Microbiology and Epidemiology of Orbital Cellulitis in Pediatric and Young Adult Patients.

INTRODUCTION: Using data from the large and geographically diverse Military Health System (MHS) beneficiary population, we aimed to characterize and update the epidemiology and microbiology of pediatric orbital cellulitis given previous data are limited to small, single-center studies. MATERIALS AND METHODS: Following institutional review board approval, we performed a retrospective analysis using the Military Health System admissions, microbiology, and pharmacy data between June 2009 and September 2019. Patients less than 22 years of age with radiological confirmation of orbital cellulitis were included. Demographic data, presence of sinusitis, advanced imaging reports, blood and wound culture results with antibiotic susceptibilities, and antibiotic prescriptions were collected. Descriptive statistics were used to summarize demographic characteristics. Imaging findings were grouped by Chandler's stage (CS), an imaging-based measure of the progressive severity of orbital involvement. A Cochran-Armitage trend test was used to evaluate the relationship between CS and likelihood of positive confirmatory culture. RESULTS: There was a male predominance (66.9%) and 55.5% of subjects had comorbid sinusitis. Of the 130 subjects included, 33.8% had one or more positive cultures, 30.8% had a positive wound culture, and 4.6% had a positive blood culture. The most identified organism was coagulase-negative staphylococci (23.3%), followed by Staphylococcus aureus (18.9%), Streptococcus intermedius (17.8%), and strict anaerobes as a group (13.3%). Gram-negative organisms were rare. Twenty-five percent of S. aureus were methicillin-resistant. Clindamycin resistance was identified in 9% of all S. aureus, 50% of coagulase-negative staphylococci, and 25% of S. intermedius. Clindamycin plus ceftriaxone was the most prescribed empiric antibiotic regimen (36.2%). Likelihood of a positive culture significantly increased with advancing CS. CONCLUSIONS: Orbital cellulitis occurs most frequently in males with sinusitis. Likelihood of positive wound culture is increased with a more advanced CS. Staphylococcus and Streptococcus spp. and anaerobes are the most identified pathogens in orbital cellulitis, while gram-negative organisms are rare. Empiric antibiotic selection should include an anti-methicillin-resistant S. aureus agent combined with a broad-spectrum beta-lactam and anaerobic coverage.

Training loads and microcycle periodisation in Italian Serie A youth soccer players.

Microcycles are fundamental structures for training prescription and load management, helping to optimise training effects and performance. This study quantified external and internal loads of Italian Serie A youth soccer players across competitive weeks and their periodisation within microcycles. Data were collected from 90 players belonging to four age groups (under-19, -17, -16, -15) across a season. Methods of monitoring external [duration and global navigation satellite systems (GNSS)] and internal load [heart rate (HR) and rating of perceived exertion (RPE)] were employed. Linear mixed models determined differences in training loads across age groups, training days and player positions. Under-19 and under-17 players trained five times per week, while younger players trained four times. Late-stage academy players (under-19 and -17) demonstrated higher weekly accumulated external and sRPE training load compared to their younger counterparts (p < 0.05 between groups). Weekly accumulated HR internal loads were higher in under-15 players (p < 0.05 between groups). Marked fluctuations of daily load were observed across microcycles in under-19 and under-17 groups (p < 0.05 between days). These findings highlight progressive increases in training load throughout the development pathway, with late-stage academy players training with higher frequency, volume and marked periodisation compared to younger players.

TREO Aortic Endograft Demonstrates Superior Aneurysmal Sac Regression Over Mid-Term Follow-up.

INTRODUCTION: Aneurysmal sac regression is a predictor of long-term outcomes after endovascular aneurysm repair (EVAR). This study aimed to compare a large cohort of TREO and non-TREO endografts over a mid-term follow-up and compare abdominal aortic aneurysm sac regression. The hypothesis was that TREO endografts have an increased sac regression by 24 mo. METHODS: This is a retrospective analysis of all EVARs completed at a single institution between 2015 and 2024. Clinical and imaging data were collected from an institutional database and patients' records. The analysis included all TREO and age, sex, anticoagulation use and current smoking-matched non-TREO endografts that satisfied anatomic indications for use of the TREO graft. The primary outcomes were sac regression at 12 and 24 mo, and secondary outcomes were rates of mortality, endoleak, and reintervention. RESULTS: Twenty-one TREO grafts were matched to 68 non-TREO grafts. The groups were similar in demographics, comorbidities, and preoperative anatomy. Preoperative abdominal aortic aneurysm sac size was larger in the TREO cohort. The mean reduction in sac size in mm was greater in the TREO cohort compared to the non-TREO cohort (-12.6 ± 8.95 versus -7.83 ± 7.74 mm, P = 0.039) over the study period. Cox regression analysis identified the TREO stent graft to be associated with 1-y sac regression (hazard ratio = 2.42, P = 0.019). The incidence of all-cause endoleaks, reintervention, and mortality were similar between cohorts. CONCLUSIONS: These findings suggest that the TREO endograft offers better mid-term outcomes with respect to sac regression with no differences in the incidence of endoleak, mortality, or reintervention.

