Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.

Ligand-Dependent Modulation of G Protein Conformation Alters Drug Efficacy.

G protein-coupled receptor (GPCR) signaling, mediated by hetero-trimeric G proteins, can be differentially controlled by agonists. At a molecular level, this is thought to occur principally via stabilization of distinct receptor conformations by individual ligands. These distinct conformations control subsequent recruitment of transducer and effector proteins. Here, we report that ligand efficacy at the calcitonin GPCR (CTR) is also correlated with ligand-dependent alterations to G protein conformation. We observe ligand-dependent differences in the sensitivity of the G protein ternary complex to disruption by GTP, due to conformational differences in the receptor-bound G protein hetero-trimer. This results in divergent agonist-dependent receptor-residency times for the hetero-trimeric G protein and different accumulation rates for downstream second messengers. This study demonstrates that factors influencing efficacy extend beyond receptor conformation(s) and expands understanding of the molecular basis for how G proteins control/influence efficacy. This has important implications for the mechanisms that underlie ligand-mediated biased agonism. VIDEO ABSTRACT.

Carnosine supplementation improves glucose control in adults with pre-diabetes and type 2 diabetes: A randomised controlled trial.

BACKGROUND AND AIMS: Type 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. METHODS AND RESULTS: In this randomised controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 g) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via a 2-h 75 g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT, and anthropometry. Carnosine supplementation decreased blood glucose at 90 min (-1.31 mmol/L; p = 0.02) and 120 min (-1.60 mmol/L, p = 0.02) and total glucose area under the curve (-3.30 mmol/L; p = 0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. CONCLUSION: This study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the initial stages of T2DM. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation.

Methods of measurement for pneumothorax in pediatric patients: a systematic review.

Accurate measurement of pneumothorax (PTX) size is necessary to guide clinical decision making; however, there is no consensus as to which method should be used in pediatric patients. This systematic review seeks to identify and evaluate the methods used to measure PTX size with CXR in pediatric patients. A systematic review of the literature through 2021 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was conducted using the following databases: Ovid/MEDLINE, Scopus, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar. Original research articles that included pediatric patients (< 18 years old) and outlined the PTX measurement method were included. 45 studies were identified and grouped by method (Kircher and Swartzel, Rhea, Light, Collins, Other) and societal guideline used. The most used method was Collins (n = 16; 35.6%). Only four (8.9%) studies compared validated methods. All found the Collins method to be accurate. Seven (15.6%) studies used a standard classification guideline and 3 (6.7%) compared guidelines and found significant disagreement between them. Pediatric-specific measurement guidelines for PTX are needed to establish consistency and uniformity in both research and clinical practice. Until there is a better method, the Collins method is preferred.

Characterization of age-associated B cells in early drug-naïve rheumatoid arthritis patients.

Age-associated B cells (ABCs) are an immune cell subset linked to autoimmunity, infection and ageing, and whose pathophysiological importance was recently highlighted using single cell synovial tissue profiling. To elucidate their pathophysiological relevance, peripheral blood (PB) ABCs from early rheumatoid arthritis (eRA) patients naïve to disease-modifying anti-rheumatic drugs (DMARDs) were compared with their synovial fluid (SF) counterparts, and to PB ABCs from psoriatic arthritis patients and healthy controls. PB and SF B-cell subsets were phenotyped by multi-parameter flow cytometry, sorted and subjected to gene expression profiling (NanoString nCounter® Immunology V2 Panel) and functional characterization (stimulated cytokine measurements by immunoassay). PB ABCs of eRA patients, which are transcriptionally distinct from those of control cohorts, express chemokine receptors and adhesion molecules, such as CXCR3, that favour homing to inflammatory sites over lymphoid tissue. These cells are an activated, class-switched B-cell subset expressing high levels of HLA-DR, co-stimulatory molecules and T-bet. Their secretion profile includes IL-12p70 and IL-23 but low levels of IL-10. High surface expression of FcRL family members, including FcRL3, furthermore suggests a role for these cells in autoimmunity. Finally, and unlike in the periphery where they are rare, ABCs are the predominant B-cell subsets in SF. These observations indicate the predilection of ABCs for inflammatory tissue in RA, where their propensity for antigen presentation and pro-inflammatory phenotype may support autoimmune pathology. Their potential as a therapeutic target therefore warrants further study.

