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Purpose: This case report describes a rare organism causing endogenous endophthalmitis in a patient with sickle cell disease. Methods: A case report was conducted. Results: A 41-year-old man with sickle cell disease presented with acute onset of blurry vision of the right eye. His visual acuity was counting fingers in the right eye and 20/20 in the left eye. He had ophthalmic findings of hypopyon and vitritis in the right eye, consistent with endophthalmitis. He was treated with intravitreal and systemic antibiotics. Vitreous cultures grew Bordetella holmesii. His visual acuity at follow-up visits improved to 20/40 in the setting of improved vitritis. Conclusions: This is the first case describing B holmesii, a rare causative organism of endogenous endophthalmitis, in a patient with sickle cell disease. More studies are needed to improve the early detection and treatment of this unusual organism.

An epithelial-mesenchymal transition (EMT) represents a basic morphogenetic process of high cell plasticity underlying embryogenesis, wound healing, cancer metastasis and drug resistance. It involves a profound transcriptional and epigenetic reprogramming of cells. A critical role of epigenetic modifiers and their specific chromatin modifications has been demonstrated during EMT. However, it has remained elusive whether epigenetic control differs between the dynamic cell state transitions of reversible EMT and the fixed differentiation status of irreversible EMT. We have employed varying EMT models of murine breast cancer cells to identify the key players establishing epithelial-mesenchymal cell plasticity during reversible and irreversible EMT. We demonstrate that the Mbd3/NuRD complex and the activities of histone deacetylases (HDACs), and Tet2 hydroxylase play a critical role in keeping cancer cells in a highly metastatic mesenchymal state. Combinatorial interference with their functions leads to mesenchymal-epithelial transition (MET) and efficiently represses metastasis formation by invasive murine and human breast cancer cells in vivo.

Objective The risks of cardio-renal complications of diabetes increase with age. In the EMPA-REG OUTCOME® trial, empagliflozin reduced cardiovascular (CV) mortality by 38% in patients with type 2 diabetes (T2D) and CV disease. Here we compare outcomes with empagliflozin in older patients in EMPA-REG OUTCOME. Methods Patients with T2D and CV disease were randomised to empagliflozin 10 or 25 mg, or placebo plus standard of care. In post hoc analyses, risks of 3-point major adverse CV events (3P-MACE: composite of CV death, non-fatal myocardial infarction (MI) or non-fatal stroke), CV death, hospitalisation for heart failure, all-cause mortality, all-cause hospitalisation and incident/worsening nephropathy were evaluated for empagliflozin versus placebo by baseline age ( Results Effect of empagliflozin on all outcomes was consistent across age categories (P ≥ 0.05 for interactions) except 3P-MACE. The 3P-MACE hazard ratios (HRs) were 1.04 (95% confidence interval [CI] 0.84, 1.29), 0.74 (0.58, 0.93) and 0.68 (0.46, 1.00) in patients aged Conclusions In the EMPA-REG OUTCOME trial, empagliflozin reduced risks of CV mortality, heart failure and renal outcomes, supporting its cardio-renal benefits in older patients.

Background Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. Objective We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. Methods Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. Results A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. Conclusions EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

The aim of this study was to understand how high- and low-intensity locomotor training (LT) affects sympathetic-somatomotor (SS) coupling in people with incomplete spinal cord injury (SCI). Proper coupling between sympathetic and somatomotor systems allows controlled regulation of cardiovascular responses to exercise. In people with SCI, altered connectivity between descending pathways and spinal segments impairs sympathetic and somatomotor coordination, which may have deleterious effects during exercise and limit rehabilitation outcomes. We postulated that high-intensity LT, which repeatedly engages SS systems, would alter SS coupling. Thirteen individuals (50 ± 7.2 years) with motor incomplete spinal cord injuries (American Spinal Injury Association Impairment Scale C or D; injury level >T6) participated in a locomotor treadmill training program. Patients were randomized into either a high-intensity (high-LT; 70–85% of maximum predicted heart rate; n = 6) group or a low-intensity (low-LT; 50–65% of maximum predicted heart rate; n = 7) group and completed up to 20 LT training sessions over 4–6 weeks, 3–5 days/week. Before and after taining, we tested SS coupling by eliciting reflexive sympathetic activity through a cold stimulation, noxious stimulation, and a mental math task while we measured tendon reflexes, blood pressure, and heart rate. Participants who completed high- versus low-LT exhibited significant decreases in reflex torques during triggered sympathetic activity (cold: −83 vs. 13%, p