Role of Kindlin 2 in prostate cancer.

Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach to knockout expression of Kindlin-2 in both androgen-independent and dependent prostate cancer cell lines, and the effects of Kindlin-2 suppression on oncogenic properties of these prostate cancer cell lines was examined. Adhesion to extracellular matrix proteins was markedly blunted, consistent with the control of integrin function by Kindlin-2. Migration across matrices was also affected. Anchorage independent growth was markedly suppressed. These observations indicate that Kindlin-2 regulates hallmark features of prostate cancer cells. In androgen expressing cells, testosterone-stimulated adhesion was Kindlin-2-dependent. Furthermore, tumor growth of a prostate cancer cell line lacking Kindlin-2 and implanted into the prostate gland of immunocompromised mice was markedly blunted and was associated with suppression of angiogenesis in the developing tumor. These results establish a key role of Kindlin-2 in prostate cancer progression and suggest that Kindlin-2 represents an interesting therapeutic target for treatment of prostate cancer.

SSN2: The next generation of spatial stream network modeling in R.

The SSN2 R package provides tools for spatial statistical modeling, parameter estimation, and prediction on stream (river) networks. SSN2 is the successor to the SSN R package (Ver Hoef, Peterson, Clifford, & Shah, 2014), which was archived alongside broader changes in the R-spatial ecosystem (Nowosad, 2023) that included 1) the retirement of rgdal (Bivand, Keitt, & Rowlingson, 2021), rgeos (Bivand & Rundel, 2020), and maptools (Bivand & Lewin-Koh, 2021) and 2) the lack of active development of sp (Bivand, Pebesma, & Gómez-Rubio, 2013). SSN2 maintains compatibility with the input data file structures used by the SSN R package but leverages modern R-spatial tools like sf (Pebesma, 2018). SSN2 also provides many useful features that were not available in the SSN R package, including new modeling and helper functions, enhanced fitting algorithms, and simplified syntax consistent with other R generic functions.

Alpha-2-adrenergic agonists reduce resting energy expenditure in humans during external cooling.

Intravenous alpha-2-adrenergic receptor agonists reduce energy expenditure and lower the temperature when shivering begins in humans, allowing a decrease in core body temperature. Because there are few data about similar effects from oral drugs, we tested whether single oral doses of the sedative dexmedetomidine (1 µg/kg sublingual or 4 µg/kg swallowed) or the muscle relaxant tizanidine (8 mg or 16 mg), combined with surface cooling, reduce energy expenditure and core body temperature in humans. A total of 26 healthy participants completed 41 one-day laboratory studies measuring core body temperature using an ingested telemetry capsule and measuring energy expenditure using indirect calorimetry for up to 6 hours after drug ingestion. Dexmedetomidine induced a median 13% - 19% peak reduction and tizanidine induced a median 15% - 22% peak reduction in energy expenditure relative to baseline. Core body temperature decreased a median of 0.5°C - 0.6°C and 0.5°C - 0.7°C respectively. Decreases in temperature occurred after peak reductions in energy expenditure. Energy expenditure increased with a decrease in core temperature in control participants but did not occur after 4 µg/kg dexmedetomidine or 16 mg tizanidine. Plasma levels of dexmedetomidine but not tizanidine were related to mean temperature change. Decreases in heart rate, blood pressure, respiratory rate, cardiac stroke volume index, and cardiac index were associated with the change in metabolic rate after higher drug doses. We conclude that both oral dexmedetomidine and oral tizanidine reduce energy expenditure and allow decrease in core temperature in humans.

Graphene Oxide Surface Modification of Reverse Osmosis (RO) Membrane via Langmuir-Blodgett Technique: Balancing Performance and Antifouling Properties.