A spectroscopic liquid biopsy for the earlier detection of multiple cancer types.

BACKGROUND: A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational. METHODS: In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer. RESULTS: Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%). CONCLUSIONS: This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic. STATEMENT OF TRANSLATIONAL RELEVANCE: The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis.

Liquid biopsies: the future of cancer early detection.

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.

Biological Responses of Pacific Herring Embryos to Crude Oil Are Quantifiable at Exposure Levels Below Conventional Limits of Quantitation for PAHs in Water and Tissues.

Pacific herring (Clupea pallasii), a cornerstone of marine food webs, generally spawn on marine macroalgae in shallow nearshore areas that are disproportionately at risk from oil spills. Herring embryos are also highly susceptible to toxicity from chemicals leaching from oil stranded in intertidal and subtidal zones. The water-soluble components of crude oil trigger an adverse outcome pathway that involves disruption of the physiological functions of cardiomyocytes in the embryonic herring heart. In previous studies, impaired ionoregulation (calcium and potassium cycling) in response to specific polycyclic aromatic hydrocarbons (PAHs) corresponds to lethal embryolarval heart failure or subtle chamber malformations at the high and low ends of the PAH exposure range, respectively. Sublethal cardiotoxicity, which involves an abnormal outgrowth (ballooning) of the cardiac ventricular chamber soon after hatching, subsequently compromises juvenile heart structure and function, leading to pathological hypertrophy of the ventricle and reduced individual fitness, measured as cardiorespiratory performance. Previous studies have not established a threshold for these sublethal and delayed-in-time effects, even with total (∑)PAH exposures as low as 29 ng/g of wet weight (tissue dose). Here, we extend these earlier findings showing that (1) cyp1a gene expression provides an oil exposure metric that is more sensitive than typical quantitation of PAHs via GC-MS and (2) heart morphometrics in herring embryos provide a similarly sensitive measure of toxic response. Early life stage injury to herring (impaired heart development) thus occurs below the quantitation limits for PAHs in both water and embryonic tissues as a conventional basis for assessing oil-induced losses to coastal marine ecosystems.

Dobutamine effects on systolic and diastolic left ventricular long-axis excursion and timing - significance for the interpretation of s' and e'.

BACKGROUND: Dobutamine effects on the relationships of the peak velocity of left ventricular (LV) long-axis systolic motion (s') with systolic excursion (SExc), systolic duration (SDur) and heart rate, of LV long-axis early diastolic excursion (EDExc) with SExc, and of the peak velocity of LV long-axis early diastolic motion (e') with EDExc, early diastolic duration (EDDur) and isovolumic relaxation time (IVRT') are unknown. METHODS: Two groups of adult subjects, one young and healthy (n = 10), and one with impaired LV long-axis function (n = 10), were studied, with the aim of identifying consistent findings for the two groups and for the septal and lateral walls. Dobutamine was infused at doses of 5 and 10 µg/kg/min. The relationships between tissue Doppler imaging (TDI) variables acquired before and during dobutamine infusion were analysed using mixed effect multivariate regression modelling. RESULTS: In both groups, heart rate increased and SDur decreased during dobutamine infusion, and there were independent inverse correlations of SDur with heart rate and dobutamine dose. In contrast, there was no change in EDDur during dobutamine infusion, and no consistent changes in IVRT' independent of heart rate. s' was positively correlated with SExc and inversely correlated with SDur, and there were positive correlations between EDExc and SExc and between e' and EDExc. CONCLUSION: Dobutamine increases s' due to effects on both systolic excursion and duration and it increases e' due to the associated increases in systolic and early diastolic excursion. A lack of effect on diastolic times does not support the presence of a lusitropic effect of dobutamine.

Decrements of mobility and power in recreationally active septuagenarians is related to loss of force, but not slowing of the muscle: a 5-year longitudinal study.

