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Background: Emerging research suggests exposure to high levels of air pollution at critical points in the life-course is detrimental to brain health, including cognitive decline and dementia. Social determinants play a significant role, including socio-economic deprivation, environmental factors and heightened health and social inequalities. Policies have been proposed more generally, but their benefits for brain health have yet to be fully explored. Objective and methods: Over the course of two years, we worked as a consortium of 20+ academics in a participatory and consensus method to develop the first policy agenda for mitigating air pollution's impact on brain health and dementia, including an umbrella review and engaging 11 stakeholder organisations. Results: We identified three policy domains and 14 priority areas. Research and Funding included: (1) embracing a complexities of place approach that (2) highlights vulnerable populations; (3) details the impact of ambient PM2.5 on brain health, including current and historical high-resolution exposure models; (4) emphasises the importance of indoor air pollution; (5) catalogues the multiple pathways to disease for brain health and dementia, including those most at risk; (6) embraces a life course perspective; and (7) radically rethinks funding. Education and Awareness included: (8) making this unrecognised public health issue known; (9) developing educational products; and (10) providing publicly available monitoring and screening tools. Policy Evaluation included: (11) engaging in co-production; (12) conducting complex systems evaluation; (13) attaching brain health to air pollution strategies and, in turn, attaching air pollution to brain health campaigns; and (14) evaluating air quality policies for their brain health benefits. Conclusion: Given the pressing issues of brain health, dementia and air pollution, setting a policy agenda is crucial. Policy needs to be matched by scientific evidence and appropriate guidelines, including bespoke strategies to optimise impact and mitigate unintended consequences. The agenda provided here is the first step toward such a plan.

Background Advanced technologies, like robotics, provide enhanced precision for implanting total knee arthroplasty (TKA) components; however, the optimal targets for implant position specifically in the sagittal plane do not exist. This study identified sagittal implant position which may predict improved outcomes using machine learning algorithms. Methods A retrospective review of 1091 consecutive TKAs was performed. All TKAs were posterior cruciate ligament retaining or sacrificing with an anterior-lip (49.4%) or conforming bearing (50.6%) and performed with modern perioperative protocols. Preoperative and postoperative tibial slope and postoperative femoral component flexion were measured with standardized radiographic protocols. Analysis groups were categorized by satisfaction scores and the Knee Society Score question ‘does this knee feel normal to you?’ Machine learning algorithms were used to identify optimal sagittal alignment zones that predict superior satisfaction and knees “always feeling normal” scores. Results Mean age and median body mass index were 66 years and 34 kg/m2, respectively, with 67% being female. The machine learning model predicted an increased likelihood of being “satisfied or very satisfied” and a knee “always feeling normal” with a change in tibial slope closer to native (−2 to +2°) and femoral component flexion 0 to +7°. Worse outcomes were predicted with any femoral component extension, femoral component flexion beyond +10°, and adding or removing >5° of native tibial slope. Conclusion Superior patient-reported outcomes were predicted with approximating native tibial slope and incorporating some femoral component flexion. Deviation from native tibial slope and excessive femoral flexion or any femoral component extension were predictive of worse outcomes. Level of Evidence Therapeutic level III.

Particulate matter exposure is a risk factor for lower respiratory tract infection in children. Here, we investigated the geospatial patterns of community-acquired pneumonia and the impact of PM2.5(particulate matter with an aerodynamic diameter ≤2.5 µm) on geospatial variability of pneumonia in children. We performed a retrospective analysis of prospectively collected population-based surveillance study data of community-acquired pneumonia hospitalizations among children 2.5was defined as exposure to PM2.5concentrations greater than the mean value (>10.75 μg/m3), and low PM2.5is defined as exposure to PM2.5concentrations less than or equal to the mean value (≤10.75 μg/m3). We also assessed the effects of age, sex, race/ethnicity, history of wheezing, insurance type, tobacco smoke exposure, bacterial etiology, and viral etiology of infection. Of 810 (96.1%) subjects with radiographic community-acquired pneumonia, who resided in the Memphis metropolitan area and had addresses which were successfully geocoded (Supplementary Figure F2), 220 (27.2%) patients were identified to be from high- ( n = 126) or low-risk ( n = 94) community-acquired pneumonia areas. Community-acquired pneumonia in Memphis metropolitan area had a non-homogenous geospatial pattern. PM2.5was associated with residence in high-risk areas for community-acquired pneumonia. In addition, children with private insurance and bacterial, as opposed to viral, etiology of infection had a decreased risk of residence in a high-risk area for community-acquired pneumonia. The results from this paper suggest that environmental exposures as well as social risk factors are associated with childhood pneumonia.

We use a regional chemistry transport model (Weather Research and Forecasting model coupled with chemistry, WRF-Chem) in conjunction with surface observations of tropospheric ozone and Ozone Monitoring Instrument (OMI) satellite retrievals of tropospheric column NO2 to evaluate processes controlling the regional distribution of tropospheric ozone over western Siberia for late spring and summer in 2011. This region hosts a range of anthropogenic and natural ozone precursor sources, and it serves as a gateway for near-surface transport of Eurasian pollution to the Arctic. However, there is a severe lack of in situ observations to constrain tropospheric ozone sources and sinks in the region. We show widespread negative bias in WRF-Chem tropospheric column NO2 when compared to OMI satellite observations from May–August, which is reduced when using ECLIPSE (Evaluating the Climate and Air Quality Impacts of Short-Lived Pollutants) v5a emissions (fractional mean bias (FMB) = −0.82 to −0.73) compared with the EDGAR (Emissions Database for Global Atmospheric Research)-HTAP (Hemispheric Transport of Air Pollution) v2.2 emissions data (FMB = −0.80 to −0.70). Despite the large negative bias, the spatial correlations between model and observed NO2 columns suggest that the spatial pattern of NOx sources in the region is well represented. Scaling transport and energy emissions in the ECLIPSE v5a inventory by a factor of 2 reduces column NO2 bias (FMB = −0.66 to −0.35), but with overestimates in some urban regions and little change to a persistent underestimate in background regions. Based on the scaled ECLIPSE v5a emissions, we assess the influence of the two dominant anthropogenic emission sectors (transport and energy) and vegetation fires on surface NOx and ozone over Siberia and the Russian Arctic. Our results suggest regional ozone is more sensitive to anthropogenic emissions, particularly from the transport sector, and the contribution from fire emissions maximises in June and is largely confined to latitudes south of 60∘ N. Ozone dry deposition fluxes from the model simulations show that the dominant ozone dry deposition sink in the region is to forest vegetation, averaging 8.0 Tg of ozone per month, peaking at 10.3 Tg of ozone deposition during June. The impact of fires on ozone dry deposition within the domain is small compared to anthropogenic emissions and is negligible north of 60∘ N. Overall, our results suggest that surface ozone in the region is controlled by an interplay between seasonality in atmospheric transport patterns, vegetation dry deposition, and a dominance of transport and energy sector emissions.