The reverse osmosis water treatment process is prone to fouling issues, prompting the exploration of various membrane modification techniques to address this challenge. The primary objective of this study was to develop a precise method for modifying the surface of reverse osmosis membranes to enhance their antifouling properties. The Langmuir-Blodgett technique was employed to transfer aminated graphene oxide films assembled at the air-liquid interface, under specific surface pressure conditions, to the polyamide surface with pre-activated carboxylic groups. The microstructure and distribution of graphene oxide along the modified membrane were characterized using SEM, AFM, and Raman mapping techniques. Modification carried out at the optimal surface pressure value improved the membrane hydrophilicity and reduced the surface roughness, thereby enhancing the antifouling properties against colloidal fouling. The flux recovery ratio after modification increased from 65% to 87%, maintaining high permeability. The modified membranes exhibited superior performance compared to the unmodified membranes during long-term fouling tests. This membrane modification technique can be easily scaled using the roll-to-roll approach and requires minimal consumption of the modifier used.

Development of Novel Bacterial Topoisomerase Inhibitors Assisted by Computational Screening.

Multidrug-resistant bacterial infections pose an ever-evolving threat to public health. Since the outset of the antibacterial age, bacteria have developed a multitude of diverse resistance mechanisms that suppress the effectiveness of current therapies. New drug entities, such as Novel Bacterial Topoisomerase Inhibitors (NBTIs), can circumvent this major issue. A computational docking model was employed to predict the binding to DNA gyrase of atypical NBTIs with novel pharmacophores. Synthesis of NBTIs based on computational docking and subsequent antibacterial evaluation against both Gram-positive and Gram-negative bacteria yielded congeners with outstanding anti-staphylococcal activity and varying activity against select Gram-negative pathogens.

Synthesis of Stereodefined Enones from the Cross-Electrophile Coupling of Activated Acrylic Acids with Alkyl Bromides.

We report a one-pot synthesis of (E)-trisubstituted enones from acrylic acids through the in situ generation of a 2-pyridyl ester and subsequent cross-electrophile coupling with a nickel catalyst under reducing conditions. The scope of trisubstituted enones is broad and compatible with functionality that can be challenging in established olefination techniques. We highlight conditions necessary to suppress undesired side reactions from the α,ß-unsaturated carbonyl and improve cross-electrophile coupling approaches to prepare enones.

The activity-regulated cytoskeleton-associated protein (Arc) functions in a cell type- and sex-specific manner in the adult nucleus accumbens to regulate non-contingent cocaine behaviors.

Repeated cocaine use produces adaptations in brain function that contribute to long-lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity-regulated cytoskeleton-associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)-a brain region linked to CUD-related behavior. We show here that repeated, non-contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience-dependent sensitization of conditioned place preference (CPP). In contrast to the global Arc KO mice, viral-mediated reduction of Arc in the adult male, but not female, NAc (shArcNAc) reduced both CPP and cocaine-induced locomotor activity, but without altering basal miniature or evoked glutamatergic synaptic transmission. Interestingly, cell type-specific knockdown of Arc in D1 dopamine receptor-expressing NAc neurons reduced cocaine-induced locomotor sensitization, but not cocaine CPP; whereas, Arc knockdown in D2 dopamine receptor-expressing NAc neurons reduced cocaine CPP, but not cocaine-induced locomotion. Taken together, our findings reveal that global, developmental loss of Arc produces hypersensitized cocaine responses; however, these effects cannot be explained by Arc's function in the adult mouse NAc since Arc is required in a cell type- and sex-specific manner to support cocaine-context associations and locomotor responses.

A biofilm-tropic Pseudomonas aeruginosa bacteriophage uses the exopolysaccharide Psl as receptor.

Bacteria in nature can exist in multicellular communities called biofilms. Biofilms also form in the course of many infections. Pseudomonas aeruginosa infections frequently involve biofilms, which contribute materially to the difficulty to treat these infections with antibiotic therapy. Many biofilm-related characteristics are controlled by the second messenger, cyclic-di-GMP, which is upregulated on surface contact. Among these factors is the exopolysaccharide Psl, which is a critically important component of the biofilm matrix. Here we describe the discovery of a P. aeruginosa bacteriophage, which we have called Clew-1, that directly binds to and uses Psl as a receptor. While this phage does not efficiently infect planktonically growing bacteria, it can disrupt P. aeruginosa biofilms and replicate in biofilm bacteria. We further demonstrate that the Clew-1 can reduce the bacterial burden in a mouse model of P. aeruginosa keratitis, which is characterized by the formation of a biofilm on the cornea. Due to its reliance on Psl for infection, Clew-1 does not actually form plaques on wild-type bacteria under standard in vitro conditions. This argues that our standard isolation procedures likely exclude bacteriophage that are adapted to using biofilm markers for infection. Importantly, the manner in which we isolated Clew-1 can be easily extended to other strains of P. aeruginosa and indeed other bacterial species, which will fuel the discovery of other biofilm-tropic bacteriophage and expand their therapeutic use.

