd. en nombre de la Sociedad Internacional de Ultrasonido en Obstetricia y Ginecología.