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BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

PURPOSE: Digital methods to augment traditional contact tracing approaches were developed and deployed globally during the COVID-19 pandemic. These Exposure Notification (EN) systems present new opportunities to support public health interventions. To date, there have been attempts to model the impact of such systems, yet no reports have explored the value of real-time system data for predictive epidemiological modeling. METHODS: We investigated the potential to short-term forecast COVID-19 caseloads using data from Californias implementation of the Google Apple Exposure Notification (GAEN) platform, branded as CA Notify. CA Notify is a digital public health intervention leveraging residents smartphones for anonymous EN. We extended a published statistical model that uses prior case counts to investigate the possibility of predicting short-term future case counts and then added EN activity to test for improved forecast performance. Additional predictive value was assessed by comparing the pandemic forecasting models with and without EN activity to the actual reported caseloads from 1-7 days in the future. RESULTS: Observation of time series presents noticeable evidence for temporal association of system activity and caseloads. Incorporating earlier ENs in our model improved prediction of the caseload counts. Using Bayesian inference, we found nonzero influence of EN terms with probability one. Furthermore, we found a reduction in both the mean absolute percentage error and the mean squared prediction error, the latter of at least 5% and up to 32% when using ENs over the model without. CONCLUSIONS: This preliminary investigation suggests smartphone based ENs can significantly improve the accuracy of short-term forecasting. These predictive models can be readily deployed as local early warning systems to triage resources and interventions.

ObjectivesToward common methods for system monitoring and evaluation, we proposed a key performance indicator framework and discussed lessons learned while implementing a statewide exposure notification (EN) system in California during the COVID-19 epidemic.Materials and methodsCalifornia deployed the Google Apple Exposure Notification framework, branded CA Notify, on December 10, 2020, to supplement traditional COVID-19 contact tracing programs. For system evaluation, we defined 6 key performance indicators: adoption, retention, sharing of unique codes, identification of potential contacts, behavior change, and impact. We aggregated and analyzed data from December 10, 2020, to July 1, 2021, in compliance with the CA Notify privacy policy.ResultsWe estimated CA Notify adoption at nearly 11 million smartphone activations during the study period. Among 1 654 201 CA Notify users who received a positive test result for SARS-CoV-2, 446 634 (27%) shared their unique code, leading to ENs for other CA Notify users who were in close proximity to the SARS-CoV-2-positive individual. We identified at least 122 970 CA Notify users as contacts through this process. Contact identification occurred a median of 4 days after symptom onset or specimen collection date of the user who received a positive test result for SARS-CoV-2.Practice implicationsSmartphone-based EN systems are promising new tools to supplement traditional contact tracing and public health interventions, particularly when efficient scaling is not feasible for other approaches. Methods to collect and interpret appropriate measures of system performance must be refined while maintaining trust and privacy.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting on November 4 to November 6, 2021. This meeting brought together speakers to discuss various developments within the field of diabetes technology. Meeting topics included blood glucose monitoring, continuous glucose monitoring, novel sensors, direct-to-consumer telehealth, metrics for glycemia, software for diabetes, regulation of diabetes technology, diabetes data science, artificial pancreas, novel insulins, insulin delivery, skin trauma, metabesity, precision diabetes, diversity in diabetes technology, use of diabetes technology in pregnancy, and green diabetes. A live demonstration on a mobile app to monitor diabetic foot wounds was presented.

Continuous subcutaneous insulin infusion (CSII) therapy is becoming increasingly popular. CSII provides convenient insulin delivery, precise dosing, easy adjustments for physical activity, stress, or illness, and integration with continuous glucose monitors in hybrid or other closed-loop systems. However, even as insulin pump hardware and software have advanced, technology for insulin infusion sets (IISs) has stayed relatively stagnant over time and is often referred to as the "Achilles heel" of CSII. To discuss barriers to insulin pump therapy and present information about advancements in, and results from clinical trials of extended wear IISs, Diabetes Technology Society virtually hosted the "Improving the Patient Experience with Longer Wear Infusion Sets Symposium" on December 1, 2021. The symposium featured experts in the field of IISs, including representatives from Steno Diabetes Center Copenhagen, University of California San Francisco, Stanford University, Medtronic Diabetes, and Science Consulting in Diabetes. The webinar's seven speakers covered (1) advancements in insulin pump therapy, (2) efficacy of longer wear infusion sets, and (3) innovations to reduce plastics and insulin waste.