A lesser 6-min walk distance (6MWD) and timed up-and-go (TUG) in old compared with young adults was previously linked to slowing of muscle contractile properties. The purpose of the present study was to determine whether any further reductions in 6MWD and TUG over a 5-year period in septuagenarians are associated with further slowing of muscle contractile properties. We measured muscle function by a countermovement jump, isometric maximal knee extensor strength (MVC) on a dynamometer and quadriceps muscle size by magnetic resonance imaging (MRI) in 17 older women (71.1 ± 2.8 y) and 17 older men (71.3 ± 4.1y). Performance in TUG and 6MWD were reduced over the 5-year period, irrespective of sex (P < 0.001), and both were correlated with power at both baseline and follow-up (R ≥ 0.53; P ≤ 0.001). Jump take-off velocity (VCMJ) was slower at follow-up (P < 0.01) and correlated with 6MWD and TUG at both baseline and follow-up in both sexes (R ≥ 0.54; P ≤ 0.001). However, the relationship between 'body mass: maximal muscle force ratio' with VCMJ was not significantly changed, indicating that the lower VCMJ was attributable to muscles working at a higher relative load, hence a lower part of the force-velocity relationship, due to a reduction in MVC (body mass had not changed significantly), rather than slowing of the muscle. The lower VCMJ in women than men (P < 0.001) was likewise attributable to a lower MVC rather than slower contractile properties in women. In conclusion, the decrement in 6MWD and TUG in septuagenarians is due to a loss of muscle mass, rather than further loss of muscle quality.

Characterizing the Chemical Profile of Biological Decline in Stormwater-Impacted Urban Watersheds.

Chemical contamination is an increasingly important conservation issue in urban runoff-impacted watersheds. Regulatory and restoration efforts typically evaluate limited conventional parameters and pollutants. However, complex urban chemical mixtures contain hundreds to thousands of organic contaminants that remain unidentified, unregulated, and poorly understood. This study aimed to develop broadly representative metrics of water quality impairment corresponding to previously documented biological degradation along gradients of human impacts. Stream samples (n = 65, baseflow/rainfall conditions, 2017-2018) were collected from 15 regional watersheds (Puget Sound, WA, USA) across an urbanization gradient defined by landscape characteristics. Surface water chemical composition characterized via non-targeted high-resolution mass spectrometry (7068 detections) was highly correlated with landscape-based urbanization gradient (p < 0.01) and season (p < 0.01). Landscape-scale changes in chemical composition closely aligned with two anchors of biological decline: coho salmon (Oncorhynchus kisutch) mortality risk (p < 0.001) and loss of stream macroinvertebrate diversity and abundance (p < 0.001). We isolated and identified 32 indicators for urban runoff impacts and corresponding receiving water ecological health, including well-known anthropogenic contaminants (e.g., caffeine, organophosphates, vehicle-derived chemicals), two related environmental transformation products, and a novel (methoxymethyl)melamine compound. Outcomes support data-directed selection of next-generation water quality indicators for prioritization and evaluation of watershed management efforts intended to protect aquatic ecosystems.

Cutting Edge: CRISPR-Based Transcriptional Regulators Reveal Transcription-Dependent Establishment of Epigenetic Memory of Foxp3 in Regulatory T Cells.

Transcription factor Foxp3 specifies and maintains regulatory T cell (Treg) identity. During Treg differentiation, a CpG-rich Foxp3 intronic enhancer, conserved noncoding sequence 2 (CNS2), is activated via DNA demethylation to establish epigenetic memory of Foxp3 expression to protect Treg identity. However, it is unclear how this epigenetic memory of Foxp3 expression is established, as CNS2 is thought to be demethylated independently of Foxp3 expression. In this article, we uncover an unexpected causal relationship between Foxp3-transcriptional activation and CNS2 demethylation in mice. CRISPR/dCas9-mediated Foxp3-transcriptional activation elicits CNS2 demethylation. Sustaining Foxp3-transcriptional activation in induced Tregs also promotes CNS2 demethylation, enhancing Treg lineage stability and suppressive function. Importantly, CRISPR-mediated silencing of Foxp3 transcription, but not protein expression, abolishes CNS2 demethylation. The novel finding that Foxp3-transcriptional activation promotes CNS2 demethylation may facilitate the development of Treg-based therapies and represent a general mechanism for the establishment of epigenetic memory of immune gene expression.

Left ventricular contractile reserve as a determinant of adverse clinical outcomes: a systematic review.