OBJECTIVE While sodium–glucose cotransporter inhibitor (SGLTi) therapy has been evaluated in type 1 diabetes (T1D) trials, patient reactions to benefits and risks are unknown. Using established methodology, we evaluated patient preferences for different adjunct-to-insulin therapy options in T1D. RESEARCH DESIGN AND METHODS An online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, and 228 Germany), used conjoint analysis to present six hypothetical, masked, pairwise drug profile choices composed of different benefit-risk attributes and effect ranges. Data used in analyses were derived from actual phase 3 trials of a low-dose SGLTi (comparable to oral empagliflozin 2.5 mg q.d.), a high-dose SGLTi (comparable to oral sotagliflozin 400 mg q.d.), and an available adjunct-to-insulin therapy (comparable to subcutaneous pramlintide 60 μg t.i.d.). RESULTS Conjoint analysis identified diabetic ketoacidosis risk as most important to patients (23% relative score; z test, P < 0.05); ranked second were HbA1c reduction (14%), risk of severe hypoglycemia (13%), oral versus injectable treatment (12%), and risk of genital infection (12%). Next was risk of nausea (11%), followed by weight reduction (8%) and the risk of diarrhea (7%). A low-dose SGLTi drug profile was identified by conjoint analysis as the top patient preference (83% of participants; z test, P < 0.05) versus high-dose SGLTi (8%) or pramlintide (9%). Separate from conjoint analysis, when respondents were asked to choose their preferred adjunct-to-insulin therapy (masked to drug name/dose), 69%, 17%, 6%, and 9% of respondents chose low-dose SGLTi, high-dose SGLTi, pramlintide, and insulin therapy alone, respectively. CONCLUSIONS Low-dose SGLTi profile was the favored adjunct-to-insulin therapy by persons with T1D.

Aim In the EMPA‐REG OUTCOME trial, empagliflozin therapy reduced cardiovascular death by 38% compared with placebo when added to standard of care. Using the trial results, we created a discrete‐event simulation model to assess lifetime health economic outcomes in people with Type 2 diabetes and established cardiovascular disease. Methods Time‐dependent survival regression analysis was performed on data from EMPA‐REG OUTCOME for 10 cardiovascular and renal events (e.g. stroke, heart failure hospitalization, macroalbuminuria, cardiovascular mortality) to capture event rates over time, and interaction between events. Model performance was assessed by comparing predicted and observed outcomes at 3 years. Costs in the United Kingdom (UK) and health utilities were obtained from published literature. Outcomes included cumulative event rates, life‐years, costs and quality‐adjusted life‐years (QALYs). Results The model predicted an 18% relative increase (by 2.1 life‐years) in survival for empagliflozin (14.0 life‐years) vs. standard of care (11.9 life‐years), attributable to direct treatment effect on cardiovascular mortality, and to indirect effect via reductions in other events. Participants treated with empagliflozin may experience improved quality of life (1.0 QALY) and higher costs (£3737/participant), yielding an incremental cost‐effectiveness ratio (ICER) of £4083/QALY. Sensitivity analyses confirmed the robustness of these results to changes in input parameters. Conclusions Based on extrapolation of EMPA‐REG OUTCOME trial data using a participant‐level simulation model, empagliflozin in addition to standard of care is projected to be highly cost‐effective using UK healthcare costs. The impact in other countries will vary due to differences in drug pricing and accrual of other costs. (Clinical Trial Registry No: NCT01131676), What's new? The sodium–glucose co‐transporter 2 inhibitor empagliflozin has been shown to mitigate cardiovascular risk and cardiovascular death in people with Type 2 diabetes with established cardiovascular disease.An economic model was developed to extrapolate the outcomes of empagliflozin plus standard of care compared with standard of care alone over peoples’ remaining lifetime in the United Kingdom.Patient‐level data from EMPA‐REG OUTCOME were analysed to generate time‐to‐event distributions for 10 cardiovascular and renal outcomes, including myocardial infarction, stroke, heart failure hospitalization, development of chronic kidney disease and cardiovascular mortality.Empagliflozin may have a positive benefit for people at costs acceptable to payers.