PurposeTo assess the correlation between changes in hip capsule morphology with improvements in patient-reported outcome (PRO) scores after arthroscopic surgery for femoroacetabular impingement syndrome (FAIS) using the periportal capsulotomy technique.MethodsTwenty-eight patients with cam morphology FAIS (without arthritis, dysplasia, or hypermobility) were prospectively enrolled before arthroscopic labral repair and femoroplasty through periportal capsulotomy (anterolateral/midanterior portals) without closure. Patients completed the Hip Disability and Osteoarthritis Outcomes Score (HOOS) and had nonarthrographic 3T magnetic resonance imaging (MRI) scans of the affected hip before and 1 year after surgery. Anterior capsule thickness, posterior capsule thickness, anterior-posterior capsule thickness ratio, and proximal-distal anterior capsule thickness ratio were measured on axial-oblique MRI sequences. Pearson correlation coefficients were calculated to determine the association between hip capsule morphology and PRO scores.ResultsPostoperative imaging showed that for all 28 patients (12 female), labral repairs and capsulotomies had healed within 1 year of surgery. Analysis revealed postoperative decreases in anterior hip capsule thickness (1395.4 ± 508.4 mm3 vs 1758.4 ± 487.9 mm3; P = .003) and anterior-posterior capsule thickness ratio (0.92 ± 0.33 vs 1.12 ± 0.38; P = .02). Higher preoperative anterior-posterior capsule thickness ratio correlated with lower preoperative scores for HOOS pain (R = -0.43; P = .02), activities of daily living (ADL) (R = -0.43; P = .02), and sport (R = -0.38; P = .04). Greater decrease from preoperative to postoperative anterior-posterior capsule thickness ratio correlated with greater improvement for HOOS pain (R = -0.40; P = .04), ADL (R = -0.45; P = .02), and sport (R = -0.46; P = .02).ConclusionsPeriportal capsulotomy without closure demonstrates capsule healing by 1 year after arthroscopic FAIS treatment. Changes in hip capsule morphology including decreased anterior-posterior capsule thickness ratio after surgery may be correlated with improvements in patient pain, function, and ability to return to sports.Level of evidenceLevel II, prospective cohort study.

Diabetes complications remain a leading cause of death, which may be due to poor glycemic control resulting from medication nonadherence. The relationship between adherence status and HbA1c (glycemic control) has not been well-studied for clinical pharmacist interventions. This study evaluated medication adherence, patient satisfaction, and HbA1c, in a collaborative pharmacist-endocrinologist diabetes clinic over 6 months. Of 127 referred, 83 patients met the inclusion criteria. Mean medication adherence scores, considered "good" at baseline, 1.4 ± 1.2, improved by 0.05 points (p = 0.018), and there was a 26% increase in patients with good adherence. A significant improvement of 0.40 percentage points (95% CI: -0.47, -0.34) was observed in mean HbA1c across the three time points (p < 0.001). Mean total satisfaction scores were high and increased, with mean 91.3 ± 12.2 at baseline, 94.7 ± 9.6 at 3 months, and 95.7 ± 10.8 at 6 months (p = 0.009). A multimodal personalized treatment approach from a pharmacist provider significantly and positively impacted glycemic control regardless of self-reported medication adherence, and patient satisfaction remained high despite changing to a clinical pharmacist provider and increased care intensity.

[Figure: see text].