Mitochondrial dynamics regulate cell morphology in the developing cochlea.

In multicellular tissues, the size and shape of cells are intricately linked with their physiological functions. In the vertebrate auditory organ, the neurosensory epithelium develops as a mosaic of sensory hair cells (HCs), and their glial-like supporting cells, which have distinct morphologies and functional properties at different frequency positions along its tonotopic long axis. In the chick cochlea, the basilar papilla (BP), proximal (high-frequency) HCs, are larger than their distal (low-frequency) counterparts, a morphological feature essential for sound perception. Mitochondrial dynamics, which constitute the equilibrium between fusion and fission, regulate differentiation and functional refinement across a variety of cell types. We investigate this as a potential mechanism for regulating the shape of developing HCs. Using live imaging in intact BP explants, we identify distinct remodelling of mitochondrial networks in proximal compared with distal HCs. Manipulating mitochondrial dynamics in developing HCs alters their normal morphology along the proximal-distal (tonotopic) axis. Inhibition of the mitochondrial fusion machinery decreased proximal HC surface area, whereas promotion of fusion increased the distal HC surface area. We identify mitochondrial dynamics as a key regulator of HC morphology in developing inner ear epithelia.

Adapting and Evaluating the Feasibility and Acceptability of a Behavioral Intervention to Promote Sleep Health in Cardiac Rehabilitation.

OBJECTIVES: Study objectives were to: 1) iteratively adapt the Transdiagnostic Sleep and Circadian Intervention (TranS-C) for patients in cardiac rehabilitation (CR; Phase 1) and 2) conduct a preliminary single group pre-post intervention test to a) evaluate procedural feasibility and intervention acceptability and b) to explore preliminary pre-post changes in self-reported sleep, disability, and health-related quality of life (HRQoL; Phase 2). METHOD: In Phase 1, 12 individuals in CR and six content experts completed interviews to inform TranS-C adaptations. Interviews were analyzed using rapid qualitative analysis. In Phase 2, eight individuals in CR completed a baseline assessment, the adapted TranS-C intervention, and a post-intervention assessment. Intervention acceptability was assessed via questionnaire and interview. Sleep, disability, and HRQoL outcomes were assessed using questionnaires. Descriptive statistics were calculated for quantitative measures; interviews were analyzed using rapid qualitative analysis. RESULTS: Phase 1 participants were receptive to the premise and structure of the adapted intervention. In Phase 2, participants endorsed positive attitudes toward the intervention. Seven of eight participants demonstrated improvements in sleep outcomes. Disability and HRQoL results did not consistently improve. CONCLUSION: The adapted TranS-C intervention was acceptable to CR patients and could yield improvements in subjective sleep outcomes. Larger-scale testing in CR is warranted.

Two sub-annual timescales and coupling modes for terrestrial water and carbon cycles.

To bridge the knowledge gap between (a) our (instantaneous-to-seasonal-scale) process understanding of plants and water and (b) our projections of long-term coupled feedbacks between the terrestrial water and carbon cycles, we must uncover what the dominant dynamics are linking fluxes of water and carbon. This study uses the simplest empirical dynamical systems models-two-dimensional linear models-and observation-based data from satellites, eddy covariance towers, weather stations, and machine-learning-derived products to determine the dominant sub-annual timescales coupling carbon uptake and (normalized) evaporation fluxes. We find two dominant modes across the Contiguous United States: (1) a negative correlation timescale on the order of a few days during which landscapes dry after precipitation and plants increase their carbon uptake through photosynthetic upregulation. (2) A slow, seasonal-scale positive covariation through which landscape drying leads to decreased growth and carbon uptake. The slow (positively correlated) process dominates the joint distribution of local water and carbon variables, leading to similar behaviors across space, biomes, and climate regions. We propose that vegetation cover/leaf area variables link this behavior across space, leading to strong emergent spatial patterns of water/carbon coupling in the mean. The spatial pattern of local temporal dynamics-positively sloped tangent lines to a convex long-term mean-state curve-is surprisingly strong, and can serve as a benchmark for coupled Earth System Models. We show that many such models do not represent this emergent mean-state pattern, and hypothesize that this may be due to lack of water-carbon feedbacks at daily scales.