Stress-related disorders, such as posttraumatic stress disorder (PTSD), are highly prevalent and often difficult to treat. In rodents, stress-related, anxiety-like defensive behavioral responses may be characterized by social avoidance, exacerbated inflammation, and altered metabolic states. We have previously shown that, in rodents, subcutaneous injections of a heat-killed preparation of the soil-derived bacterium Mycobacterium vaccae NCTC 11659 promotes stress resilience effects that are associated with immunoregulatory signaling in the periphery and the brain. In the current study, we sought to determine whether treatment with a heat-killed preparation of the closely related M. vaccae type strain, M. vaccae ATCC 15483, would also promote stress-resilience in adult male rats, likely due to biologically similar characteristics of the two strains. Here we show that immunization with either M. vaccae NCTC 11659 or M. vaccae ATCC 15483 prevents stress-induced increases in hippocampal interleukin 6 mRNA expression, consistent with previous studies showing that M. vaccae NCTC 11659 prevents stress-induced increases in peripheral IL-6 secretion, and prevents exaggeration of anxiety-like defensive behavioral responses assessed 24 h after exposure to inescapable tail shock stress (IS) in adult male rats. Analysis of mRNA expression, protein abundance, and flow cytometry data demonstrate overlapping but also unique effects of treatment with the two M. vaccae strains on immunological and metabolic signaling in the host. These data support the hypothesis that treatment with different M. vaccae strains may immunize the host against stress-induced dysregulation of physiology and behavior.

Background: Standard preoperative protocols in total joint arthroplasty utilise the international normalised ratio (INR) to determine patient coagulation profiles. However, the relevance of preoperative INR values in joint arthroplasty remains controversial. Therefore, we examined (1) the relationship between preoperative INR values and various outcome measures, including, but not limited to: surgical site complications, medical complications, bleeding, number of readmissions, and mortality. Additionally, we sought to determine (2) specific INR values associated with these complications and (3) cutoff INR levels which correlated with specific outcomes. We additionally applied these analyses to (4) examine the relationship between INR and length-of-stay (LOS). Methods: The American College of Surgeons National Surgical Quality Improvement Program database (ACS-NSQIP) was queried for rTHA procedures performed between 2006 and 2017. INR ranges were used to stratify cohorts: ⩽1.0, 1.0–⩽1.25, 1.25–⩽1.5, >1.5. INR values were determined using receiver operating characteristics (ROC) curves for each outcome of interest. Optimal cutoff INR values for each outcome were then obtained using univariate/multivariate models. 2012 patients who underwent rTHA met inclusion criteria. Results: Patients with progressively higher INR values had a significantly different risk of mortality within 30 days ( p = 0.005), bleeding requiring transfusion ( p < 0.001), sepsis ( p = 0.002), stroke ( p < 0.001), failure to wean from ventilator within 48 hours ( p = 0.001), readmission ( p = 0.01), and hospital length of stay ( p < 0.001). Similar results were obtained when utilising optimal INR cutoff values. When correcting for other factors, the following poor outcomes were significantly associated with the respective INR cutoff values (Estimate, 95% CI, p-value): LOS >4 days (1.67, 1.34–2.08, p < 0.001), bleeding requiring transfusion (1.65, 1.30–2.09, p < 0.001), sepsis (2.15, 1.11–4.17, p = 0.022), and any infection (1.82, 1.01–3.29, p = 0.044). Conclusions: Our analysis illustrates a direct relationship between specific preoperative INR levels and poor outcomes following rTHA, including increased LOS, transfusion requirements and infection. Therefore, current INR guideline targets may need to be re-examined when optimising patients for revision arthroplasty.

BACKGROUND Citrobacter, Enterobacter, Morganella, and Serratia (AmpC organisms) species can exhibit third-generation cephalosporin (TGC) resistance after TGC exposure. We aimed to assess if institutional TGC utilization correlated with institutional AmpC organism susceptibility and if prior TGC exposure ≤48 hours were associated with TGC resistance in the first culture of a future infection episode caused by an AmpC organism. METHODS A 5-year retrospective cohort study was performed, including AmpC organisms isolated from pediatric urinary and respiratory tract cultures at an institution with TGC courses reviewed by the antimicrobial stewardship program at 48 hours. Correlations were assessed by Pearson's correlation. Multivariable logistic regression identified factors independently associated with TGC resistance in a subcohort of infection episodes. RESULTS Among 654 cultures, AmpC organism TGC susceptibility increased from 74% in 2013 to 89.3% in 2017, and this correlated with a 26.1% decrease in TGC utilization (R = -0.906; P = 0.034). Among 275 AmpC organism infections, 21.1% were resistant. Resistance occurred in 13.6%, 17.4%, and 56.5% of infections with no exposure, ≤48 hours, and >48 hours of TGC exposure in the past 30 days, respectively. TGC exposure ≤48 hours was not associated with resistance (odds ratio [OR], 1.26; 95% confidence interval [CI], 0.32-4.94; P = 0.74), whereas, TGC exposure >48 hours was (OR, 8.7; 95% CI, 3.67-20.6; P

Following chemotherapy and relapse, high-risk neuroblastoma tumors harbor more genomic alterations than at diagnosis, including increased transcriptional activity of the Yes-associated protein (YAP), a key downstream component of the Hippo signaling network. Although YAP has been implicated in many cancer types, its functional role in the aggressive pediatric cancer neuroblastoma is not well-characterized. In this study, we performed genetic manipulation of YAP in human-derived neuroblastoma cell lines to investigate YAP function in key aspects of the malignant phenotype, including mesenchymal properties, tumor growth, chemotherapy response, and MEK inhibitor response. Standard cytotoxic therapy induced YAP expression and transcriptional activity in patient-derived xenografts treated in vivo, which may contribute to neuroblastoma recurrence. Moreover, YAP promoted a mesenchymal phenotype in high-risk neuroblastoma that modulated tumor growth and therapy resistance in vivo. Finally, the BH3-only protein, Harakiri (HRK), was identified as a novel target inhibited by YAP, which, when suppressed, prevented apoptosis in response to nutrient deprivation in vitro and promoted tumor aggression, chemotherapy resistance, and MEK inhibitor resistance in vivo. Collectively, these findings suggest that YAP inhibition may improve chemotherapy response in patients with neuroblastoma via its regulation of HRK, thus providing a critical strategic complement to MEK inhibitor therapy. Significance: This study identifies HRK as a novel tumor suppressor in neuroblastoma and suggests dual MEK and YAP inhibition as a potential therapeutic strategy in RAS-hyperactivated neuroblastomas.