The relationship between morphological characteristics of the hip capsule and patient symptoms in the setting of femoroacetabular impingement (FAI) is undefined. In this study, patients with symptomatic FAI prospectively underwent 3T magnetic resonance (MR) imaging of the affected hip and completed the hip disability and osteoarthritis outcome score (HOOS) to determine the correlation between hip capsule anatomy and patient symptoms. Anterior hip capsule volume, posterior capsule volume, anterior-posterior capsule volume ratio, and proximal-distal volume ratio in the anterior capsule were quantified and measured using axial-oblique intermediate-weighted 3D fast spin echo MR images. A total of 35 patients (35 hips) were included for analysis (mean age: 30.6 years; mean body mass index [BMI]: 24.9 kg/m2 ; 57% male). The mean alpha angle was 62.2° ± 4.7°, the mean anterior hip capsule volume was 1705.1 ± 450.3 mm3 , the mean posterior hip capsule volume was 1284.8 ± 268.5 mm3 , the mean anterior to posterior capsule volume ratio was 1.1 ± 0.39, and the mean proximal to distal volume ratio of the anterior capsule was 0.65 ± 0.28. There was no correlation between age, gender, or BMI, and any hip capsule characteristics. Worse scores on the HOOS pain scale were correlated with increased anterior to posterior volume ratio (r = -.38; 95% confidence interval: -0.06 to -0.63). In conclusion, hip capsule morphology correlates with patient symptoms in the setting of FAI as increased anterior capsular volume, relative to posterior capsular volume, is associated with greater patient pain.

PurposeCompare results obtained using infrared two-photon microperimetry (2PM-IR) with conventional visual function tests in healthy subjects of varying ages with and without simulated media opacities.MethodsSubjects from two separate cohort studies completed cone contrast threshold (CCT) testing, conventional microperimetry, visible light microperimetry from a novel device (2PM-Vis), and infrared two-photon microperimetry. The first cohort study, which consisted of six healthy volunteers (23 to 29 years of age), evaluated the effects of simulated media opacities on visual performance testing. Subjects underwent testing on four visual function devices nine separate times under the following conditions: no filter, red filter, green filter, blue filter, light brown filter, dark brown filter, polarized black filter (0° rotation), and polarized black filter (90° rotation). Subjects subsequently performed 2PM-IR and 2PM-Vis testing without a filter in the mydriatic state. The second cohort study evaluated the effect of age on visual test performance in 42 healthy subjects split between two groups (ages 20-40 years and 60-80 years).ResultsRetinal sensitivity measured by 2PM-IR demonstrated lower variability than all other devices relying on visible spectrum stimuli. Retinal sensitivity decreased proportionally with the transmittance of light through each filter. CCT scores and retinal sensitivity decreased with age in all testing modalities. Visible spectrum testing modalities demonstrated larger test result differences between young and old patient cohorts; this difference was inversely proportional to the wavelength of the visual function test.Conclusions2PM-IR mitigates media opacities that may mask small differences in retinal sensitivity when tested with conventional visual function testing devices.Translational relevanceConventional visual function tests that emit visible light may not detect differences in retinal function during the early stages of age-related diseases due to the confounding effects of cataracts. Infrared light, which has greater transmittance through ocular tissue, may reliably quantify retinal sensitivity and thereby detect degenerative changes early on.

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. PATIENT SUMMARY: Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