Temporary diverting loop ileostomy in Crohn's disease surgery; indications and outcome.

INTRODUCTION: Crohn's disease can present with complex surgical pathologies, posing a significant risk of morbidity and mortality for patients. The implementation of a loop ileostomy for selected patients may help minimize associated risks. METHODS: In this retrospective cohort study, we investigated the utilization of temporary fecal diversion through the creation of a loop ileostomy in Crohn's surgery. Closure of all ostomies involved a hand-sewn single-layer technique. We then conducted bivariate analysis on 30-day outcomes for closures, focusing on favorable recovery defined as the restoration of bowel continuity without the occurrence of two challenges in recovery: newly developed organ dysfunction or the necessity for reoperation. RESULTS: In total, 168 patients were included. The median age of the patients was 38 years (IQR 27-51). The most common indication for a loop ostomy was peritonitis (49%). After ileostomy closure, 163 patients (97%) achieved favorable recovery, while five encountered challenges; four (2.4%) underwent abdominal surgery, and one (0.6%) developed acute renal failure requiring dialysis. Two patients (1.2%) had a re-creation of ileostomy. Patients encountering challenges were older (56 [IQR 41-61] vs. 37 [IQR 27-50]; p 0.039) and more often required secondary intention wound healing (40% vs. 6.7%; p 0.049) and postoperative parenteral nutrition following their index surgery (83% vs. 26%; p 0.006). CONCLUSION: Selectively staging the Crohn's disease operations with a loop ileostomy is a reliable practice with low morbidity and high restoration rates of bowel continuity. Our hand-sewn single-layer technique proves effective in achieving successful surgical recovery.

OMERACT systemic lupus erythematosus domain survey.

BACKGROUND: Since the development of the OMERACT Systemic Lupus Erythematosus (SLE) Core Outcome Set (COS) in 1998, many new SLE domains have been identified and measures developed, creating a need to update the SLE COS. To revisit the 1998 SLE COS and research agenda domains, and generate new candidate domains, we conducted this study of patients with SLE and collaborators. OBJECTIVE: (1) To evaluate existing candidate SLE domains for inclusion in the SLE COS. (2) To generate additional candidate SLE domains for COS consideration. (3) To engage SLE collaborators, including patients, in developing the updated SLE COS. METHODS: The OMERACT SLE Working Group's steering committee developed a survey to assess the importance of candidate SLE domains and generate additional domains for consideration towards the SLE COS. Patients with SLE followed at the University of Toronto Lupus Clinic (patient group) and members of the OMERACT SLE Working Group (collaborator group) were invited to complete the survey between August 2022 and February 2023. RESULTS: A total of 175 patients were invited and 100 completed the survey. Of 178 collaborators invited, 145 completed the survey. Patients tended to prioritize life-impact domains while collaborators prioritized clinical domains. Both patients and collaborators recommended additional domains to those included in the 1998 SLE COS and research agenda. CONCLUSION: The domain inclusion and importance results demonstrate that patients and collaborators prioritize different domains, so capturing the perspectives of both groups is essential to ensure a holistic assessment of SLE. The results of the study identify domains that already have a high level of agreement for potential inclusion in the SLE COS, domains that require further explanation, and novel domains that warrant consideration.

From fibrositis to fibromyalgia to nociplastic pain: how rheumatology helped get us here and where do we go from here?

