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Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) drive cancer through their respective receptors, MET and VEGF receptor 2 (VEGFR2). VEGFR2 inhibits MET by promoting MET dephosphorylation. However, whether MET conversely regulates VEGFR2 remains unknown. Here we show that MET suppresses VEGFR2 protein by inducing its endoplasmic-reticulum-associated degradation (ERAD), via intracrine VEGF action. HGF–MET signaling in epithelial cancer cells promoted VEGF biosynthesis through PI3-kinase. In turn, VEGF and VEGFR2 associated within the ER, activating inositol-requiring enzyme 1α, and thereby facilitating ERAD-mediated depletion of VEGFR2. MET disruption upregulated VEGFR2, inducing compensatory tumor growth via VEGFR2 and MEK. However, concurrent disruption of MET and either VEGF or MEK circumvented this, enabling more profound tumor inhibition. Our findings uncover unique cross-regulation between MET and VEGFR2—two RTKs that play significant roles in tumor malignancy. Furthermore, these results suggest rational combinatorial strategies for targeting RTK signaling pathways more effectively, which has potentially important implications for cancer therapy.

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.

The electron field emission properties of the nanodiamond films were examined using scanning tunneling microscopic (STM) technique. Current image tunneling spectroscopic measurements reveal the direct dependence of electron tunneling/field emission behavior of the films on the proportion of grain boundaries present. Local tunneling current-voltage (It–V) measurements show that incorporation of boron species insignificantly alters the occupied state, but markedly modifies the empty state of the diamond films, viz. it induces the presence of impurity states for the films heavily doped with borons, resulting in smaller emission energy gap for the samples. Such a characteristic improves both the local electron field emission behavior of the diamond films measured by STM and the average electron field emission properties measured by conventional parallel plate setup. These results infer clearly that the presence of impurity states due to boron doping is a prime factor improving the field emission properties for these boron-doped nanodiamond films. [ABSTRACT FROM AUTHOR]

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor b (TGFb) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-Bmediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes. [ABSTRACT FROM AUTHOR]

Background: Little is known about the frequency, hospital-level variation, predictors, and clinical outcomes of antibiotic de-escalation in suspected sepsis., Methods: We retrospectively analyzed all adults admitted to 236 US hospitals between 2017-2021 with suspected sepsis (defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration) who were initially treated with ≥2 days of anti-MRSA and anti-pseudomonal antibiotics but had no resistant organisms requiring these agents identified through hospital day 4. De-escalation was defined as stopping anti-MRSA and anti-pseudomonal antibiotics or switching to narrower antibiotics by day 4. We created a propensity score for de-escalation using 82 hospital, demographic, and clinical variables, matched de-escalated to non-de-escalated patients, and then assessed associations between de-escalation and outcomes., Results: Among 124,577 eligible patients, antibiotics were de-escalated in 36,806 (29.5%) including narrowing in 27,177 (21.8%) and cessation in 9,629 (7.7%). De-escalation rates varied widely between hospitals (median 29.4%, IQR 21.3-38.0%). Predictors of de-escalation included less severe disease on day 3-4, positive cultures for non-resistant organisms, and negative/absent MRSA nasal swabs. De-escalation was more common in medium, large, or teaching hospitals in the Northeast or Midwest. De-escalation was associated with lower adjusted risks for acute kidney injury (OR 0.80, 95% CI: 0.76-0.84), ICU admission after day 4 (OR 0.59, 95% CI: 0.52-0.66), and in-hospital mortality (OR 0.92, 95% CI: 0.86-0.996)., Conclusions: Antibiotic de-escalation in patients with suspected sepsis is infrequent, variable across hospitals, linked with clinical and microbiologic factors, and associated with lower risk for acute kidney injury, ICU admission, and in-hospital mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study systematically reviewed and meta-analyzed the differential attrition and utilization of occupational mental health interventions, specifically examining delivery methods (internet-based versus in-person)., Methods: The research, with papers spanning 2010-2024, involved filtering criteria and comprehensive searches across PubMed, Scopus, and Web of Science Core (PROSPERO registration n. CRD42022322394). Of 28 683 titles, 84 records were included in the systematic review, with 75 in meta-analyses. Risk of bias was assessed through the revised Cochrane risk of bias tool for randomized control trials and funnel plots. Differential attrition across studies was meta-analysed through a random-effects model with limited maximum-likelihood estimation for the degree of heterogeneity., Results: Findings reveal higher mean differential attrition in the intervention group, indicating a potential challenge in maintaining participant engagement. The attrition rates were not significantly influenced by the mode of intervention delivery (internet versus in-person). Compensation for participation and year of publication could potentially influence differential attrition from baseline to follow-up measurements., Conclusions: These results suggest a need for cautious consideration of attrition in occupational mental health intervention study designs and emphasize the importance of adapting statistical analyses to mitigate potential bias arising from differential attrition.