PurposeTo evaluate effects of age and simulated and real cataractous changes on color vision as measured by the high-definition cone contrast test (CCT).MethodsTwenty-four healthy volunteers from two cohort studies performed CCT using best-corrected visual acuity, filters, mydriasis, and pinhole correction. Retrospective cross-sectional study of patients seen in eye clinics evaluated the relationship between age and color vision, and age and lens status in 355 eyes. Last, 25 subjects underwent CCT before and after cataract surgery.ResultsCCT scores were most reliable in the nonmydriatic condition without pinhole correction. Progressively dense brown filters produced small decreases in S-cone sensitivity. Linear regression analysis of phakic subjects showed a decline for all cone classes with age. Rate of decline was greater for S-cones (slope = -1.09; 95% confidence interval [CI], -1.30 to 0.86) than M-cones (slope = -0.80; 95% CI, -1.03 to -0.58) and L-cones (slope = -0.66; 95% CI, -0.88 to -0.44). CCT scores increased for S-cones but reduced for L- and M-cones in pseudophakic subjects compared with phakic patients. CCT scores after cataract surgery increased for S-cones, M-cones, and L-cones by 33.0 (95% CI, 8.6 to 57.4), 24.9 (95% CI, 3.8 to 46.0), and 22.0 (95% CI, -3.2 to 47.3), respectively.ConclusionsCCT assessment allows for clinically practical quantitation of color and contrast vision improvement after cataract surgery and aging patients who note poor vision despite good visual acuity.Translational relevanceCCT testing, which quantifies hereditary and acquired color deficiency, can also quantify the degree of cataract severity and, combined with other parameters, can provide more precise guidance for cataract extraction to optimize patient care.

Tobacco cigarette (TC) smoking has never been lower in the United States, but electronic cigarette (EC) vaping has reached epidemic proportions among our youth. Endothelial dysfunction, as measured by flow-mediated vasodilation (FMD) is a predictor of future atherosclerosis and adverse cardiovascular events and is impaired in young TC smokers, but whether FMD is also reduced in young EC vapers is uncertain. The aim of this study in otherwise healthy young people was to compare the effects of acute and chronic tobacco cigarette (TC) smoking and electronic cigarette (EC) vaping on FMD. FMD was compared in 47 nonsmokers (NS), 49 chronic EC vapers, and 40 chronic TC smokers at baseline and then after EC vapers (n = 31) and nonsmokers (n = 47) acutely used an EC with nicotine (ECN), EC without nicotine (EC0), and nicotine inhaler (NI) at ~4-wk intervals and after TC smokers (n = 33) acutely smoked a TC, compared with sham control. Mean age (NS, 26.3 ± 5.2 vs. EC, 27.4 ± 5.45 vs. TC, 27.1 ± 5.51 yr, P = 0.53) was similar among the groups, but there were more female nonsmokers. Baseline FMD was not different among the groups (NS, 7.7 ± 4.5 vs. EC:6.6 ± 3.6 vs. TC, 7.9 ± 3.7%∆, P = 0.35), even when compared by group and sex. Acute TC smoking versus control impaired FMD (FMD pre-/postsmoking, -2.52 ± 0.92 vs. 0.65 ± 0.93%∆, P = 0.02). Although the increase in plasma nicotine was similar after EC vapers used the ECN versus TC smokers smoked the TC (5.75 ± 0.74 vs. 5.88 ± 0.69 ng/mL, P = 0.47), acute EC vaping did not impair FMD. In otherwise healthy young people who regularly smoke TCs or ECs, impaired FMD compared with that in nonsmokers was not present at baseline. However, FMD was significantly impaired after smoking one TC, but not after vaping an equivalent "dose" (estimated by change in plasma nicotine) of an EC, consistent with the notion that non-nicotine constituents in TC smoke mediate the impairment. Although it is reassuring that acute EC vaping did not acutely impair FMD, it would be dangerous and premature to conclude that ECs do not lead to atherosclerosis.NEW & NOTEWORTHY In our study of otherwise healthy young people, baseline flow-mediated dilation (FMD), a predictor of atherosclerosis and increased cardiovascular risk, was not different among tobacco cigarette (TC) smokers or electronic cigarette (EC) vapers who had refrained from smoking, compared with nonsmokers. However, acutely smoking one TC impaired FMD in smokers, whereas vaping a similar EC "dose" (as estimated by change in plasma nicotine levels) did not. Finally, although it is reassuring that acute EC vaping did not acutely impair FMD, it would be premature and dangerous to conclude that ECs do not lead to atherosclerosis or increase cardiovascular risk.