Rheumatologists and rheumatology have had a prominent role in the conceptualisation of nociplastic pain since the prototypical nociplastic pain condition is fibromyalgia. Fibromyalgia had been previously known as fibrositis, until it became clear that this condition could be differentiatied from autoimmune disorders because of a lack of systemic inflammation and tissue damage. Nociplastic pain is now thought to be a third descriptor/mechanism of pain, in addition to nociceptive pain (pain due to peripheral damage or inflammation) and neuropathic pain. Nociplastic pain can occur in isolation, or as a co-morbidity with other mechanisms of pain, as commonly occurs in individuals with autoimmune disorders. We now know that the cardinal symptoms of nociplastic pain are widespread pain (or pain in areas not without evidence of inflammation/damage), accompanied by fatigue, sleep and memory issues. There is objective evidence of amplification/augmentation of pain, as well as of non-painful stimuli such as the brightness of lights and unpleasantness of sound or odors. Nociplastic pain states can be triggered by a variety of stressors such as trauma, infections and chronic stressors. Together these features suggest that the central nervous system (CNS) is playing a major role in causing and maintaining nociplastic pain, but these CNS factors may in some be driven by ongoing peripheral nociceptive input. The most effective drug therapies for nociplastic pain are non-opioid centrally acting analgesics such as tricyclics, serotonin-norepinephrine reuptake inhibitors and gabapentinoids. However the mainstay of therapy of nociplastic pain is the use of a variety of non-pharmacological integrative therapies, especially those which improve activity/exercise, sleep and address psychological co-morbidities.

Cannabis policy bundles and traffic fatalities in the American States over time.

BACKGROUND AND AIM: Since 1996, 38 US states have legalized access to cannabis (medical and/or adult-use recreational). We aimed to estimate the effect of three dimensions of state cannabis policy design - pharmaceutical, permissive and fiscal - on levels of overall, alcohol-impaired, occupant, light truck and pedestrian fatality rates. DESIGN AND SETTING: Observational study of US states' overall, alcohol-impaired, occupant, light truck and pedestrian fatalities between 1994 and 2020. CASES: The unit of analysis was at the state level, consisting of 50 states and 27 years of time series data, resulting in a total of 1350 state-year observations. MEASUREMENTS: Fatality rates associated with alcohol-impaired, pedestrian, total occupant, passenger car and light truck fatality rates were obtained from the Fatality Analysis Reporting System of the National Highway Traffic Safety Administration and normalized per 10 billion vehicle miles traveled. State cannabis policies are measured in three bundles (scales): pharmaceutical, permissive and fiscal. FINDINGS: The pharmaceutical bundle was associated with increases in all fatality rates [ß = 0.145; 95% confidence interval (CI) = 0.116-0.173; P < 0.000]. The permissive bundle was associated with lower overall fatality rates (ß = -0.319; 95% CI = -0.361 to -0.277; P < 0.000). The fiscal bundle was generally associated with higher fatality rates (ß = 0.062; 95% CI = 0.043-0.081; P < 0.000), occupant (ß = 0.070; 95% CI = 0.042-0.098; P < 0.000), light trucks (ß = 0.049; 95% CI = 0.026-0.072; P < 0.000). CONCLUSIONS: US state cannabis regulations influence traffic safety. Greater permissiveness in US state cannabis regulations does not appear to correlate with traffic fatality rate increases, but greater medicalization and fiscal operation does.

Sodium-glucose cotransporter 2 inhibitors reduce the risk of incident type 2 diabetes in people with heart failure without diabetes: An analysis of real-world, cohort data.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is), used as a glucose-lowering therapy in people with type 2 diabetes (T2D), have significant cardiorenal benefits, reducing hospitalization for heart failure (HF) and cardiovascular mortality in patients with and without T2D. Recent clinical trial evidence suggests their potential utility in preventing incident T2D among the high-risk HF populations. Therefore, we aimed to assess whether this finding was reproducible in a real-world setting. METHODS: We performed a retrospective cohort analysis of 484 643 patients with HF, without baseline diabetes, prescribed either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with/without SGLT2is (treatment, n = 42 018; reference, n = 442 625) across 95 global health care organizations, using a large real-world ecosystem. Propensity score matching balanced arms 1:1 for confounders (n = 39 168 each arm). Subgroup analysis further evaluated the impact on patients with prediabetes and the efficacy of dapagliflozin/empagliflozin, specifically, on incident T2D and secondary outcomes, including all-cause mortality, acute pulmonary oedema and hospitalization. RESULTS: Treatment with SGLT2is significantly reduced incident T2D {hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.63, 0.75]} in patients with HF. The analysis of patients with prediabetes found that SGLT2is further reduced incident T2D [HR 0.62 (95% CI 0.45, 0.80)]. The magnitude of reduction in incident T2D was higher in patients prescribed dapagliflozin [HR 0.47 (95% CI 0.39, 0.56)] versus empagliflozin [HR 0.81 (95% CI 0.70, 0.93)]. CONCLUSION: Treatment with SGLT2is in patients with HF was associated with a reduced risk of incident T2D, most strikingly in people with prediabetes.