Background Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. Methods We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. Conclusion PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8–17.3] vs (11.1 [8.9–12.9] ng/ml, p p During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305–2.360; p p = 0.039) were independently associated with adverse outcomes. In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593

Aims Thresholds for operative eligibility based on body mass index (BMI) alone may restrict patient access to the benefits of arthroplasty. The purpose of this study was to evaluate the relationship between BMI and improvements in patient-reported outcome measures (PROMs), and to determine how many patients would have been denied improvements in PROMs if BMI cut-offs were to be implemented. Methods A prospective cohort of 3,449 primary total hip arthroplasties (THAs) performed between 2015 and 2018 were analyzed. The following one-year PROMs were evaluated: hip injury and osteoarthritis outcome score (HOOS) pain, HOOS Physical Function Shortform (PS), University of California, Los Angeles (UCLA) activity, Veterans Rand-12 Physical Component Score (VR-12 PCS), and VR-12 Mental Component Score (VR-12 MCS). Positive predictive values for failure to improve and the number of patients denied surgery in order to avoid a failed improvement were calculated for each PROM at different BMI cut-offs. Results There was a trend to improved outcomes in terms of pain and function improvements with higher BMI. Patients with BMI ≥ 40 kg/m2 had median (Q1, Q3) HOOS pain improvements of 58 points (interquartile range (IQR) 41 to 70) and those with BMI 35 to 40 kg/m2 had median improvements of 55 (IQR 40 to 68). With a BMI cut-off of 30 kg/m2, 21 patients would have been denied a meaningful improvement in HOOS pain score in order to avoid one failed improvement. At a 35 kg/m2 cut-off, 18 patients would be denied improvement, at a 40 kg/m2 cut-off 21 patients would be denied improvement, and at a 45 kg/m2 cut-off 21 patients would be denied improvement. Similar findings were observed for HOOS-PS, UCLA, and VR-12 scores. Conclusion Patients with higher BMIs show greater improvements in PROMs. Using BMI alone to determine eligibility criteria did not improve the rate of clinically meaningful improvements. BMI thresholds prevent patients who may benefit the most from surgery from undergoing THA. Surgeons should consider PROMs improvements in determining eligibility for THA while balancing traditional metrics of preoperative risk stratification. Cite this article: Bone Joint J 2020;102-B(6):683–692.

Early findings of superior total knee arthroplasty (TKA) outcomes at high volume centers have been thought to have led to distinct referral patterns. However, the effect of these selective referral processes has not been well assessed. Therefore, this study compared the characteristics of primary TKA patients at high, intermediate, and low volume hospitals.A total of 12,541 primary TKA patients were stratified into risk groups based on age (65 years), body mass index (40), and Charlson Comorbidity Index (≥4). Hospitals were classified as low, intermediate, or high volume based on mean annual TKA volumes (250, 250-499, and500). Multivariate logistic regression models evaluated the relationship between baseline patient characteristics and hospital volume.There was a greater percentage of high risk patients at high volume (19%, n = 853) compared to those at intermediate (16%, n = 899) or low volume (17%, n = 444) hospitals (P.001). Patients with a body mass index40 were more likely to be treated at high compared to intermediate (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2-1.6, P.001) and low volume centers (OR 1.4, 95% CI 1.2-1.7, P.001). Patients with Charlson Comorbidity Index scores ≥4 were also more likely be treated at high compared to intermediate (OR 1.5, 95% CI 1.3-1.6, P.001) or low (OR 1.2, 95% CI 1.0-1.4, P = .002) volume centers.This study found that TKA patients at high volume centers have significantly different baseline characteristics compared to those at lower volume centers. This study highlights the importance of considering hospital volume status and the associated disparity in the preoperative risk of patients when comparing primary TKA outcomes between centers.

The exact relationships between group 2 innate lymphoid cells (ILC2s) and Th2 cells in type 2 pathology, as well as the mechanisms that restrain the responses of these cells, remain poorly defined. Here we examined the roles of ILC2s and Th2 cells in type 2 lung pathology in vivo using germline and conditional Relb-deficient mice. We found that mice with germline deletion of Relb (Relb(−/−)) spontaneously developed prominent type 2 pathology in the lung, which contrasted sharply with mice with T-cell-specific Relb deletion (Relb(f/f)Cd4-Cre), which were healthy with no observed autoimmune pathology. We also found that in contrast to wild-type B6 mice, Relb-deficient mice showed markedly expanded ILC2s but not ILC1s or ILC3s. Moreover, adoptive transfer of naive CD4(+) T cells into Rag1(−/−)Relb(−/−) hosts induced prominent type 2 lung pathology, which was inhibited by depletion of ILC2s. Mechanistically, we showed that Relb deletion led to enhanced expression of Bcl11b, a key transcription factor for ILC2s. We concluded that RelB plays a critical role in restraining ILC2s, primarily by suppressing Bcl11b activity, and consequently inhibits type 2 lung pathology in vivo.

Strain assessment allows accurate evaluation of myocardial function and mechanics in ST-segment elevation myocardial infarction (STEMI). Strain using cardiovascular magnetic resonance (CMR) has traditionally been assessed with tagging but limitations of this technique have led to more widespread use of alternative methods, which may be more robust. We compared the inter-study repeatability of circumferential global peak-systolic strain (Ecc) and peak-early diastolic strain rate (PEDSR) derived by tagging with values obtained using novel cine-based software: Feature Tracking (FT) (TomTec, Germany) and Tissue Tracking (TT) (Circle cvi42, Canada) in patients following STEMI. Twenty male patients (mean age 56 ± 10 years, mean infarct size 13.7 ± 7.1% of left ventricular mass) were randomised to undergo CMR 1–5 days post-STEMI at 1.5 T or 3.0 T, repeated after ten minutes at the same field strength. Ecc and PEDSR were assessed using tagging, FT and TT. Inter-study repeatability was evaluated using Bland–Altman analyses, coefficients of variation (CoV) and intra-class correlation coefficient (ICC). Ecc (%) was significantly lower with tagging than with FT or TT at 1.5 T (− 9.5 ± 3.3 vs. − 17.5 ± 3.8 vs. −15.5 ± 5.2, respectively, p −1): 1.5 T (0.6 ± 0.2 vs. 1.5 ± 0.4 vs. 1.0 ± 0.4, for tagging, FT and TT respectively, p Ecc at 1.5 T was good for tagging and excellent for FT and TT: CoV 16.7%, 6.38%, and 8.65%, respectively. Repeatability for Ecc at 3.0 T was good for all three techniques: CoV 14.4%, 11.2%, and 13.0%, respectively. However, repeatability of PEDSR was generally lower than that for Ecc at 1.5 T (CoV 15.1%, 13.1%, and 34.0% for tagging, FT and TT, respectively) and 3.0 T (CoV 23.0%, 18.6%, and 26.2%, respectively). Following STEMI, Ecc and PEDSR are higher when measured with FT and TT than with tagging. Inter-study repeatability of Ecc is good for tagging, excellent for FT and TT at 1.5 T, and good for all three methods at 3.0 T. The repeatability of PEDSR is good to moderate at 1.5 T and moderate at 3.0 T. Cine-based methods to assess Ecc following STEMI may be preferable to tagging.