Electronic cigarettes (ECs) and tobacco cigarettes (TCs) both release nicotine, a sympathomimetic drug. We hypothesized that baseline heart rate variability (HRV) and hemodynamics would be similar in chronic EC and TC smokers and that after acute EC use, changes in HRV and hemodynamics would be attributable to nicotine, not non-nicotine, constituents in EC aerosol. In 100 smokers, including 58 chronic EC users and 42 TC smokers, baseline HRV and hemodynamics [blood pressure (BP) and heart rate (HR)] were compared. To isolate the acute effects of nicotine vs. non-nicotine constituents in EC aerosol, we compared changes in HRV, BP, and HR in EC users after using an EC with nicotine (ECN), EC without nicotine (EC0), nicotine inhaler (NI), or sham vaping (control). Outcomes were also compared with TC smokers after smoking one TC. Baseline HRV and hemodynamics were not different in chronic EC users and TC smokers. In EC users, BP and HR, but not HRV outcomes, increased only after using the ECN, consistent with a nicotine effect on BP and HR. Similarly, in TC smokers, BP and HR but not HRV outcomes increased after smoking one TC. Despite a similar increase in nicotine, the hemodynamic increases were significantly greater after TC smokers smoked one TC compared with the increases after EC users used the ECN. In conclusion, chronic EC and TC smokers exhibit a similar pattern of baseline HRV. Acute increases in BP and HR in EC users are attributable to nicotine, not non-nicotine, constituents in EC aerosol. The greater acute pressor effects after TC compared with ECN may be attributable to non-nicotine, combusted constituents in TC smoke.NEW & NOTEWORTHY Chronic electronic cigarette (EC) users and tobacco cigarette (TC) smokers exhibit a similar level of sympathetic nerve activity as estimated by heart rate variability. Acute increases in blood pressure (BP) and heart rate in EC users are attribute to nicotine, not non-nicotine, constituents in EC aerosol. Acute TC smoking increased BP significantly more than acute EC use, despite similar increases in plasma nicotine, suggestive of additional adverse vascular effects attributable to combusted, non-nicotine constituents in TC smoke.

Tobacco cigarette smoking is associated with increased sudden death risk, perhaps through adverse effects on ventricular repolarization. The effect of electronic (e-)cigarettes on ventricular repolarization is unknown. The objective of the study was to test the hypothesis that tobacco cigarettes and e-cigarettes have similar adverse effects on electrocardiogram (ECG) indexes of ventricular repolarization and these effects are attributable to nicotine. ECG recordings were obtained in 37 chronic tobacco cigarette smokers, 43 chronic e-cigarette users, and 65 nonusers. Primary outcomes, Tpeak to Tend (Tp-e), Tp-e/QT ratio, and Tp-e/QTc ratio, were measured in tobacco cigarette smokers pre-/post-straw control and smoking one tobacco cigarette and in e-cigarette users and nonusers pre-/post-straw control and using an e-cigarette with and without nicotine (different days). Mean values of the primary outcomes were not different among the three groups at baseline. In chronic tobacco cigarette smokers, all primary outcomes, including the Tp-e (12.9 ± 5.0% vs. 1.5 ± 5%, P = 0.017), Tp-e/QT (14.9 ± 5.0% vs. 0.7 ± 5.1%, P = 0.004), and Tp-e/QTc (11.9 ± 5.0% vs. 2.1 ± 5.1%, P = 0.036), were significantly increased pre-/post-smoking one tobacco cigarette compared with pre-/post-straw control. In chronic e-cigarette users, the Tp-e/QT (6.3 ± 1.9%, P = 0.046) was increased only pre/post using an e-cigarette with nicotine but not pre/post the other exposures. The changes relative to the changes after straw control were greater after smoking the tobacco cigarette compared with using the e-cigarette with nicotine for Tp-e (11.4 ± 4.4% vs. 1.1 ± 2.5%, P < 0.05) and Tp-e/QTc (9.8 ± 4.4% vs. -1.6 ± 2.6%, P = 0.05) but not Tp-e/QT(14.2 ± 4.5% vs. 4.2 ± 2.6%, P = 0.061) . Heart rate increased similarly after the tobacco cigarette and e-cigarette with nicotine. Baseline ECG indexes of ventricular repolarization were not different among chronic tobacco cigarette smokers, electronic cigarette users and nonusers. An adverse effect of acute tobacco cigarette smoking on ECG indexes of ventricular repolarization was confirmed. In chronic e-cigarette users, an adverse effect of using an e-cigarette with nicotine, but not without nicotine, on ECG indexes of ventricular repolarization was also observed.NEW & NOTEWORTHY Abnormal ventricular repolarization, as indicated by prolonged Tpeak-end (Tp-e), is associated with increased sudden death risk. Baseline ECG indexes of repolarization, Tp-e, Tp-e/QT, and Tp-e/QTc, were not different among tobacco cigarette (TC) smokers, electronic cigarette (EC) users, and nonsmokers at baseline, but when TC smokers smoked one TC, all parameters were prolonged. Using an electronic cigarette with nicotine, but not without nicotine, increased the Tp-e/QT. Smoking induces changes in ECG indexes of ventricular repolarization associated with increased sudden death risk.