Recent data demonstrate improved locomotion with high-intensity locomotor training (LT) in individuals with incomplete spinal cord injury (iSCI), although concerns remain regarding reinforcement of abnormal motor strategies. The present study evaluated the effects of LT intensity on kinematic and neuromuscular coordination in individuals with iSCI. Using a randomized, crossover design, participants with iSCI received up to 20 sessions of high-intensity LT, with attempts to achieve 70–85% of age-predicted maximum heart rate (HRmax), or low-intensity LT (50–65% HRmax), following which the other intervention was performed. Specific measures included spatiotemporal variables, sagittal-plane gait kinematics, and neuromuscular synergies from electromyographic (EMG) recordings. Correlation analyses were conducted to evaluate associations between variables. Significant improvements in sagittal-plane joint excursions and intralimb hip-knee coordination were observed following high- but not low-intensity LT when comparing peak treadmill (TM) speed before and after LT. Neuromuscular complexity (i.e., number of synergies to explain >90% of EMG variance) was also increased following high- but not low-intensity LT. Comparison of speed-matched trials confirmed significant improvements in the knee excursion of the less impaired limb and intralimb hip-knee coordination, as well as improvements in neuromuscular complexity following high-intensity LT. These findings suggest greater neuromuscular complexity may be due to LT and not necessarily differences in speeds. Only selected kinematic changes (i.e., weak hip excursion) was correlated to improvements in treadmill speed. In conclusion, LT intensity can facilitate gains in kinematic variables and neuromuscular synergies in individuals with iSCI.

Reduced daily stepping in stroke survivors may contribute to decreased functional capacity and increased mortality. We investigated the relationships between clinical and biomechanical walking measures that may contribute to changes in daily stepping activity following physical interventions provided to participants with subacute stroke. Following ≤40 rehabilitation sessions, 39 participants were categorized into three groups: responders/retainers increased daily stepping >500 steps/day post-training (POST) without decreases in stepping at 2–6 month follow-up (F/U); responders/non-retainers increased stepping at POST but declined >500 steps/day at F/U; and, non-responders did not change daily stepping from baseline testing (BSL). Gait kinematics and kinetics were evaluated during graded treadmill assessments at BSL and POST. Clinical measures of gait speed, timed walking distance, balance and balance confidence were measured at BSL, POST and F/U. Between-group comparisons and regression analyses were conducted to predict stepping activity from BSL and POST measurements. Baseline and changes in clinical measures of walking demonstrated selective associations with stepping, although kinematic measures appeared to better discriminate responders. Specific measures suggest greater paretic vs non-paretic kinematic changes in responders with training, although greater non-paretic changes predicted greater gains (i.e., smaller declines) in stepping in retainers at F/U. No kinetic variables were primary predictors of changes in stepping activity at POST or F/U. The combined findings indicate specific biomechanical assessments may help differentiate changes in daily stepping activity post-stroke.

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. Significance: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy. See related commentary by Farrington and Narla, p. 1756

Purpose Next-generation physiotherapists offer the potential to improve health and prevent non-communicable illness through the promotion of physical activity. The aim of this pilot study was to determine MSc (pre-reg) Physiotherapy student’s experiences and perceptions of social prescribing and promoting specific community-based physical activity initiatives. Specifically, whether these students would ‘prescribe’ parkrun as a social form of physical activity. Methods An online Qualtrics survey was used to capture a cohort of physiotherapy students’ understanding and experience of parkrun, promoting physical activity, and social prescribing relative to their academic and practice-based physiotherapy training. Ethical approval was granted from the University of Lincoln – Lincoln Ethical Application System (LEAS) LEAS Code 2019-1061. A cohort of 18 second year MSc (pre-reg) Physiotherapy students from one UK University were invited to complete the online survey. Quantitative descriptive analysis of the nominal data was performed. Results 50% response rate (n=9) to the pilot study. All participants stated that recommending physical activity is part of a physiotherapist’s role, and all participants felt that social prescribing is part of a physiotherapist role. All respondents had heard of parkrun, with 44% (n=4) of respondents having participated in parkrun previously. Despite an overall positive feeling after taking part, only 22% (n=2) said they had recommended parkrun to their patients whilst on a practice placement as part of their pre-registration physiotherapy training. When asked whether they would recommend parkrun as a social form of physical activity all (n=9) respondents answered that they would. Conclusion Despite all students identifying parkrun as a social form of physical activity that they would recommend to patients as part of their professional role, only a minority of students had previously recommended parkrun whilst on practice placement. This discrepancy may reflect the reduced experience of social prescribing in the university and practice placement setting. Implications The results of this study suggest that UK pre-registration Physiotherapy students perceive the promotion of physical activity and social prescribing as part of their professional role. However, their experience of signposting to social forms of physical activity, like parkrun, for health and wellbeing are limited. Further research should focus on the readiness and experience of larger cohorts and explore the curriculum content of pre-registration physiotherapy training in the UK. Acknowledgements University of Lincoln, College of Social Science ‘College Teaching Innovation Fund’. References Clifford, R. (2018) Promoting physical activity for health. A survey of knowledge, confidence and role-perception in final-year UK physiotherapy students. Physiotherapy Practice and Research, 39 (1). 53-62. Lowe, A., Littlewood, C., McLean, S., and Kilner, K. (2017) Physiotherapy and physical activity: a cross-sectional survey exploring physical activity promotion, knowledge of physical activity guidelines and the physical activity habits of UK physiotherapists. BMJ Open Sport and Exercise Medicine, 3(1). Reece, L.J., Quirk, H., Wellington, C., Haake, S.J. and Wilson, F. (2018) Bright Spots, physical activity investments that work: Parkrun; a global initiative striving for healthier and happier communities. British Journal of Sports Medicine, 53(6), 326-327. World Health Organization (2018). Global action plan on physical activity 2018–2030: more active people for a healthier world. Geneva: World Health Organization. Licence: CC BY-NC-SA 3.0 IGO.