Background A mesh-related intestinal fistula is an uncommon and challenging complication of ventral hernia repair. Optimal management is unclear owing to lack of prospective or long-term data. Methods We reviewed our prospective data for mesh-related intestinal fistulas from 2004 to 2017and compared suture repair versus ventral hernia repair with mesh at the time of mesh-related intestinal fistula takedown. Results Eighty-two mesh-related intestinal fistulas were treated; none of the fistulas had closed spontaneously, and all fistula persisted at the time of our treatment. Mean age was 61 ± 12 years with 33-month follow-up. Comorbidities were similar between groups. Defects were 2.5-times larger in ventral hernia repair with mesh (324 ± 392 cm2 vs 1301 ± 133 cm2; P = .044). Components separation (64% vs 21%; P = .0003) and panniculectomy (35% vs 7%; P = .0074) were more common in ventral hernia repair with mesh. Mortality occurred in 4 patients. Complications were similar. In patients undergoing ventral hernia repair with non-bridged, acellular, porcine dermal matrix, hernia recurrence was less than in patients without mesh (26% vs 66%; P = .0030). Only partial excision of the mesh involved with the fistula resulted in a substantial increase in developing another fistula (29% vs 6%; P Conclusion Patients undergoing preperitoneal ventral hernia repair with mesh for mesh-related intestinal fistula had a lesser rate of hernia recurrence and similar complications compared to suture repair despite larger hernias. Complete mesh excision decreases the risk of fistula recurrence. We maintain that ventral hernia repair with mesh during mesh-related intestinal fistula takedown represents the best opportunity for a durable herniorrhaphy.

Aims To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. Methods and results One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case–control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P 4 were associated with larger infarcts [>10% left ventricular (LV) mass]. Conclusion The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy Body Dementia (LBD), which includes Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer pathology as well as novel biomarkers were discussed.

To identify the time at which point of care ultrasound static image recognition and image acquisition skills decay in novice learners.The University of Iowa Hospitals and Clinics.Twenty-four subjects (23 first-year medical students and one first-year physician assistant student).The subjects completed an initial didactic and hands-on session with immediate testing of learned image acquisition and static image identification skills.Retesting occurred at 1, 4, and 8 weeks after the initial training session with no retraining in between. Image acquisition skills were obtained on the same healthy male volunteers, and the students were given no immediate feedback on their performance. The image identification skills were assessed with a 10 question test at each follow-up session.For pleural ultrasound by 4 weeks, there was a significant decline of the ability to identify A-lines (p = 0.0065). For pleural image acquisition, there was no significant decline in the ability to demonstrate lung sliding. Conversely, cardiac image recognition did not significantly decline throughout the study, while the ability to demonstrate cardiac images at 4 weeks (parasternal short axis view) did (p = 0.0008).Motor and cognitive skills decay at different times for pleural and cardiac images. Future ultrasound curricula should retrain skills at a maximum of 8 weeks from initial training. They should focus more on didactic sessions related to image identification for pleural images, and more hands-on image acquisition training for cardiac images, which represents a novel finding.

Although Fusobacterium necrophorum is well described as an emerging pathogen of acute mastoiditis in young children, infection with other anaerobes can lead to similar severe sequelae including intracranial and extracranial suppurative thrombophlebitis and sepsis. We describe a patient whose unremarkable exposure history assumed increased significance upon obtaining the results of 16S next generation sequencing from a surgical specimen. The novel pathogen Bacteroides pyogenes is reviewed herein.

Background Chronic total occlusions (CTO) are a frequent angiographic finding. Viability of CTO-subtended myocardium is dependent on the presence of an adequate collateral circulation. At rest, collateral supply may be sufficient to avert ischaemia and maintain normal systolic function. However, it remains unclear whether CTO-subtended myocardium may be considered truly normal, or whether subtle functional abnormalities may be present at rest. Purpose To determine whether, in the absence of infarction and hibernation, CTO-subtended myocardium remains functionally normal or whether abnormalities of strain and/or mechanical dispersion may be present at rest. Methods In a retrospective, single centre, observational study, we studied patients with ≥1 angiographically-diagnosed CTO referred for clinical stress perfusion cardiovascular magnetic resonance (CMR), and compared healthy volunteers (HVs) with a normal stress CMR scan. CMR imaging comprised functional and scar assessment with qualitative [visual] evaluation of infarction and segmental wall motion. Patients with infarction and/or wall motion score index (WMSI) ≥1 were excluded from further analysis. In remaining CTO subjects and HVs, segmental peak systolic longitudinal strain and circumferential strain were analysed (in 3 long-axis planes and 3 short-axis planes, respectively) and mechanical dispersion for both orientations was computed. Image analysis was performed using Medis (QStrain) software blinded to all clinical information. Results From a total of 389 patients with ≥1 angiographically-diagnosed CTO, 68 had normal WMSI and no infarction (63.0±11.7 years, 79.4% male, LVEF 62.6±4.5%). Fifty HVs (61.1±7.0 years, 74.0% males, LVEF 61.1±5.3%) were also studied. The majority of CTO patients had concomitant coronary artery disease in at least one non-CTO vessel (n=37, 54.4%). GLS was lower in CTO patients than HVs (−21.8%±1.5% versus −24.0±1.1%; p Conclusion Subclinical changes in left ventricular dynamics are present at rest in CTO patients with fully viable myocardium and no evidence of resting regional wall abnormality. Further study is warranted to evaluate the potential association between mechanical dispersion and arrhythmic events in CTO. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): NIHR Clinician Scientist Award (CS-2018-18-ST2-007 to J.R.A.) and Research Professorship award (RP-2017-08-ST2-007 to G.P.M.). Figure 1. Strain analysis. CTO vs HVFigure 2. Mechanical dispersion. CTO vs HV

Reports analyzing the impact of pediatric antimicrobial stewardship programs (ASP) over long periods of time are lacking. We thus report our ASP experience in a pediatric tertiary referral center over a long-term period from 2011 to 2018. Our ASP was implemented in 2011. The program was based primarily on guideline development with key stakeholders, engaging and educating providers, followed by prospective audit with feedback (PAF). Monitored antibiotics included meropenem, piperacillin–tazobactam, and cefepime, followed by the addition of ceftriaxone, ceftazidime, cefotaxime, ciprofloxacin, levofloxacin, linezolid, and vancomycin at various time points. Specifically, the program did not implemented the core strategy of formulary restriction with prior authorization. Process- and outcome-related ASP measures were analyzed. We saw a 32% decrease in overall antibiotic utilization, a 51% decrease in the utilization of antibiotics undergoing PAF, and a 72% reduction in the use of broad-spectrum antibiotics such as meropenem. There was a concomitant increase in organism susceptibility and a reduction in yearly drug purchasing costs of over USD 560,000 from baseline without changes in sepsis-related mortality. Our study highlights that a pediatric ASP based primarily on the principles of guideline development and PAF can improve antibiotic utilization and institutional bacterial susceptibilities without a detrimental impact on patient outcomes by changing the culture of antimicrobial utilization within the institution.