Objective: To assess trends in antibiotic prescribing for patients hospitalized with COVID-19 with and without sepsis., Design: Retrospective cohort study using electronic health record (EHR) data., Setting: Five hospitals in eastern Massachusetts., Patients: Adults (≥18 years) hospitalized with community-onset SARS-CoV-2 infections between March 2020 and November 2022., Methods: We assessed quarterly trends in the use of prolonged initial antibiotic therapy (≥4 antibiotic days within one week of admission, including discharge antibiotics) amongst COVID-19 patients with and without sepsis, defined using clinical signs of organ dysfunction before hospital day 3. Poisson regression models were used to adjust for baseline characteristics and severity of illness., Results: Of 431,017 hospitalizations in the study period, 21,563 (5.0%) had community-onset COVID-19. 4,769/21,563 (20.5%) presented with sepsis. Prolonged antibiotics were prescribed in 2,323/4,769 (48.7%) COVID-19 patients with sepsis and 2,866/16,794 (17.1%) without sepsis despite low rates of positive bacterial cultures on admission (15.0% vs 6.3%, respectively). Quarterly rates of prolonged antibiotics declined between the first and second pandemic quarters for both sepsis (66.8% to 43.9%) and no-sepsis (31.8% to 24.4%) groups. However, there was no significant change thereafter through November 2022 in either group (quarterly aORs 1.02, 95% CI 0.99-1.05 and 1.01, 95% CI 0.99-1.03, respectively)., Conclusions: Prolonged antibiotics were common in hospitalized COVID-19 patients with and without sepsis during the first 33 months of the pandemic despite low rates of proven bacterial infection. Decreases in antibiotic utilization occurred primarily between the first and second pandemic quarter with no further reduction thereafter., Competing Interests: Dr Klompas reports personal fees from UpToDate outside the submitted work. Dr Rhee reports personal fees from UpToDate and Cytovale outside the submitted work. No other potential conflicts of interest relevant to the submitted work were reported., (© The Author(s) 2024.)

Objective: To evaluate whether financial incentives lead to improvement in self-management behaviors and glycemia in adolescents with type 1 diabetes (T1D)., Research Design and Methods: Adolescents (12- to 18-year-olds) with T1D selected incentivized self-management behavior and clinical outcome goals in a three-treatment (gain frame, loss frame, no incentives) crossover randomized controlled trial. Participants could earn up to $180 in each 12-week incentive treatment arm., Results: Compared with a mean 41% behavioral goal attainment within the nonfinancial incentives arm, mean behavioral goal attainment under gain and loss frames was 50% (P < 0.01) and 45% (P < 0.01), respectively. Mean time in range (TIR) in gain frame and loss frame arms was higher 43% (P < 0.01) and 42% (P < 0.01), respectively, compared with when not receiving financial incentives (38%). There was no difference in A1C among the three arms., Conclusions: Financial incentives can improve diabetes self-management behaviors and TIR in adolescents with T1D in the short-term., (© 2024 by the American Diabetes Association.)

Aims: This study aimed to quantify preferences for the characteristics of a financial incentives program that would motivate adolescent engagement in type 1 diabetes (T1D) self-care., Method: We performed a discrete choice experiment with 12-18 year-olds with T1D from two pediatric hospital endocrinology clinics (n = 317). We identified key attributes of incentives: (1) monthly value of the reward, (2) payment structure, and (3) difficulty of incentivized behaviors. In twelve choice questions, adolescents chose the incentive option from a pair of profiles that was more likely to motivate them to increase adherence to recommended self-care. Options presented were tailored to adolescents' T1D technology use and perceived difficulty of completing each behavior. We analyzed data using a conditional logit model., Results: The value of the reward accounted for 60.8% of preferences. Adolescents were willing to accept lower value rewards when incentive payments used positive vs. negative reinforcement (-$10.88 (95% CI: -$12.60, -9.24)) and preferred higher incentives for performing hard vs. easier behaviors (+$14.92 (95% CI: +$12.66, +$17.28))., Conclusions: Stated preferences can inform intervention design. Future research will evaluate the external validity of the discrete choice experiment-informed intervention design by assessing adolescent health and behavioral outcomes in a randomized controlled trial., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Many hospitals have scaled back measures to prevent nosocomial SARS-CoV-2 infection given large decreases in the morbidity and mortality of SARS-CoV-2 infections for most people. Little is known, however, about the morbidity and mortality of nosocomial SARS-CoV-2 infections for hospitalized patients in the Omicron era., Objective: To estimate the effect of nosocomial SARS-CoV-2 infection on hospitalized patients' outcomes during the pre-Omicron and Omicron periods., Design: Retrospective matched cohort study., Setting: 5 acute care hospitals in Massachusetts, December 2020 to April 2023., Patients: Adults testing positive for SARS-CoV-2 on or after hospital day 5, after negative SARS-CoV-2 test results on admission and on hospital day 3, were matched to control participants by hospital, service, time period, days since admission, and propensity scores that incorporated demographics, comorbid conditions, vaccination status, primary diagnosis category, vital signs, and laboratory test values., Measurements: Primary outcomes were hospital mortality and time to discharge. Secondary outcomes were intensive care unit (ICU) admission, need for advanced oxygen support, discharge destination, hospital-free days, and 30-day readmissions., Results: There were 274 cases of hospital-onset SARS-CoV-2 infection during the pre-Omicron period and 1037 cases during the Omicron period (0.17 vs. 0.49 cases per 100 admissions). Patients with hospital-onset SARS-CoV-2 infection were older and had more comorbid conditions than those without. During the pre-Omicron period, hospital-onset SARS-CoV-2 infection was associated with increased risk for ICU admission, increased need for high-flow oxygen, longer time to discharge (median difference, 4.7 days [95% CI, 2.9 to 6.6 days]), and higher mortality (risk ratio, 2.0 [CI, 1.1 to 3.8]) versus matched control participants. During the Omicron period, hospital-onset SARS-CoV-2 infection remained associated with increased risk for ICU admission and increased time to discharge (median difference, 4.2 days [CI, 3.6 to 5.0 days]). The association with increased hospital mortality was attenuated but still significant (risk ratio, 1.6 [CI, 1.2 to 2.3])., Limitation: Residual confounding may be present., Conclusion: Hospital-onset SARS-CoV-2 infection during the Omicron period remains associated with increased morbidity and mortality., Primary Funding Source: Harvard Medical School Department of Population Medicine., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0199.

Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0400.

Introduction: Electronic health records (EHRs) are increasingly being leveraged for public health surveillance. EHR-based small area estimates (SAEs) are often validated by comparison to survey data such as the Behavioral Risk Factor Surveillance System (BRFSS). However, survey and EHR-based SAEs are expected to differ. In this cross-sectional study, SAEs were generated using MDPHnet, a distributed EHR-based surveillance network, for all Massachusetts municipalities and zip code tabulation areas (ZCTAs), compared to BRFSS PLACES SAEs, and reasons for differences explored., Methods: This study delineated reasons a priori for how SAEs derived using EHRs may differ from surveys by comparing each strategy's case classification criteria and reviewing the literature. Hypertension, diabetes, obesity, asthma, and smoking EHR-based SAEs for 2021 in all ZCTAs and municipalities in Massachusetts were estimated with Bayesian mixed effects modeling and poststratification in the summer/fall of 2023. These SAEs were compared to BRFSS PLACES SAEs published by the U.S. Centers for Disease Control and Prevention., Results: Mean prevalence was higher in EHR data versus BRFSS in both municipalities and ZCTAs for all outcomes except asthma. ZCTA and municipal symmetric mean absolute percentages ranged from 12.0 to 38.2% and 13.1 to 39.8%, respectively. There was greater variability in EHR-based SAEs versus BRFSS PLACES in both municipalities and ZCTAs., Conclusions: EHR-based SAEs tended to be higher than BRFSS and more variable. Possible explanations include detection of undiagnosed cases and over-classification using EHR data, and under-reporting within BRFSS. Both EHR and survey-based surveillance have strengths and limitations that should inform their preferred uses in public health surveillance., (Copyright © 2024 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Importance: Little is known about the degree to which suspected sepsis drives broad-spectrum antibiotic use in hospitals, what proportion of antibiotic courses are unnecessarily broad in retrospect, and whether these patterns are changing over time., Objective: To describe trends in empiric broad-spectrum antibiotic use for suspected community-onset sepsis., Design, Setting, and Participants: This cross-sectional study used clinical data from adults admitted to 241 US hospitals in the PINC AI Healthcare Database. Eligible participants were aged 18 years or more and were admitted between 2017 and 2021 with suspected community-onset sepsis, defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration on admission., Exposures: Empiric anti-methicillin-resistant Staphylococcus aureus (MRSA) and/or antipseudomonal β-lactam agent use., Main Outcomes and Measures: Annual rates of empiric anti-MRSA and/or antipseudomonal β-lactam agent use and the proportion that were likely unnecessary in retrospect based on the absence of β-lactam resistant gram-positive or ceftriaxone-resistant gram-negative pathogens from clinical cultures obtained through hospital day 4. Annual trends were calculated using mixed-effects logistic regression models, adjusting for patient and hospital characteristics., Results: Among 6 272 538 hospitalizations (median [IQR] age, 66 [53-78] years; 443 465 male [49.6%]; 106 095 Black [11.9%], 65 763 Hispanic [7.4%], 653 907 White [73.1%]), 894 724 (14.3%) had suspected community-onset sepsis, of whom 582 585 (65.1%) received either empiric anti-MRSA (379 987 [42.5%]) or antipseudomonal β-lactam therapy (513 811 [57.4%]); 311 213 (34.8%) received both. Patients with suspected community-onset sepsis accounted for 1 573 673 of 3 141 300 (50.1%) of total inpatient anti-MRSA antibiotic days and 2 569 518 of 5 211 745 (49.3%) of total antipseudomonal β-lactam days. Between 2017 and 2021, the proportion of patients with suspected sepsis administered anti-MRSA or antipseudomonal therapy increased from 63.0% (82 731 of 131 275 patients) to 66.7% (101 003 of 151 435 patients) (adjusted OR [aOR] per year, 1.03; 95% CI, 1.03-1.04). However, resistant organisms were isolated in only 65 434 cases (7.3%) (30 617 gram-positive [3.4%], 38 844 gram-negative [4.3%]) and the proportion of patients who had any resistant organism decreased from 9.6% to 7.3% (aOR per year, 0.87; 95% CI, 0.87-0.88). Most patients with suspected sepsis treated with empiric anti-MRSA and/or antipseudomonal therapy had no resistant organisms (527 356 of 582 585 patients [90.5%]); this proportion increased from 88.0% in 2017 to 91.6% in 2021 (aOR per year, 1.12; 95% CI, 1.11-1.13)., Conclusions and Relevance: In this cross-sectional study of adults admitted to 241 US hospitals, empiric broad-spectrum antibiotic use for suspected community-onset sepsis accounted for half of all anti-MRSA or antipseudomonal therapy; the use of these types of antibiotics increased between 2017 and 2021 despite resistant organisms being isolated in less than 10% of patients treated with broad-spectrum agents.