An abnormal left ventricular contractile reserve is often seen in patients undergoing stress echocardiogram and may indicate the presence of obstructive coronary artery disease. The techniques and indexes used to identify abnormal left ventricular contractile response and its prognostic value in the absence of known causes has not been well studied. To describe the characteristics and clinical outcomes associated with an abnormal left ventricular contractile response, we performed a systematic review that identified 27 eligible studies. A diverse range of indices were utilised to measure left ventricular contractile reserve, most commonly Δleft ventricular ejection fraction in 11 studies. Dobutamine stress echocardiogram was the most commonly performed modality (19 studies) followed by exercise stress echocardiogram (4 studies), dipyridamole stress echocardiogram (2 studies), invasive hemodynamic measurement (1 study) and dobutamine stress magnetic resonance imaging (1 study). All but one study demonstrated a significant association between the absence of left ventricular contractile reserve and increased rate of cardiovascular events, cardiac death and all-cause mortality.

Diagnostic Performance of CT-Derived Fractional Flow Reserve in Australian Patients Referred for Invasive Coronary Angiography.

BACKGROUND: Non-invasive computed tomography (CT)-derived fractional flow reserve (FFRCT) is computed from standard coronary CT angiography (CTA) datasets and provides accurate vessel-specific ischaemia assessment of coronary artery disease (CAD). To date, the technique and its diagnostic performance has not been verified in the Australian clinical context. The aim of this study was to describe and compare the diagnostic performance of FFRCT and CTA for the detection of vessel-specific ischaemia as determined by invasive fractional flow reserve (FFR) in the Australian patient population. METHODS: One-hundred-and-nine patients (219 vessels) referred for clinically mandated invasive angiography were retrospectively assessed. Each patient underwent research mandated CTA and FFRCT within 3 months of invasive angiography and invasive FFR assessment. Independent core laboratory assessments were made to determine visual CTA stenosis, FFRCT and invasive FFR values. FFRCT values were matched with the corresponding invasive FFR measurement taken at the given wire position. Visual CTA stenosis ≥50%, FFRCT values ≤0.8 and invasive FFR values ≤0.8 were considered significant for ischaemia. RESULTS: Per vessel accuracy, sensitivity, specificity, positive predictive value and negative predictive value of FFRCT were 80.4%, 80.0%, 80.6%, 64.9% and 90.0% respectively. Corresponding values for CTA were 75.1%, 87.1%, 69.2%, 58.1% and 91.7% respectively. In receiver operating characteristic curve analysis, FFRCT demonstrated superior area under the curve (AUC) compared with CTA in both per vessel (0.87 vs 0.77, p=0.004) and per patient analysis (0.86 vs 0.74, p=0.011). Per vessel AUC of combined CTA and FFRCT was superior to CTA alone (0.89 vs 0.77, p<0.0001). CONCLUSION: In this cohort of Australian patients, the diagnostic performance of FFRCT was found to be comparable to existing international literature, with demonstrated improvement in performance compared with CTA alone for the detection of vessel-specific ischaemia.

Prosthesis Geometrical Predictors of Leaflet Thrombosis Following Transcatheter Aortic Valve Replacement With Intra-Annular Prostheses.

OBJECTIVE: To determine the association between prosthesis geometry with leaflet thrombosis (LT). BACKGROUND: Leaflet thrombosis following transcatheter aortic valve replacement (TAVR) is a recognised entity. The association between prosthesis geometry with LT is unclear but maybe a potential modifiable factor in its prevention. METHODS: Patients who received an intra-annular TAVR prosthesis and were prospectively planned to undergo post-procedural computed tomography (CT) imaging were included. Leaflet thrombosis was defined as at least 50% restricted leaflet motion on CT. Prosthesis expansion and eccentricity was measured at prosthesis inflow, annulus and outflow levels. Prosthesis misalignment was defined as the average angle deviation between native and prosthesis leaflet commissure, greater than 30°. RESULTS: Prevalence of LT was 13.7% in 117 patients. None of the patients with LT were on anticoagulation therapy. Patients with LT had reduced prosthesis annular expansion (89.4±5.2% vs 97.0±4.4%, p<0.01), greater prosthesis misalignment (81.3% vs 48.5%, p=0.02) and deeper implants (6.3±1.7 mm vs 4.3±1.5 mm, p<0.01). Threshold for the presence of LT on ROC analysis was an implant depth of 5.7 mm (AUC [area under curve]=0.81). Independent predictors of LT were annular under-expansion (Odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2-1.7, p=0.03) prosthesis misalignment (OR 6.8, 95%CI 1.1-45.5, p=0.04) and implant depth (OR 1.9, 95%CI 1.1-3.2, p=0.03). Anticoagulation therapy was a protective factor (OR 0.2; 95%CI 0.1-0.4, p<0.01). CONCLUSION: Geometrical predictors of LT post intra-annular TAVR were reduced prosthesis expansion at the annular level, lower implant depth and greater prosthesis misalignment. These factors may be important considerations during procedural planning for TAVR.