Forest and vegetation fires, used as tools for agriculture and deforestation, are a major source of air pollutants and can cause serious air quality issues in many parts of Asia. Actions to reduce fire may offer considerable, yet largely unrecognized, options for rapid improvements in air quality. In this study, we used a combination of regional and global air quality models and observations to examine the impact of forest and vegetation fires on air quality degradation and public health in Southeast Asia (including Mainland Southeast Asia and south‐eastern China). We found that eliminating fire could substantially improve regional air quality across Southeast Asia by reducing the population exposure to fine particulate matter (PM2.5) concentrations by 7% and surface ozone concentrations by 5%. These reductions in PM2.5 exposures would yield a considerable public health benefit across the region; averting 59,000 (95% uncertainty interval (95UI): 55,200–62,900) premature deaths annually. Analysis of subnational infant mortality rate data and PM2.5 exposure suggested that PM2.5 from fires disproportionately impacts poorer populations across Southeast Asia. We identified two key regions in northern Laos and western Myanmar where particularly high levels of poverty coincide with exposure to relatively high levels of PM2.5 from fires. Our results show that reducing forest and vegetation fires should be a public health priority for the Southeast Asia region., Key Points Eliminating forest and vegetation fires could substantially improve regional air quality in Mainland Southeast AsiaReducing exposure to particulate and ozone pollution from fires would yield a considerable public health benefit across Southeast AsiaParticulate air pollution from fires disproportionately impacts poorer populations across Southeast Asia

ObjectivesTo determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19.MethodsIn a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis.ResultsIn 52 patients (median age: 54 (IQR 51–57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; pConclusionsPatients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities.Trial registration numberNCT04625075.

Background Widespread abnormalities of the myocardium have been reported in patients with COVID-19. However, these patients often have substantial co-morbidities and it is essential to understand whether cardiac abnormalities represent pre-existing disease or are the consequence of COVID-19. Objective To determine the contribution and cardiac impact of co-morbidities in patients who have recovered from COVID-19. Methods In a prospective observational study, adult patients hospitalized with confirmed COVID-19 were recruited from the Edinburgh Heart Centre between May and November 2020 and compared to healthy and co-morbidity-matched volunteers. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging and coronary computed tomography angiography. Results Twenty-three patients (54±11 years, 20 male) who recovered from COVID-19 were recruited. Half (n=11, 48%) required admission to the intensive care unit and a third (n=7, 31%) received non-invasive or invasive ventilation. Patients had a high prevalence of known cardiovascular disease (n=18, 78%), associated risk factors (n=11, 45%) and coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), myocardial native T1 values (1202±25 versus 1162±27 ms, P=0.008, figure 1) and extracellular volume fraction (31.9±1.7 versus 29.8±0.5 %, P=0.001, figure 1) were higher with no differences in manganese uptake. Compared to co-morbidity-matched volunteers (n=20), there were no differences in native T1 values (1202±25 versus 1196±39 ms, P=0.61, figure 1), extracellular volume fraction (31.9±1.7 versus 31.0±0.5 %, P=0.11), presence of late gadolinium enhancement or manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of concomitant myocardial injury or coronary artery disease. Conclusions Patients who have recovered following hospitalization with COVID-19 have no evidence of a major excess in myocardial injury or dysfunction compared to co-morbidity-matched volunteers. The presence of co-morbidities likely explains many of the previously reported myocardial abnormalities. Conflict of Interest None

Traumatic intraperitoneal bladder rupture (IBR) requires surgical repair. Traditionally performed via laparotomy, experience with laparoscopic bladder repair (LBR) after blunt trauma is limited. Benefits of laparoscopy include decreased length of stay (LOS), less pain, early return to work, fewer adhesions, and lower risk of incisional hernia. The aim of this series is to demonstrate the potential superiority of LBR in select trauma patients. This is a retrospective review performed of all IBR patients from 2008 to 2016. Demographics, clinical management, outcomes, and follow-up were compared between LBR and open bladder repair (OBR) patients. Twenty patients underwent OBR, and seven underwent LBR. There was no significant difference in gender, age, or Injury Severity Score. There were no deaths or reoperations in either group. Average hospital length of stay and ICU days were similar between groups. There was one patient with UTI and one with readmission in each group. There were two incisional hernias and two bowel obstructions in the OBR group, with one patient requiring operative intervention. No such complications occurred in the LBR group. LBR for traumatic IBR can be safely performed in select patients, even in those with multiple extra-abdominal injuries.

Background/Purpose While childhood obesity is a growing problem, the implications of BMI on elective pediatric surgery remains poorly described. This study evaluates the impact of obesity on surgical outcomes after elective colorectal procedures. Methods Children ages 2–18 years undergoing elective colorectal surgery for IBD were identified from the NSQIP-Pediatric database. Patients were classified as underweight (UW), normal weight (NW), overweight (OW) and obese (OB) based on their age- and sex-adjusted BMI. Postoperative complications were compared between cohorts. Results 858 patients (14.8% UW, 64.3% NW, 13.1% OW, 7.8% OB) were identified, with overall complications occurring in 15.3% and SSI in 10.1%. Obese/overweight patients had higher rates of deep incisional SSI (4.5%OB, 4.5%OW, 0%NW, p = 0.002) and superficial wound disruption (5.4%OB, 5.8%OW, 1.6%NW, p = 0.04). Incremental increase in BMI by 1.0kg/m2 was associated with 4.3% increased likelihood of developing deep incisional SSI and 2.3% increase of superficial wound disruption. Obese/overweight children also had increased incidence of septic shock and UTI, as well as longer operative times, days of mechanical ventilation and LOS. Conclusions Increasing BMI was associated with increased wound complications in IBD patients undergoing elective intestinal surgery. Preoperative optimization and weight loss strategies may potentially reduce SSI and other infectious complications. Level of Evidence III

Indonesia contains large areas of peatland that have been drained and cleared of natural vegetation, making them susceptible to burning. Peat fires emit considerable amounts of carbon dioxide, particulate matter (PM) and other trace gases, contributing to climate change and causing regional air pollution. However, emissions from peat fires are uncertain, due to uncertainties in emission factors and fuel consumption. We used the Weather Research and Forecasting model with chemistry and measurements of PM concentrations to constrain PM emissions from Indonesian fires during 2015, one of the largest fire seasons in recent decades. We estimate primary PM2.5 (particles with diameters less than 2.5 µm) emissions from fires across Sumatra and Borneo during September–October 2015 were 7.33 Tg, a factor 3.5 greater than those in the Fire Inventory from NCAR (FINNv1.5), which does not include peat burning. We estimate similar dry fuel consumption and CO2 emissions to those in the Global Fire Emissions Database (GFED4s, including small fires) but PM2.5 emissions that are a factor of 1.8 greater, due to updated PM2.5 emission factors for Indonesian peat. Fires were responsible for an additional 3.12 Tg of secondary organic aerosol formation. Through comparing simulated and measured PM concentrations, our work provides independent support of these updated emission factors. We estimate peat burning contributed 71 % of total primary PM2.5 emissions from fires in Indonesia during September–October 2015. We show that using satellite-retrieved soil moisture to modify the assumed depth of peat burn improves the simulation of PM, increasing the correlation between simulated and observed PM from 0.48 to 0.56. Overall, our work suggests that peat fires in Indonesia produce substantially greater PM emissions than estimated in current emission inventories, with implications for the predicted air quality impacts of peat burning.