Objectives: This study's aims were to describe the outcomes of patients with diabetes presenting with their first ED visit for hyperglycemia, and to identify predictors of recurrent ED visits for hyperglycemia., Methods: Using linked databases, we conducted a population-based cohort study of adult and pediatric patients with types 1 and 2 diabetes presenting with a first ED visit for hyperglycemia from April 2010 to March 2020 in Ontario, Canada. We determined the proportion of patients with a recurrent ED visit for hyperglycemia within 30 days of the index visit. Using multivariable regression analysis, we examined clinical and socioeconomic predictors for recurrent visits., Results: There were 779,632 patients with a first ED visit for hyperglycemia. Mean (SD) age was 64.3 (15.2) years; 47.7% were female. 11.0% had a recurrent visit for hyperglycemia within 30 days. Statistically significant predictors of a recurrent visit included: male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, more family physician or internist visits within the past year, being rostered to a family physician, previous ED visits in the past year, ED or hospitalization within the previous 14 days, access to homecare services, and previous hyperglycemia encounters in the past 5 years. Alcoholism and depression or anxiety were positive predictors for the 18-65 age group., Conclusions: This population-level study identifies predictors of recurrent ED visits for hyperglycemia, including male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, higher previous healthcare system utilization (ED visits and hospitalization) for hyperglycemia, being rostered to a family physician, and access to homecare services. Knowledge of these predictors may be used to develop targeted interventions to improve patient outcomes and reduce healthcare system costs., (© 2024. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Background: People with HIV (PWH) may be at risk for more severe COVID-19 outcomes. We compared risk for severe COVID-19 in PWH with matched individuals without HIV., Methods: We identified adults in Massachusetts with a positive SARS-CoV-2 test, March 2020-July 2022, using electronic medical record data from 3 large clinical practice groups. We then used regression models to compare outcomes among PWH versus propensity score-matched people without HIV (matched 20:1) for severe COVID-19 (pneumonia or acute respiratory distress syndrome), hospitalization, and hospital length of stay., Results: We identified 171,058 individuals with COVID-19; among them, 768 PWH were matched to 15,360 individuals without HIV. Overall, severe COVID-19 and hospitalization were similar in PWH and those without HIV (severe COVID-19: 3.8% vs 3.0%, adjusted odds ratio [OR] 1.27, 95% confidence interval [CI]: 0.86-1.87; hospitalization: 12.1% vs 11.3%, adjusted OR: 1.08, 95% CI: 0.87 to 1.35). Compared with people without HIV, PWH with low CD4 T-cell counts (<200 cells/mm 3 ) had more severe COVID-19 (adjusted OR: 3.99, 95% CI: 2.06 to 7.74) and hospitalization (adjusted OR: 2.26, 95% CI: 1.35 to 3.80), but PWH with high CD4 counts had lower odds of hospitalization (adjusted OR: 0.73, 95% CI: 0.52 to 1.03)., Conclusions: PWH with low CD4 T-cell counts had worse COVID-19 outcomes compared with people without HIV, but outcomes for those with high CD4 counts were similar to, or better than, those without HIV. It is unclear whether these findings are generalizable to settings where PWH have less access to and engagement with health care., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We reviewed hospital-onset respiratory viral infections, 2015-2023, in one hospital to determine whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission prevention measures prevented non-SARS-CoV-2 respiratory viral infections. Masking, employee symptom attestations, and screening patients and visitors for symptoms were associated with a 44%-53% reduction in hospital-onset influenza and respiratory syncytial virus (RSV), accounting for changes in community incidence., Competing Interests: Potential conflicts of interest . M. K. reports institutional grant funding from CDC, Agency for Healthcare Research and Quality (AHRQ), and Massachusetts Department of Public Health as well as royalties from UpToDate for chapters on pneumonia. C. R. reports institutional grant funding from CDC (for research related to infection prevention and control) and AHRQ (for research related to sepsis treatment and metrics); royalties from UpToDate for chapters on procalcitonin; consulting fees from Cytovale regarding sepsis diagnostics; and payments from the Infectious Diseases Society of America for his role as an associate editor for Clinical Infectious Diseases. M. B. reports grant funding from CDC for ESP VAERS for COVID-19 and a role on the SHEA Guidelines Committee for the IDSA Standards and Practice Guidelines Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis., Objective: To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria., Design, Setting, and Participants: This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022., Exposures: SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis)., Main Outcomes and Measures: Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models., Results: This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity)., Conclusions and Relevance: In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

Objective: To examine the impact of commonly used case definitions for coronavirus disease 2019 (COVID-19) hospitalizations on case counts and outcomes., Design, Patients, and Setting: Retrospective analysis of all adults hospitalized between March 1, 2020, and March 1, 2022, at 5 Massachusetts acute-care hospitals., Interventions: We applied 6 commonly used definitions of COVID-19 hospitalization: positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) polymerase chain reaction (PCR) assay within 14 days of admission, PCR plus dexamethasone administration, PCR plus remdesivir, PCR plus hypoxemia, institutional COVID-19 flag, or COVID-19 International Classification of Disease, Tenth Revision (ICD-10) codes. Outcomes included case counts and in-hospital mortality. Overall, 100 PCR-positive cases were reviewed to determine each definition's accuracy for distinguishing primary or contributing versus incidental COVID-19 hospitalizations., Results: Of 306,387 hospital encounters, 15,436 (5.0%) met the PCR-based definition. COVID-19 hospitalization counts varied substantially between definitions: 4,628 (1.5% of all encounters) for PCR plus dexamethasone, 5,757 (1.9%) for PCR plus remdesivir, 11,801 (3.9%) for PCR plus hypoxemia, 15,673 (5.1%) for institutional flags, and 15,868 (5.2%) for ICD-10 codes. Definitions requiring dexamethasone, hypoxemia, or remdesivir selected sicker patients compared to PCR alone (mortality rates 12.2%, 10.7%, and 8.8% vs 8.3%, respectively). Definitions requiring PCR plus remdesivir or dexamethasone did not detect a reduction in in-hospital mortality associated with the SARS-CoV-2 Omicron variant. ICD-10 codes had the highest sensitivity (98.4%) but low specificity (39.5%) for distinguishing primary or contributing versus incidental COVID-19 hospitalizations. PCR plus dexamethasone had the highest specificity (92.1%) but low sensitivity (35.5%)., Conclusions: Commonly used definitions for COVID-19 hospitalizations generate variable case counts and outcomes and differentiate poorly between primary or contributing versus incidental COVID-19 hospitalizations. Surveillance definitions that better capture and delineate COVID-19-associated hospitalizations are needed.