Ambulatory management of primary spontaneous pneumothorax: an open-label, randomised controlled trial.

BACKGROUND: Primary spontaneous pneumothorax occurs in otherwise healthy young patients. Optimal management is not defined and often results in prolonged hospitalisation. Data on efficacy of ambulatory options are poor. We aimed to describe the duration of hospitalisation and safety of ambulatory management compared with standard care. METHODS: In this open-label, randomised controlled trial, adults (aged 16-55 years) with symptomatic primary spontaneous pneumothorax were recruited from 24 UK hospitals during a period of 3 years. Patients were randomly assigned (1:1) to treatment with either an ambulatory device or standard guideline-based management (aspiration, standard chest tube insertion, or both). The primary outcome was total length of hospital stay including re-admission up to 30 days after randomisation. Patients with available data were included in the primary analysis and all assigned patients were included in the safety analysis. The trial was prospectively registered with the International Standard Randomised Clinical Trials Number, ISRCTN79151659. FINDINGS: Of 776 patients screened between July, 2015, and March, 2019, 236 (30%) were randomly assigned to ambulatory care (n=117) and standard care (n=119). At day 30, the median hospitalisation was significantly shorter in the 114 patients with available data who received ambulatory treatment (0 days [IQR 0-3]) than in the 113 with available data who received standard care (4 days [IQR 0-8]; p<0·0001; median difference 2 days [95% CI 1-3]). 110 (47%) of 236 patients had adverse events, including 64 (55%) of 117 patients in the ambulatory care arm and 46 (39%) of 119 in the standard care arm. All 14 serious adverse events occurred in patients who received ambulatory care, eight (57%) of which were related to the intervention, including an enlarging pneumothorax, asymptomatic pulmonary oedema, and the device malfunctioning, leaking, or dislodging. INTERPRETATION: Ambulatory management of primary spontaneous pneumothorax significantly reduced the duration of hospitalisation including re-admissions in the first 30 days, but at the expense of increased adverse events. This data suggests that primary spontaneous pneumothorax can be managed for outpatients, using ambulatory devices in those who require intervention. FUNDING: UK National Institute for Health Research.

What is the Accuracy of the ACS-NSQIP Surgical Risk Calculator in Emergency Abdominal Surgery? A Meta-Analysis.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) surgical risk calculator provides an estimation of 30-d post-operative complications including mortality. This tool has the potential to both aid in decision-making for patients and their families and also in optimizing the clinical management of high-risk patients. However, it's utility in patients requiring emergency abdominal surgery has shown to be inconsistent outside of NSQIP participating institutions. This study undertook a meta-analysis to assess the calculator's accuracy in predicting mortality in these patients. METHODS: A literature search of PubMed, Medline and Cochrane databases was conducted between October 2019 to April 2020. The PubMed, Medline and Cochrane Databases were searched for relevant studies. The search strategy included studies from January 2013 to April 2020. Studies including elective surgery were excluded. A random effects model was used and fitted using restricted maximum likelihood estimation. The O:E ratio was used to validate the calculator's accuracy in predicting mortality. RESULTS: Six studies were included in the meta-analysis, with a total of 1835 patients undergoing emergency intra-abdominal surgery. The summary estimate of the O:E ratio of the ACS-NSQIP surgical risk calculator in predicting 30-d post-operative mortality was 1.06 (95% CI 0.74-1.51). There was significant heterogeneity between studies with a Cochrane Q of 11.96 (P = 0.04) and I2 = 57.5%. CONCLUSIONS: The ACS-NSQIP surgical risk calculator is a reliable predictor of mortality in this external cohort and has potential to be utilised in the multi-disciplinary care of patients undergoing emergency abdominal surgery.