To evaluate the effects of neoprene sleeves (NSs) and prophylactic knee braces (PKBs) on neuromuscular control and cutting agility.Markerless motion-capture technology tracked subjects (1) without a brace as a control (2) with NSs and (3) with PKBs during single-leg drop vertical jump (SLDVJ), single-leg squat (SLS), Y-excursion, and cutting movements. Movements were recorded five times per bracing condition in three different sessions.University laboratory.Ten healthy, active subjects (5 male, 5 female; age range, 22-26 years).Degrees of motion and time to completion.Use of NSs and PKBs reduced subjects' hip internal rotation in the loading phase of SLDVJ (p = 0.026, 0.02) and SLS (p = 0.005,0.001), reduced knee flexion in the loading phase of SLDVJ (p = 0.038,0.001), and reduced knee frontal plane abduction (FPA) with SLS (p = 0.015, 0.024) and Y-excursion (p = 0.002, 0.005) compared to control. Use of PKBs decreased subjects' hip internal rotation in the Y-excursion (p = 0.024) and reduced knee FPA in the SLDVJ loading phase (p = 0.014) compared to control. There was no difference in cutting agility for either group (p = 0.145, 0.347).Both NSs and PKBs positively impacted neuromuscular control without impacting cutting agility.

Emergent surgeries have different causes and physiologic patient responses than the same elective surgery, many of which are due to infectious etiologies. Therefore, we hypothesized that emergency cases have a higher risk of postoperative SSI than their elective counterparts. The ACS NSQIP database was queried from 2005 to 2016 for all cholecystectomies, ventral hernia repairs, and partial colectomies to examine common emergency and elective general surgery operations. Thirty-day outcomes were compared by emergent status. Any SSI was the primary outcome. There were 863,164 surgeries: 416,497 cholecystectomies, 220,815 ventral hernia repairs, and 225,852 partial colectomies. SSIs developed in 38,865 (4.5%) patients. SSIs increased with emergencies (5.3% vs 3.6% for any SSI). Postoperative sepsis (5.8% vs 1.5%), septic shock (4.7% vs 0.6%), length of stay (8.1 vs 2.9 days), and mortality (3.6% vs 0.4%) were increased in emergent surgery; P < 0.001 for all. When controlling for age, gender, BMI, diabetes, smoking, wound classification, comorbidities, functional status, and procedure on multivariate analysis, emergency surgery (odds ratio 1.15, 95% confidence interval 1.11–1.19) was independently associated with the development of SSI. Patients undergoing emergency general surgery experience increased rates of SSI. Patients and their families should be appropriately counseled regarding these elevated risks when consenting for emergency surgery.

Trauma recidivism accounts for approximately 44% of emergency department admissions and remains a significant health burden with this patient cohort carrying higher rates of morbidity and mortality.A level 1 trauma center registry was queried for patients aged 18-25 y presented between 2009 and 2015. Patients with nonaccidental gunshot wounds, stab wounds, or blunt assault-related injuries were categorized as violent injuries. Primary outcomes included mortality and recidivism, which were defined as patients with two unrelated traumas during the study period. Hospital records and the Social Security Death Index were used to aid in outcomes.A total of 6484 patients presented with 1215 (18.7%) sustaining violent injuries (87.4% male, median age 22.2 y). Mechanism of violent injuries included 64.4% gunshot wound, 21.1% stab, and 14.8% blunt assault. Compared with nonviolent injuries, violent injury patients had increased risk of mortality (9.3% versus 2.1%, P 0.0001). Out-of-hospital mortality was 2.6% (versus 0.5% nonviolent, P 0.0005), with an average time to death being 6.4 mo from initial injury. Recidivism was 24.9% with mean time to second violent injury at 31.9 ± 21.0 mo; 14.9% had two trauma readmissions, and 8.0% had ≥3. Ninety percent of subsequent injuries occurred within 5 y, with 19.1% in the first year.The burden of injury after violent trauma extends past discharge as patients have significantly higher mortality rates following hospital release. Over one-quarter present with a second unrelated trauma or death. Improved medical, psychological, and social collaborative treatment of these high-risk patients is needed to interrupt the cycle of violent injury.

Background Systolic strain and peak-early diastolic strain rate (PEDSR) measure subclinical cardiac dysfunction. These parameters can be derived from cardiovascular magnetic resonance (CMR) cine images using new software packages, but the comparative test-retest reproducibility of these software in disease states is unknown. This study compared the test-retest reproducibility of strain measures derived from two software packages (feature-tracking software (FT) and tissue-tracking (TT)) in disease populations with preserved ejection fractions. Methods This was a prospective study of 10 patients with aortic stenosis (AS), 10 haemodialysis patients and 10 diabetic patients at 1.5 and 3-Tesla. 30 subjects underwent test-retest reproducibility scans of global circumferential strain (GCS), global longitudinal strain (GLS), circumferential-PEDSR and longitudinal-PEDSR calculated using TT and FT software. Results Test-retest reproducibility of GCS and GLS were similar for FT and TT across patient groups. Coefficient of variability (CoV) for FT-derived GCS 8.1%, 5% and 7.9% for AS, diabetic and haemodialysis patients, compared to 3.3%, 9.2% and 5.4% for TT-derived GCS, with CoV for FT-derived GLS 8%, 6.4% and 8.2% for AS, diabetic and haemodialysis patients, compared to 5.3%, 4.8% and 7% for TT-derived GLS). Reproducibility of FT-derived circumferential and longitudinal-PEDSR was worse than TT-derived circumferential and longitudinal-PEDSR (CoV for FT-derived circumferential-PEDSR 18.2%, 18% and 17.4% for AS, diabetic and haemodialysis patients, compared to 6.1%, 11.7% and 11% for TT-derived circumferential-PEDSR with CoV for FT-derived longitudinal PEDSR 18.2%, 18.9%, 18.3% for AS, diabetic and haemodialysis patients, compared to 8.9%, 9.1% and 11.4% for TT-derived longitudinal-PEDSR). Bland-Altman analysis revealed no systematic bias with tighter limits of agreement for TT-derived strain measures. Conclusions Reproducibility of GCS and GLS are excellent with FT and TT software across diseases. TT had superior test-retest reproducibility for quantification of longitudinal and circumferential-PEDSR than FT-derived PEDSR across diseases.

In an era of rising obesity and an aging population, there are conflicting data regarding outcomes of laparoscopic weight loss surgery in older Americans. The aim of this study was to characterize the short-term outcomes of laparoscopic weight loss surgery in the elderly. The ACS NSQIP database was queried for obese patients aged ≥40 years undergoing laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy. Patients were subdivided into age groups: 40 to 49, 50 to 59, 60 to 64, 65 to 69, and ≥70 years, and compared with univariate and multivariate analyses. Fifty-three thousand five hundred thirty-three patients were identified. Roux-en-Y gastric bypass was performed in 57.5 per cent of cases and was more common than sleeve gastrectomy in all age groups ( P < 0.05). Comorbidities increased significantly with increasing age. There was an increase in minor (4.6% vs 9.1%; P < 0.0001) and major complications (2.2% vs 6.3%; P < 0.0001), and 30-day mortality (0.1% vs 0.5%; P = 0.0001) between the 40 to 49 and ≥70 years age groups. Increased age was independently associated with major complications. Mortality also increased with age. Older patients undergoing laparoscopic weight loss surgery have increased morbidity and mortality. When controlling for comorbidities, increases in age continued to impact major and minor complications and mortality.