Contouring has become an increasingly important aspect of radiotherapy due to inverse planning. Several studies have suggested that the clinical implementation of automated contouring tools can reduce inter-observer variation while increasing contouring efficiency, thereby improving the quality of radiotherapy treatment and reducing the time between simulation and treatment. In this study, a novel, commercial automated contouring tool based on machine learning, the AI-Rad Companion Organs RT™ (AI-Rad) software (Version VA31) (Siemens Healthineers, Munich, Germany), was assessed against both manually delineated contours and another commercially available automated contouring software, Varian Smart Segmentation™ (SS) (Version 16.0) (Varian, Palo Alto, CA, United States). The quality of contours generated by AI-Rad in Head and Neck (H&N), Thorax, Breast, Male Pelvis (Pelvis&#95;M), and Female Pelvis (Pevis&#95;F) anatomical areas was evaluated both quantitatively and qualitatively using several metrics. A timing analysis was subsequently performed to explore potential time savings achieved by AI-Rad. Results showed that most automated contours generated by AI-Rad were not only clinically acceptable and required minimal editing, but also superior in quality to contours generated by SS in multiple structures. In addition, timing analysis favored AI-Rad over manual contouring, indicating the largest time saving (753s per patient) in the Thorax area. AI-Rad was concluded to be a promising automated contouring solution that generated clinically acceptable contours and achieved time savings, thereby greatly benefiting the radiotherapy process., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Maternal obesity elevates non-esterified fatty acids (NEFA) follicular concentrations. Bovine cumulus-oocyte complexes (COCs) matured in vitro under high NEFA have altered metabolism and reduced quality. Systemically, obesity promotes altered mitochondrial metabolism linked to L-carnitine insufficiency. We hypothesized that L-carnitine supplementation during IVM of bovine COCs in the presence of high NEFA would lessen the negative effects of exposure to excessive lipids on embryonic development and oxidative stress. COCs were collected from abattoir ovaries and matured in four groups: CON (control), LC (3 mM L-carnitine), HN (high NEFA: 200uM oleic, 150uM palmitic and 75uM stearic acid), and HNLC (HN and LC). Mature oocytes were assayed for aerobic and anaerobic metabolism utilizing oxygen and pH microsensors or fertilized in vitro (D0). Cleavage (D3) and blastocyst (D7, D8) rates were assessed. D3 embryos with ≥ 4 cells were stained for cytosolic and mitochondrial ROS. D8 blastocysts were assayed for gene transcript abundance of metabolic enzymes. Oocyte metabolism was not affected by IVM treatment. D3 formation of embryos with ≥ 4 cells were lower in LC or HN than CON or HNLC; blastocyst rates were greater for CON and lower for HN than LC and HNLC. D3 embryo mitochondrial and cytosolic ROS were reduced in HNLC when compared to other groups. IVM in HN altered blastocyst gene transcript abundance when compared to CON, but not LC or HNLC. In conclusion, supplementation with L-carnitine protects oocytes exposed to high NEFA during IVM and improves their developmental competence, suggesting that high lipid exposure may lead to L-carnitine insufficiency in bovine oocytes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest that could have influenced the work reported in this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Suspected pneumonia is the most common indication for antibiotics in hospitalized patients but is frequently overdiagnosed. We explored whether normal oxygenation could be used as an indicator to support early discontinuation of antibiotics., Methods: We retrospectively identified all patients started on antibiotics for pneumonia in 4 hospitals with oxygen saturations ≥95% on ambient air, May 2017-February 2021. We propensity-matched patients treated 1-2 days vs 5-8 days and compared hospital mortality and time to discharge using subdistribution hazard ratios (SHRs). Secondary outcomes included readmissions, 30-day mortality, Clostridioides difficile infections, hospital-free days, and antibiotic-free days., Results: Among 39 752 patients treated for possible pneumonia, 10 012 had median oxygen saturations ≥95% without supplemental oxygen. Of these, 2871 were treated 1-2 days and 2891 for 5-8 days; 4478 patients were propensity-matched. Patients treated 1-2 vs 5-8 days had similar hospital mortality (2.1% vs 2.8%; SHR, 0.75 [95% confidence interval {CI}, .51-1.09]) but less time to discharge (6.1 vs 6.6 days; SHR, 1.13 [95% CI, 1.07-1.19]) and more 30-day hospital-free days (23.1 vs 22.7; mean difference, 0.44 [95% CI, .09-.78]). There were no significant differences in 30-day readmissions (16.0% vs 15.8%; odds ratio [OR], 1.01 [95% CI, .86-1.19]), 30-day mortality (4.6% vs 5.1%; OR, 0.91 [95% CI, .69-1.19]), or 90-day C. difficile infections (1.3% vs 0.8%; OR, 1.67 [95% CI, .94-2.99])., Conclusions: One-quarter of hospitalized patients treated for pneumonia had oxygenation saturations ≥95% on ambient air. Outcomes were similar with 1-2 vs 5-8 days of antibiotics. Normal oxygenation levels may help identify candidates for early antibiotic discontinuation. Prospective trials are warranted., Competing Interests: Potential conflicts of interest. M. K. has received royalties from UpToDate for articles on pneumonia and has also received grants from the Agency for Healthcare Research and Quality. C. R. has received royalties from UpToDate for articles on procalcitonin; payments for consulting related to sepsis diagnostics from Cytovale; and payments from Pfizer for consulting related to Lyme disease surveillance. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electronic Health Record (EHR) data are increasingly being used to monitor population health on account of their timeliness, granularity, and large sample sizes. While EHR data are often sufficient to estimate disease prevalence and trends for large geographic areas, the same accuracy and precision may not carry over for smaller areas that are sparsely represented by non-random samples., Methods: We developed small-area estimation models using a combination of EHR data drawn from MDPHnet, an EHR-based public health surveillance network in Massachusetts, the American Community Survey, and state hospitalization data. We estimated municipality-specific prevalence rates of asthma, diabetes, hypertension, obesity, and smoking in each of the 351 municipalities in Massachusetts in 2016. Models were compared against Behavioral Risk Factor Surveillance System (BRFSS) state and small area estimates for 2016., Results: Integrating progressively more variables into prediction models generally reduced mean absolute error (MAE) relative to municipality-level BRFSS small area estimates: asthma (2.24% MAE crude, 1.02% MAE modeled), diabetes (3.13% MAE crude, 3.48% MAE modeled), hypertension (2.60% MAE crude, 1.48% MAE modeled), obesity (4.92% MAE crude, 4.07% MAE modeled), and smoking (5.33% MAE crude, 2.99% MAE modeled). Correlation between modeled estimates and BRFSS estimates for the 13 municipalities in Massachusetts covered by BRFSS's 500 Cities ranged from 81.9% (obesity) to 96.7% (diabetes)., Conclusions: Small-area estimation using EHR data is feasible and generates estimates comparable to BRFSS state and small-area estimates. Integrating EHR data with survey data can provide timely and accurate disease monitoring tools for areas with sparse data coverage., (© 2022. The Author(s).)

Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system. The study aims to assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM. Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study. Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dietary supplementation is the most feasible method to improve oocyte function and developmental potential in vivo . During three experiments, oocytes were collected from maturing, dominant follicles of older mares to determine whether short-term dietary supplements can alter oocyte metabolic function, lipid composition, and developmental potential. Over approximately 8 weeks, control mares were fed hay (CON) or hay and grain products (COB). Treated mares received supplements designed for equine wellness and gastrointestinal health, flaxseed oil, and a proprietary blend of fatty acid and antioxidant support (reproductive support supplement (RSS)) intended to increase antioxidant activity and lipid oxidation. RSS was modified for individual experiments with additional antioxidants or altered concentrations of n-3 to n-6 fatty acids. Oocytes from mares supplemented with RSS when compared to COB had higher basal oxygen consumption, indicative of higher aerobic metabolism, and proportionately more aerobic to anaerobic metabolism. In the second experiment, oocytes collected from the same mares prior to (CON) and after approximately 8 weeks of RSS supplementation had significantly reduced oocyte lipid abundance. In the final experiment, COB was compared to RSS supplementation, including RSS modified to proportionately reduce n-3 fatty acids and increase n-6 fatty acids. The ability of sperm-injected oocytes to develop into blastocysts was higher for RSS, regardless of fatty acid content, than for COB. We demonstrated that short-term diet supplementation can directly affect oocyte function in older mares, resulting in oocytes with increased metabolic activity, reduced lipid content, and increased developmental potential., (© The authors.)