Treading Water: Tire Wear Particle Leachate Recreates an Urban Runoff Mortality Syndrome in Coho but Not Chum Salmon.

Tire tread wear particles (TWP) are increasingly recognized as a global pollutant of surface waters, but their impact on biota in receiving waters is rarely addressed. In the developed U.S. Pacific Northwest, acute mortality of adult coho salmon (Oncorhynchus kisutch) follows rain events and is correlated with roadway density. Roadway runoff experimentally triggers behavioral symptoms and associated changes in blood indicative of cardiorespiratory distress prior to death. Closely related chum salmon (O. keta) lack an equivalent response. Acute mortality of juvenile coho was recently experimentally linked to a transformation product of a tire-derived chemical. We evaluated whether TWP leachate is sufficient to trigger the acute mortality syndrome in adult coho salmon. We characterized the acute response of adult coho and chum salmon to TWP leachate (survival, behavior, blood physiology) and compared it with that caused by roadway runoff. TWP leachate was acutely lethal to coho at concentrations similar to roadway runoff, with the same behaviors and blood parameters impacted. As with runoff, chum salmon appeared insensitive to TWP leachate at concentrations lethal to coho. Our results confirm that environmentally relevant TWP exposures cause acute mortalities of a keystone aquatic species.

Clinical predictors and sequelae of computed tomography defined leaflet thrombosis following transcatheter aortic valve replacement at medium-term follow-up.

BACKGROUND: The clinical predictors and sequelae of leaflet thrombosis (LT) following transcatheter aortic valve replacement (TAVR) is still unclear. Therefore, our aim was to determine the clinical predictors and sequelae at mid-term follow-up of computed tomography (CT)-defined LT following TAVR. METHODS AND RESULTS: We performed a prospective evaluation with a 320-multislice CT following TAVR for the presence of LT, defined as hypo-attenuated leaflet thickening (HALT). Four-dimensional CT image-rendering was performed to determine the presence of reduced leaflet motion (RELM). 172 patients [89 (51.7%) male, mean age 82.8 ± 5.7 years] treated with commercially available TAVR device (Lotus 54%, CoreValve 32% and Sapien 3 14%) were included, with median CT-scan at 6.0 weeks post-TAVR. Prevalence of HALT was 14.0% (24 cases) and RELM was 9.8% (17 cases). On multivariate analysis, patients with HALT were less prescribed oral anticoagulation (OAC) (OR 9.9), received larger TAVR prostheses (OR 5.7) and higher rates of moderate-severe para-valvular regurgitation (PVR) (OR 16.3). There was no difference in clinical outcomes at a median follow-up of 2.3 years. Patients with RELM had significantly higher transvalvular gradients after discharge when compared to those without RELM. CONCLUSIONS: Absence of OAC, large TAVR prostheses and moderate-severe PVR were predictors for LT. Transvalvular gradients were higher in patients that developed RELM but not HALT. Further studies are warranted to determine the long-term impact of LT on TAVR durability. Prevalence of different sub-types of CT-defined LT (HALT and RELM) and the clinical predictors of developing LT following TAVR. CT computed tomography, HALT hypo-attenuated leaflet thickening, LT leaflet thrombosis, RELM reduced leaflet motion, TAVR transcatheter aortic valve replacement.

Is withdrawing treatment really more problematic than withholding treatment?

There is a concern that as a result of COVID-19 there will be a shortage of ventilators for patients requiring respiratory support. This concern has resulted in significant debate about whether it is appropriate to withdraw ventilation from one patient in order to provide it to another patient who may benefit more. The current advice available to doctors appears to be inconsistent, with some suggesting withdrawal of treatment is more serious than withholding, while others suggest that this distinction should not be made. We argue that there is no ethically relevant difference between withdrawing and withholding treatment and that suggesting otherwise may have problematic consequences. If doctors are discouraged from withdrawing treatment, concern about a future shortage may make them reluctant to provide ventilation to patients who are unlikely to have a successful outcome. This may result in underutilisation of available resources. A national policy is urgently required to provide doctors with guidance about how patients should be prioritised to ensure the maximum benefit is derived from limited resources.