In the face of an increasingly aged population, surgical management in the elderly will rise. This study assesses the short-term outcomes of esophagectomies in octogenarians.The National Surgical Quality Improvement Program database was queried for esophagectomy cases from 2005 to 2014. Patients aged80 and ≥80 y were compared in univariate and multivariate analysis, controlling for confounding variables.Among 9354 esophagectomies, 4.3% were performed in patients aged ≥80 y. Ivor Lewis was the most common approach, comprising 43% of cases. Octogenarians more frequently had dependent functional status (P 0.0001) and cardiovascular disease (P 0.0001), whereas younger patients were more likely obese (P 0.0001), smokers (P 0.0001), and have excess preoperative weight loss (P = 0.0043). Compared to younger patients, in multivariate analysis, elderly patients were noted to have increased risk of 30-d mortality (odds ratio [OR] 1.67; confidence interval [CI] 1.03-2.67), discharge to facility (OR 3.08; CI 2.36-4.02), myocardial infarction (OR 2.49; CI 1.29-4.82), and pneumonia (OR 1.47; CI 1.12-1.910). However, regardless of age, dependent functional status demonstrated the strongest association with mortality (OR 3.41; CI 2.14-6.61). Within the elderly, each additional year above 80 y old increased the risk of discharge to a facility by 17% (OR 1.17; CI 1.04-1.30). Cases requiring nongastric intestinal conduit were also more likely to suffer from early mortality (OR 2.87; CI 1.87-4.40).Age is independently associated with multiple adverse outcomes, including mortality, discharge to facility, and postoperative cardiopulmonary complications. Functional dependence is even more so associated with poor outcomes. Careful selection of very elderly patients is required to minimize additional risk.

In patients with heart failure, downregulation of adenosine receptor gene expression and impaired adenosine-related signal transduction may result in a diminished response to adenosine. This may have implications for cardiac stress testing. We evaluated the haemodynamic response to intravenous adenosine in patients with left ventricular systolic dysfunction (LVSD) undergoing stress cardiovascular magnetic resonance imaging (CMR).We retrospectively examined 497 consecutive patients referred for clinical stress CMR. Blood pressure and heart rate responses with intravenous adenosine were compared in patients with normal, mild-moderately impaired and severely impaired LV systolic function (ejection fraction [EF] 55%, 36-55% and 35%, respectively). Following 2 min of adenosine infusion, there was a significant difference between the groups in the heart rate change from baseline, with a diminished heart rate response in patients with LVSD (p 0.001). An increase in the dose of adenosine (up to 210 μg/kg/min) was required to achieve a sufficient haemodynamic response in more patients with severe LVSD (41%) than those with mild-moderately impaired and normal LV systolic function (24% and 19%, respectively, p 0.001). Even with increased doses of adenosine in subjects with severe LVSD, peak haemodynamic response remained blunted. With multivariate analysis age (p 0.001) and LVEF (p = 0.031) were independent predictors of heart rate response to adenosine.Patients with reduced LVEF referred for stress CMR may have a blunted heart rate response to adenosine. Further study is warranted to determine whether this may be associated with reduced diagnostic accuracy and also the potential utility of further dose increases or alternative stressors.

Objective Evaluate outcomes of patients undergoing mesh explantation following partial mesh excision (PME) and complete mesh excision (CME). Background Ventral hernia repair (VHR) with mesh remains one of the most commonly performed procedures worldwide. Management of previously placed mesh during reexploration remains unclear. Studies describing PME as a feasible alternative have been limited. Methods The AHSQC registry was queried for VHR patients who underwent mesh excision. Variables used for propensity-matching included age, BMI, race, diabetes, COPD, OR time>2 hours, immunosuppressants, smoking, active infection, ASA class, elective case, wound classification, and history of abdominal wall infection. Results A total of 1904 VHR patients underwent excision of prior mesh. After propensity matching, complications were significantly higher (35% vs 29%, P = 0.01) after PME, including SSI/SSO, SSOPI, and reoperation. No differences were observed in patients with clean wounds, however in clean-contaminated, PME more frequently resulted in SSOPI (24% vs 9%, P = 0.02). In mesh infection/fistulas, higher rates of SSOPI (46% vs 24%, P = 0.04) and reoperation (21% vs 6%, P = 0.03) were seen after PME. Odds-ratio analysis showed increased likelihood of SSOPI (OR 1.5, 95% CI 1.05-2.14; P = 0.023) and reoperation (OR 2.2, 95% CI 1.13-4.10; P = 0.015) with PME. Conclusions With over 350,000 VHR performed annually and increasing mesh use, guidelines for management of mesh during reexploration are needed. This analysis of a multicenter hernia database demonstrates significantly increased postoperative complications in PME patients with clean-contaminated wounds and mesh infections/fistulas, however showed similar outcomes in those with clean wounds.

Historically an enzyme of the immune system, the lysosomal reductase GILT serves a unique homeostatic role in bone resorption., The extracellular bone resorbing lacuna of the osteoclast shares many characteristics with the degradative lysosome of antigen-presenting cells. γ-Interferon–inducible lysosomal thiol reductase (GILT) enhances antigen processing within lysosomes through direct reduction of antigen disulfides and maintenance of cysteine protease activity. In this study, we found the osteoclastogenic cytokine RANKL drove expression of GILT in osteoclast precursors in a STAT1-dependent manner, resulting in high levels of GILT in mature osteoclasts, which could be further augmented by γ-interferon. GILT colocalized with the collagen-degrading cysteine protease, cathepsin K, suggesting a role for GILT inside the osteoclastic resorption lacuna. GILT-deficient osteoclasts had reduced bone-resorbing capacity, resulting in impaired bone turnover and an osteopetrotic phenotype in GILT-deficient mice. We demonstrated that GILT could directly reduce the noncollagenous bone matrix protein SPARC, and additionally, enhance collagen degradation by cathepsin K. Together, this work describes a previously unidentified, non-immunological role for GILT in osteoclast-mediated bone resorption.

This clinical practice guideline for the diagnosis and treatment of acute hematogenous osteomyelitis (AHO) in children was developed by a multidisciplinary panel representing Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA). This guideline is intended for use by healthcare professionals who care for children with AHO, including specialists in pediatric infectious diseases, orthopedics, emergency care physicians, hospitalists, and any clinicians and healthcare providers caring for these patients. The panel’s recommendations for the diagnosis and treatment of AHO are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the diagnosis and treatment of AHO in children. The panel followed a systematic process used in the development of other IDSA and PIDS clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.