Background: Ending the human immunodeficiency virus (HIV) epidemic requires knowledge of key drivers of spread of HIV infection., Methods: Between 1996 and 2018, 1119 newly and previously diagnosed, therapy-naive persons with HIV (PWH) from San Diego were followed. A genetic distance-based network was inferred using pol sequences, and genetic clusters grew over time through linkage of sequences from newly observed infections. Cox proportional hazards models were used to identify factors associated with the rate of growth. These results were used to predict the impact of a hypothetical intervention targeting PWH with incident infection. Comparison was made to the Centers for Disease Control and Prevention (CDC) Ending the HIV Epidemic (EHE) molecular surveillance strategy, which prioritizes clusters recently linked to all new HIV diagnoses and does not incorporate data on incident infections., Results: Overall, 219 genetic linkages to incident infections were identified over a median follow-up of 8.8 years. Incident cluster growth was strongly associated with proportion of PWH in the cluster who themselves had incident infection (hazard ratio, 44.09 [95% confidence interval, 17.09-113.78]). The CDC EHE molecular surveillance strategy identified 11 linkages to incident infections a genetic distance threshold of 0.5%, and 24 linkages at 1.5%., Conclusions: Over the past 2 decades, incident infections drove incident HIV cluster growth in San Diego. The current CDC EHE molecular detection and response strategy would not have identified most transmission events arising from those with incident infection in San Diego. Molecular surveillance that includes detection of incident cases will provide a more effective strategy for EHE., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Motivated by the need to jointly model the longitudinal trajectories of HIV viral load levels and CD4 counts during the primary infection stage, we propose a joint penalized spline modeling approach that can be used to model the repeated measurements from multiple biomarkers of various types (eg, continuous, binary) simultaneously. This approach allows for flexible trajectories for each marker, accounts for potentially time-varying correlation between markers, and is robust to misspecification of knots. Despite its advantages, the application of multivariate penalized spline models, especially when biomarkers may be of different data types, has been limited in part due to its seemingly complexity in implementation. To overcome this, we describe a procedure that transforms the multivariate setting to the univariate one, and then makes use of the generalized linear mixed effect model representation of a penalized spline model to facilitate its implementation with standard statistical software. We performed simulation studies to evaluate the validity and efficiency through joint modeling of correlated biomarkers measured longitudinally compared to the univariate modeling approach. We applied this modeling approach to longitudinal HIV-1 RNA load and CD4 count data from Southern African cohorts to estimate features of the joint distributions such as the correlation and the proportion of subjects with high viral load levels and high CD4 cell counts over time., (© 2020 The International Biometric Society.)

Introduction: The outbreak of the coronavirus disease 2019 (COVID-19) poses an unprecedented challenge to healthcare workers (HCWs) globally. This study investigated potential factors related to depression, anxiety, and stress in a sample of Chinese HCWs during the peak of the COVID-19 epidemic., Methods: An online survey was distributed to Chinese HCWs using respondent-driven sampling. Data were collected between February 13th and February 20th, 2020, immediately following the COVID-19 contagion peak in Hubei. A total of 1208 respondents were eligible for analysis. Mental health problems and social support were measured by the Depression Anxiety Stress Scales-21 (DASS-21) and the Perceived Social Support Scale (PSS)., Results: The prevalence rates of depression, (DASS-depression > 9) anxiety (DASS-anxiety > 7) and stress (DASS-stress > 14) were 37.8%, 43.0% and 38.5%, respectively. Multivariate logistic regressions revealed that stress, anxiety, and depression were positively related to lower levels of social support, longer working hours, discrimination experience and workplace violence. The scarcity of medical equipment was correlated with increased stress and depression. Chinese HCWs working at COVID 19 designated hospitals were more likely to report anxiety. Additionally, volunteering to work in the frontline health facilities was inversely associated with depression., Conclusion: Mental health problems among Chinese HCWs were alarming during the peak of the COVID-19 epidemic. Health facilities require appropriate and standing services that address the mental health of healthcare workers, particularly during epidemic outbreaks., Competing Interests: The authors declare no conflicts of interest., (© 2021 Yang et al.)

In many biomedical investigations, parameters of interest, such as the intraclass correlation coefficient, are functions of higher-order moments reflecting finer distributional characteristics. One popular method to make inference for such parameters is through postulating a parametric random effects model. We relax the standard normality assumptions for both the random effects and errors through the use of the Fleishman distribution, a flexible four-parameter distribution which accounts for the third and fourth cumulants. We propose a Fleishman bootstrap method to construct confidence intervals for correlated data and develop a normality test for the random effect and error distributions. Recognizing that the intraclass correlation coefficient may be heavily influenced by a few extreme observations, we propose a modified, quantile-normalized intraclass correlation coefficient. We evaluate our methods in simulation studies and apply these methods to the Childhood Adenotonsillectomy Trial sleep electroencephalogram data in quantifying wave-frequency correlation among different channels.

Standard sample size calculation formulas for stepped wedge cluster randomized trials (SW-CRTs) assume that cluster sizes are equal. When cluster sizes vary substantially, ignoring this variation may lead to an under-powered study. We investigate the relative efficiency of a SW-CRT with varying cluster sizes to equal cluster sizes, and derive variance estimators for the intervention effect that account for this variation under a mixed effects model-a commonly used approach for analyzing data from cluster randomized trials. When cluster sizes vary, the power of a SW-CRT depends on the order in which clusters receive the intervention, which is determined through randomization. We first derive a variance formula that corresponds to any particular realization of the randomized sequence and propose efficient algorithms to identify upper and lower bounds of the power. We then obtain an "expected" power based on a first-order approximation to the variance formula, where the expectation is taken with respect to all possible randomization sequences. Finally, we provide a variance formula for more general settings where only the cluster size arithmetic mean and coefficient of variation, instead of exact cluster sizes, are known in the design stage. We evaluate our methods through simulations and illustrate that the average power of a SW-CRT decreases as the variation in cluster sizes increases, and the impact is largest when the number of clusters is small., (© 2019 The International Biometric Society.)

Design and analysis of cluster randomized trials must take into account the intraclass correlation coefficient (ICC), which quantifies the correlation among outcomes from the same cluster. Second-order generalized estimating equations (GEE2) provides a statistically robust way in estimating this quantity and other association parameters. However, GEE2 becomes computationally infeasible as cluster sizes grow. This paper proposes a stochastic variant to fitting GEE2 which alleviates reliance on parameter starting values and provides substantially faster speeds and higher convergence rates than the widely used deterministic Newton-Raphson method. We also propose new estimators for the ICC which account for informative missing outcome data through the use of GEE2, for which we incorporate a "second-order" inverse probability weighting scheme and "second-order" doubly robust (DR) estimating equations that guard against partial model misspecification. Our proposed methods are evaluated through simulations and applied to data from a cluster randomized trial in Bangladesh evaluating the effect of different marketing interventions on the use of hygienic latrines.