The lack of durable therapeutic interventions continues to limit cancer treatment efficacy. While breakthroughs in immunotherapy have improved patient survival for some disease subtypes, immune escape is an unfortunate and common hallmark of cancer evasion. Understanding the dynamic interplay between an evolving and heterogeneous malignant population and the adaptive immune system, consisting of millions of unique T cells, is therefore required for designing optimized treatment strategies. We begin by describing the implications of cancer escape via durable evasion events, such as major histocompatibility antigen presentation down-regulation. Durable escape is then applied to relate observed cancer age-specific incidence to physiologic impairments in T cell turnover and diversity. We then discuss a more generalized stochastic process that enables transient escape and recurrent recognition via distinct T cell subclones. This co-evolutionary model predicts repeated immune recognition and cancer evasion prior to disease manifestation. Using this model, we find that T cell turnover and cancer mutation rates explain differences in early age incidence data across nearly all cancer types. Lastly, we introduce a modeling approach for understanding the extent of optimality occurring in cancer evasion via tumor-associated antigen downregulation, emphasizing the utility of foundational modeling frameworks for optimizing cancer T cell immunotherapy. Citation Format: Jason T. George. Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2740.

To investigate whether gait and balance outcome measures in patients with severe gait and balance impairments at admission to inpatient rehabilitation provided additional and meaningful information beyond customary measures. Specifically, this study investigated whether individuals who obtained low scores at admission exhibited improvements that exceeded the established minimal detectable change during inpatient rehabilitation. We also investigated whether gait outcomes would capture changes in function not identified by customary measures.Secondary analysis of a knowledge translation project aimed at increasing the systematic collection of these outcome measures in a poststroke cohort.Subacute inpatient rehabilitation facility.Individuals2 months poststroke (N=157) with 34-43 with severe deficits including Berg Balance Scale≤5, 10-meter walk test=0 m/s, or 6-minute walk test=0 m.Not applicable.Berg Balance Scale, 10-meter walk test, 6-minute walk test.After 1 week of rehabilitation, 41%-53% of severely impaired individuals had changes above minimal detectable changes in gait and balance outcomes, which increased to 68%-84% at discharge. Across the entire cohort, FIM locomotion scores failed to identify changes in gait function for 35% of participants after 1 week of rehabilitation.Routine assessment of gait and balance outcome measures in patients with severe deficits early poststroke may be beneficial. These measures were responsive after 1 week of rehabilitation and detected changes not captured by customary measures. Routine use of a standardized gait and balance assessments may provide clinicians with important information to guide clinical decision making.