BACKGROUND: The objective of our study was to identify variables associated with inhaled medication use in smokers with normal spirometry (GOLD-0) and to examine the association of inhaled medication use with development of exacerbations and obstructive spirometry in the future. METHODS: We performed a retrospective multivariable analysis of GOLD-0 subjects identified in data from the COPDGene study to examine factors associated with medication use. Five categories were identified: (1) no medications, (2) short-acting bronchodilator, (3) long-acting bronchodilator; long-acting muscarinic antagonists and/or long-acting β agonist, (4) inhaled corticosteroids (ICS) with or without long-acting bronchodilator, and (5) dual bronchodilator with ICS. Sensitivity analysis was performed excluding subjects with history of asthma. We also evaluated whether long-acting inhaled medication use was associated with exacerbations and obstructive spirometry at the follow-up visit 5 y after enrollment. RESULTS: Of 4,303 GOLD-0 subjects within the analysis, 541 of them (12.6%) received inhaled medications. Of these, 259 (6%) were using long-acting inhaled medications and 282 (6.6%) were taking short-acting bronchodilator. Female sex (odds ratio [OR] 1.47, P = .003), numerous medical comorbidities, radiographic emphysema (OR 2.22, P = .02), chronic bronchitis (OR 1.77, P < .001), dyspnea (OR 2.24, P < .001), asthma history (OR 15.56, P < .001), prior exacerbation (OR 8.45, P < .001), and 6-min walk distance (OR 0.9, P < .001) were associated with medication use. Minimal changes were noted in a sensitivity analysis. Additionally, inhaled medications were associated with increased total (incidence rate ratio 2.83, P < .001) and severe respiratory exacerbations (incidence rate ratio 3.64, P < .001) and presence of obstructive spirometry (OR 2.83, P = .002) at follow-up. CONCLUSIONS: Respiratory symptoms, history of asthma, and radiographic emphysema were associated with inhaled medication use in smokers with normal spirometry. These individuals were more likely to develop obstructive spirometry, which suggests that health care providers may be able to identify obstructive lung disease prior to meeting the current criteria for COPD.

Aims The aim of the study was to assess the association of P‐selectin with outcomes in heart failure with preserved ejection fraction (HFpEF). Methods and results This is a prospective, observational study of 130 HFpEF patients who underwent clinical profiling, blood sampling, 6 min walk testing, Minnesota Living with Heart Failure Questionnaire evaluation, echocardiography, cardiovascular magnetic resonance imaging, calculation of the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores, and blinded plasma P‐selectin measurement. Patients were followed up for the endpoint of all‐cause mortality. The HFpEF subgroup with higher P‐selectin levels [overall median 26 372, inter‐quartile range (19 360–34 889) pg/mL] was associated with lower age, higher heart rate, less prevalent atrial fibrillation, more frequent current smoking status, and lower right ventricular end‐diastolic volumes. During follow‐up (median 1428 days), there were 38 deaths. Following maximal sensitivity and specificity receiver operating characteristic curve analysis, P‐selectin levels above 35 506 pg/mL were associated with greater risk of all‐cause mortality [hazard ratio (HR) 2.700; 95% confidence interval (CI) 1.416–5.146; log‐rank P = 0.002]. Following multivariable Cox proportional hazards regression analysis and when added to MAGGIC scores, only P‐selectin (adjusted HR 1.707; 95% CI 1.099–2.650; P

Organ transplantation is a preferred treatment option for patients with end-stage organ failure. However, transplant induces a robust rejection response that necessitates life-long immunosuppression, which often leads to a plethora of comorbidities. Thus, the goal of transplantation is to achieve a state of tolerance wherein the host permanently accepts the transplanted organ while maintaining normal immune responses to other antigens. Regulatory T cells (Tregs) play an important role in realizing this goal and are being explored in both animal models and human clinical trials. In this chapter, we discuss the key principles of transplant rejection and Treg biology, as well as the status of human clinical trials utilizing Tregs as cellular therapy. We discuss how the current immunosuppressive drugs are utilized in transplantation in favoring an increased Treg to T effector cell ratio, different approaches in generation of therapeutic Tregs, and various facets in Treg trial designs in the clinic. Such clinical trials provided many opportunities to leverage our understanding of Tregs in transplantation. They also demonstrated Tregs as a safe cellular therapy for human use, but the efficacy of this treatment has yet to be fully realized.

Social stress exacerbates anxious and depressive behaviors in humans. Similarly, anxiety- and depressive-like behaviors are triggered by social stress in a variety of non-human animals. Here, we tested whether oral administration of the putative anxiolytic probiotic strains Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces the striking increase in anxiety-like behavior and changes in gut microbiota observed following social defeat stress in Syrian hamsters. We administered the probiotic at two different doses for 21 days, and 16S rRNA gene amplicon sequencing revealed a shift in microbial structure following probiotic administration at both doses, independently of stress. Probiotic administration at either dose increased anti-inflammatory cytokines IL-4, IL-5, and IL-10 compared to placebo. Surprisingly, probiotic administration at the low dose, equivalent to the one used in humans, significantly increased social avoidance and decreased social interaction. This behavioral change was associated with a reduction in microbial richness in this group. Together, these results demonstrate that probiotic administration alters gut microbial composition and may promote an anti-inflammatory profile but that these changes may not promote reductions in behavioral responses to social stress.

Air pollution exposure is a leading public health problem in China. The majority of the total air pollution disease burden is from fine particulate matter (PM2.5) exposure, with smaller contributions from ozone (O3) exposure. Recent emission reductions have reduced PM2.5 exposure. However, levels of exposure and the associated risk remain high, some pollutant emissions have increased, and some sectors lack effective emission control measures. We quantified the potential impacts of relevant policy scenarios on ambient air quality and public health across China. We show that PM2.5 exposure inside the Greater Bay Area (GBA) is strongly controlled by emissions outside the GBA. We find that reductions in residential solid fuel use and agricultural fertilizer emissions result in the greatest reductions in PM2.5 exposure and the largest health benefits. A 50% transition from residential solid fuel use to liquefied petroleum gas outside the GBA reduced PM2.5 exposure by 15% in China and 3% within the GBA, and avoided 191,400 premature deaths each year across China. Reducing agricultural fertilizer emissions of ammonia by 30% outside the GBA reduced PM2.5 exposure by 4% in China and 3% in the GBA, avoiding 56,500 annual premature deaths across China. Our simulations suggest that reducing residential solid fuel or industrial emissions will reduce both PM2.5 and O3 exposure, whereas other policies may increase O3 exposure. Improving particulate air quality inside the GBA will require consideration of residential solid fuel and agricultural sectors, which currently lack targeted policies, and regional cooperation both inside and outside the GBA., Key Points Ambient fine particulate matter exposure inside the Greater Bay Area is strongly controlled by emissions outside the Greater Bay AreaResidential solid fuel and agricultural emissions lack effective controls that could improve air quality and public health across ChinaImproving particulate air quality inside the Greater Bay Area will require regional cooperation inside and outside the Greater Bay Area

There is a paucity of data characterizing right ventricular performance in heart failure with preserved ejection fraction (HFpEF) using the gold standard of cardiovascular magnetic resonance imaging (CMR). We aimed to assess the proportion of right ventricular systolic dysfunction (RVD) in HFpEF and the relation to clinical outcomes. As part of a single-centre, prospective, observational study, 183 subjects (135 HFpEF, and 48 age- and sex-matched controls) underwent extensive characterization with CMR. transthoracic echocardiography, blood sampling and six-minute walk testing. Patients were followed for the composite endpoint of death or HF hospitalization. RVD (defined as right ventricular ejection fraction

Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a “two hit” stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day –28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days –21, –14, –7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0–56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days –1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.