Beta-carotene (BC) degradation was studied by liquid chromatography coupled to a quadrupole time of flight mass spectrometer. Throughout/After 21 days of dark storage, 56 nonvolatile degradants were chromatographically separated from pure BC crystal and their molecular formulas were identified. Their structure information was gained by comparing the fragments to a different, but structure-related compound. For example, a newly formed double bond position in dehydrogenated BC was determined by comparing the fragments between BC and dehydrogenated BC. One of their chemical structures was confirmed by comparing its precursor ion mass, retention time, isotopic ratio, and fragmentation to a pure trans-beta-apo-8'-apocarotenal. BC cleavage was observed on double bonds as well as single bonds in BC conjugation chain. PRACTICAL APPLICATION: As evidenced in this study, beta-carotene (BC) degradation is a spontaneous process initiated when the compound is exposed to air. The stoichiometric ratio of BC to oxygen is 1:0.03 at the first oxidation, therefore, only 0.3 mg oxygen or 1.2 mL air will degrade 10 mg BC, an average daily recommended intake. Not like in enzymatic BC degradation, spontaneous BC oxidation did not produce provitamin A, either in retina C20H38O or retinol C20H40O forms. For BC application in vitamin A deficiency, spontaneous BC oxidation should be avoided., (© 2019 Institute of Food Technologists®.)

Background: China and other developing countries in Asia follow similar economic growth patterns described by the flying geese (FG) model, which explains the "catching-up" process of industrialization in latecomer economies. Japan, newly industrialized economies, and China have followed this path, with similar economic development trajectories. Based on the FG model, we postulated a "flying S" hypothesis stating that if a country is located within an FG region and its energy matrix is relatively constant, its per capita CO 2 emission curve will mirror that of "leading geese" countries in the same FG group., Method: Historical CO 2 emissions data were obtained from literature review and national reports and were calculated using bottom-up methods. A sigmoid-shaped, non-linear mixed effect model was applied to examine ex post data with 1000 simulated predictions to construct 95% empirical bands from these fits. By multiplying by estimated population, we predicted total emissions of selected FG countries., Results: Per capita CO 2 emissions from the same FG group mirror each other, especially among second and third industrial sectors. We estimated an annual 18,252.24 million tons of CO 2 emissions (MtCO 2 ) (95% CI = 9458.88-23,972.88) in China and 8281.76 MtCO2 (95% CI = 2765.68-14,959.12) in India in 2030., Conclusion: This study bridges the macroeconomic FG paradigm to study climate change and proposes a "flying S" hypothesis to predict greenhouse gas emissions in East Asia. By applying our theory to empirical data, we provide an alternative framework to predict CO 2 emissions in 2030 and beyond., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This paper presents the development of a multi-sensor platform capable of simultaneous measurement of dissolved oxygen (DO) concentration, glucose and lactate concentrations in a micro-chamber for real-time evaluation of metabolic flux in bovine embryos. A micro-chamber containing all three sensors (DO, glucose, and lactate) was made to evaluate metabolic flux of single oocytes or embryos at different stages of development in ≤ 120 µL of respiration buffer. The ability of the sensor to detect a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis was demonstrated in embryos by an ablation of oxygen consumption and an increase in lactate production following addition of oligomycin, an inhibitor of mitochondrial adenosine triphosphate (ATP) synthesis. An increased reliance upon glycolysis relative to OXPHOS was demonstrated in embryos as they developed from morula to hatched blastocysts by a progressive increase in the lactate/oxygen flux ratio, consistent with isolated metabolic assessments reported previously. These studies highlight the utility of a metabolic multi-sensor for integrative real-time monitoring of aerobic and anaerobic energy metabolism in bovine embryos, with potential applications in the study of metabolic processes in oocyte and early embryonic development., (Published by Elsevier B.V.)

Background: Exposure to ambient particulate matter generated from coal-fired power plants induces long-term health consequences. However, epidemiologic studies have not yet focused on attributing these health burdens specifically to energy consumption, impeding targeted intervention policies. We hypothesize that the generating capacity of coal-fired power plants may be associated with lung cancer incidence at the national level., Methods: Age- and sex-adjusted lung cancer incidence from every country with electrical plants using coal as primary energy supply were followed from 2000 to 2016. We applied a Poisson regression longitudinal model, fitted using generalized estimating equations, to estimate the association between lung cancer incidence and per capita coal capacity, adjusting for various behavioral and demographic determinants and lag periods., Results: The average coal capacity increased by 1.43 times from 16.01 gigawatts (GW) (2000~2004) to 22.82 GW (2010~2016). With 1 kW (KW) increase of coal capacity per person in a country, the relative risk of lung cancer increases by a factor of 59% (95% CI = 7.0%~ 135%) among males and 85% (95% CI = 22%~ 182%) among females. Based on the model, we estimate a total of 1.37 (range = 1.34 ~ 1.40) million standardized incident cases from lung cancer will be associated with coal-fired power plants in 2025., Conclusions: These analyses suggest an association between lung cancer incidence and increased reliance on coal for energy generation. Such data may be helpful in addressing a key policy question about the externality costs and estimates of the global disease burden from preventable lung cancer attributable to coal-fired power plants at the national level.