Targeted therapeutics are needed for triple-negative breast cancer (TNBC). In this study, we investigated the activation of Src family of cytoplasmic tyrosine kinases (SFKs) and two SFK substrates-CUB-domain containing protein 1 (CDCP1) and protein kinase C δ (PKCδ)-in 56 formalin-fixed, paraffin-embedded (FFPE) TNBCs. Expression of SFK phosphorylated at Y416 (SFK_pY416+) in tumor cells was strongly associated with phosphorylation of CDCP1 and PKCδ (CDCP1_ pY743+ and PKCδ_pY311+), as assessed by immunohistochemistry, indicating increased SFK activity in situ. To enable biochemical analysis, protein extraction from FFPE tissue was optimized. Cleaved CDCP1 isoform (70 kDa) was expressed to a varying degree in all samples but only phosphorylated in TNBC tumor cells that expressed SFK_pY416. Interestingly, active SFK was found to be biphosphorylated (SFK_pY416+/pY527+). Biphosphorylated active SFK was observed more frequently in forkhead box protein A1 (FOXA1)- TNBCs. In addition, in SFK_pY416- samples, FOXA1+ TNBC tended to be SFK_pY527+ (classic inactive SFK), and FOXA1- TNBC tended to be SFK_pY527- (SFK poised for activation). Strong SFK_pY416 staining was also observed in tumor-infiltrating lymphocytes in a subset of TNBCs with high tumor-infiltrating lymphocyte content. This report will facilitate protein biochemical analysis of FFPE tumor samples and justifies the development of therapies targeting the SFK/CDCP1/PKCδ pathway for TNBC treatment.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

The primary energy sources of mammalian cells are proteins, fats, and sugars that are processed by well-known biochemical mechanisms that have been discovered and studied in 1G (terrestrial gravity). Here we sought to determine how simulated microgravity (sim-µG) impacts both energy and lipid metabolism in oligodendrocytes (OLs), the myelin-forming cells in the central nervous system. We report increased mitochondrial respiration and increased glycolysis 24 hr after exposure to sim-µG. Moreover, examination of the secretome after 3 days' exposure of OLs to sim-µG increased the Krebs cycle (Krebs and Weitzman, ) flux in sim-µG. The secretome study also revealed a significant increase in the synthesis of fatty acids and complex lipids such as 1,2-dipalmitoyl-GPC (5.67); lysolipids like 1-oleoyl-GPE (4.48) were also increased by microgravity. Although longer-chain lipids were not observed in this study, it is possible that at longer time points OLs would have continued moving forward toward the synthesis of lipids that constitute myelin. For centuries, basic developmental biology research has been the pillar of an array of discoveries that have led to clinical applications; we believe that studies using microgravity will open new avenues to our understanding of the brain in health and disease-in particular, to the discovery of new molecules and mechanisms impossible to unveil while in 1G. © 2016 Wiley Periodicals, Inc.