Background. High-intensity, variable stepping training can improve walking speed in individuals poststroke, although neuromuscular strategies used to achieve faster speeds are unclear. We evaluated changes in joint kinetics and neuromuscular coordination following such training; movement strategies consistent with intact individuals were considered evidence of recovery and abnormal strategies indicative of compensation. Methods. A total of 15 individuals with stroke (duration: 23 ± 30 months) received ≤40 sessions of high-intensity stepping in variable contexts (tasks and environments). Lower-extremity kinetics and electromyographic (EMG) activity were collected prior to (BSL) and following (POST) training at peak treadmill speeds and speeds matched to peak BSL (MATCH). Primary measures included positive (concentric) joint and total limb powers, measures of interlimb (paretic/nonparetic powers) and intralimb compensation (hip/ankle or knee/ankle powers), and muscle synergies calculated using nonnegative matrix factorization. Results. Gains in most positive paretic and nonparetic joint powers were observed at higher speeds at POST, with decreased interlimb compensation and limited changes in intralimb compensation. There were very few differences in kinetic measures between BSL to MATCH conditions. However, the number of neuromuscular synergies increased significantly following training at both POST and MATCH conditions, indicating gains from training rather than altered speeds. Despite these results, speed improvements were associated primarily with changes in nonparetic versus paretic powers. Conclusion. Gains in locomotor function were accomplished by movement strategies consistent with both recovery and compensation. These and other data indicate that both strategies may be necessary to maximize walking function in patients poststroke.

It is now well-established that the host’s adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. Tumor acquisition of immune evasive phenotypes, such as class-I MHC down-regulation, remains a major limitation of successful T-cell immunotherapy. Here, we consider a population dynamical model coupling tumor and adaptive immune compartments in order to study the dynamics and survival of an evolving threat when faced with adaptive immune pressure. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. We parameterize adaptive immune functioning by T-cell turnover and repertoire diversity and predict that decreases in the latter quantity which occur in advanced age may substantially affect the ability to recognize, and therefore control, an immune evasive threat like cancer. This framework recapitulates general features of age-dependent AML incidence, thereby providing a probable association between cancer frequency and adaptive immune functioning. Lastly, we quantify therapeutic efficacy of adjuvant immunotherapeutic strategies, and predict their benefits and limitations with regard to handling immune evasion. Our model generates survival behavior consistent with known growth-dependent characteristics, and serves as a first attempt at modeling stochastic cancer evolution alongside an adaptive immune compartment.

Aims Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial. Methods and results The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes). Conclusion Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated.

Aim To investigate whether the cardiorenal benefits of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians. Methods In this exploratory analysis of the EMPA‐REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all‐cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category. Results Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all‐cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher. Conclusion Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time‐to‐first‐event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49–0.64]; WR, 1.76 [95% CI, 1.53–2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%–20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time‐to‐first‐event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01131676.

Highlights • No unique genome signature or molecular therapy exists for inflammatory breast cancer (IBC), a highly aggressive breast cancer with a 5-year survival rate of less than 30%. • We show that various gene lists proposed as molecular footprints of IBC have no overlap and thus very limited predictive accuracy in identifying IBC samples. • We observed that single-sample gene set enrichment analysis (ssGSEA) of IBC samples along the epithelial-hybrid-mesenchymal spectrum can help IBC identification. • IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. • Higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker., Inflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.

Objective This investigation estimated the incremental cost-effectiveness of high-intensity training (HIT) compared with conventional physical therapy in individuals with subacute stroke, based on the additional personnel required to deliver the therapy. Design Secondary analysis from a pilot study and subsequent randomized controlled trial. Setting Outpatient laboratory setting. Participants Data were collected from individuals with locomotor impairments 1-6 months poststroke (N=44) who participated in HIT (n=27) or conventional physical therapy (n=17). Interventions Individuals performing HIT practiced walking tasks in variable contexts (stairs, overground, treadmill) while targeting up to 80% maximum heart rate reserve. Individuals performing conventional therapy practiced impairment-based and functional tasks at lower intensities ( Main Outcome Measures Costs were assessed based on personnel use with availability of similar equipment. Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves were calculated for quality-adjusted life years (QALYs) derived from the Medical Outcomes Short Form-36 questionnaire and gains in self-selected speeds (SSSs). Results Personnel costs were higher after HIT (mean, $1420±234) vs conventional therapy (mean, $1111±219), although between-group differences in QALYs (0.05 QALYs; 95% confidence interval [CI], 0.0-0.10 QALYs) and SSS (0.20 m/s; 95% CI, 0.05-0.35 m/s) favored HIT. ICERs were $6180 (95% CI, −$96,364 to $123,211) per QALY and $155 (95% CI, 38-242) for a 0.1 m/s gain in SSS. Conclusions Additional personnel to support HIT are relatively inexpensive but can add substantial effectiveness to subacute rehabilitation. Future research should evaluate patient factors that increase the likelihood of improvement to maximize the cost-effectiveness of treatment post stroke.

Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p0.30).Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).