Smartpaddle® as a New Monitoring Feature: A Comparison Between Inertial Measurement Unit- and Strain Gauge-Based Devices on Tethered Swimming Forces.

Smartpaddle® is a novel wearable device based on inertial measurement units (IMU) for in-field arm-stroke kinetics and kinematics analysis in swimming. However, the lack of data regarding its agreement and reliability, coupled with restricted access to raw data, emphasizes the need to evaluate it against a well-established strain gauge (SG) reference method for assessing swimming forces. Thus, this study aimed to investigate the agreement and reliability between the Smartpaddle® and strain gauge in a 30-s all-out arms-only tethered swimming test. Twelve trained young adult swimmers performed a test-retest 30-s all-out arms-only tethered swimming trial. Peak and mean forces were obtained from IMU (PFIMU and MFIMU) and SG (PFSG and MFSG) simultaneously. Statistical differences and correlations were found in both peak (PFSG = 158.46 ± 48.85 N, PFIMU = 75.47 ± 12.05 N, p < 0.001, r = 0.88) and mean (MFSG = 69.62 ± 16.36 N, MFIMU = 30.06 ± 5.42 N, p < 0.001, r = 0.84) forces between devices, presenting elevated systematic errors for both variables. No differences were found in IMU data between test-retest conditions in both peak (PFIMU = 75.47 ± 12.05 N, PFIMU = 75.45 ± 11.54 N, p = 0.99, ICC = 0.96) and mean (MFIMU = 30.06 ± 5.42 N, MFIMU = 30.21 ± 5.83 N, p = 0.80, ICC = 0.95) forces, with negligible systematic errors. In conclusion, although the Smartpaddle® device is not directly comparable to the strain gauge reference method, it has demonstrated high reliability levels in test-retest trials.

ß-Alanine Plus Sodium Bicarbonate Co-Supplementation Does Not Decrease Neuromuscular Fatigue in Swimming.

This study aimed to investigate the effects of chronic ß-alanine (ßA) plus acute sodium bicarbonate (SB) co-supplementation on neuromuscular fatigue during high-intensity intermittent efforts in swimming. Eleven regional and national competitive-level young swimmers performed a neuromuscular fatigue assessment before and immediately after two 20 × 25-m front crawl maximal efforts every 90 s, performed at pre- and post-4-week co-supplementation. Neuromuscular fatigue was evaluated by percutaneous electrical stimuli through the twitch interpolation technique on the triceps brachii and quadriceps femoris. Performance was defined by the mean time of the 20 efforts and blood samples to lactate concentrations were collected every four efforts. Participants supplemented 3.2-6.4 g·day-1 of chronic ßA or placebo (PL) during four weeks, and acute 0.3 g·kg-1 of SB or PL 60 min before the second assessment (allowing ßA+SB and PL+PL groups). No statistical changes were found in neuromuscular fatigue of triceps brachii. In the quadriceps femoris, a main effect of time was found in potentiated twitch delta values in pooled groups, showing a statistical increase of 19.01% after four weeks (Δ = 13.05 [0.35-25.75] N; p = 0.044), without time × group interactions. No statistical difference was found in the swimming performance. Blood lactate increased by 25.06% only in the ßA+SB group (Δ = 6.40 [4.62-8.18] mM; p Bonf < 0.001) after the supplementation period. In conclusion, 4-week ßA and SB co-supplementation were not able to reduce neuromuscular fatigue levels and improve performance in highintensity intermittent efforts, but statistically increased blood lactate levels.

Prostate Magnetic Resonance Imaging Using the Prostate Imaging for Recurrence Reporting (PI-RR) Scoring System to Detect Recurrent Prostate Cancer: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: Prostate Imaging for Recurrence Reporting (PI-RR) was introduced in 2021 to standardize the interpretation and reporting of multiparametric magnetic resonance imaging (MRI) for prostate cancer following whole-gland treatment. The system scores image on a scale from 1 to 5 and has shown promising results in single-center studies. The aim of our systematic review and meta-analysis was to assess the diagnostic performance of the PI-RR system in predicting the likelihood of local recurrence after whole-gland treatment. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for diagnostic test accuracy were followed. Relevant databases were searched up to December 2023. Primary studies met the eligibility criteria if they reported MRI diagnostic performance in prostate cancer recurrence using PI-RR. Diagnostic performance for MRI was assessed using two different cutoff points (≥3 or ≥4 for positivity according to the PI-RR system). A meta-analysis with a random-effects model was used to estimate pooled sensitivity and specificity values. KEY FINDINGS AND LIMITATIONS: Sixteen articles were identified for full-text reading, of which six were considered eligible, involving a total of 467 patients. Using a cutoff of PI-RR ≥3 (4 studies) for recurrent disease, the sensitivity was 77.8% (95% confidence interval [CI] 69.9-84.1%) and the specificity was 80.2% (95% CI 58.2-92.2%). Using a cutoff of PI-RR ≥4 (4 studies), the sensitivity was 61.9% (95% CI 35.6-82.7%) and the specificity was 86.6% (95% CI 75.1-93.3%). Overall, the inter-rater agreement varied from fair to excellent. CONCLUSIONS AND CLINICAL IMPLICATIONS: PI-RR is accurate in detecting local recurrence after whole-gland treatment for prostate cancer and shows fair-to-good to excellent inter-reader agreement. Overall, a PI-RR cutoff of ≥3 showed high sensitivity and specificity. PATIENT SUMMARY: We reviewed studies that reported on how good MRI scans using a scoring system called PI-RR were in detecting recurrence of prostate cancer. We found that this system shows good performance, with fair to excellent agreement between different radiologists.

Secrecy Analysis of a Mu-MIMO LIS-Aided Communication Systems under Nakagami-m Fading Channels.

This study evaluates the performance of large intelligent surface (LIS) technology in the context of a multi-user MIMO mobile communication system (Mu-MIMO) proposed for the sixth generation (6G). LIS employs digitally controlled reflectors to enhance Signal-to-Interference plus Noise Ratio (SINR) and establish line of sight (LoS) connectivity in non-LoS environments, improving transmission security. Analytical expressions are derived to assess LIS performance metrics, including distribution parameters, bit error probability, and secrecy outage probability, considering the presence of eavesdroppers and environmental fading. The study highlights the potential of LIS technology to enhance the confidentiality and reliability of digital communication systems in next-generation networks.

Biomarkers to improve functional outcome prediction after ischemic stroke: Results from the SICFAIL, STRAWINSKI, and PREDICT studies.

BACKGROUND AND AIMS: Acute ischemic stroke (AIS) outcome prognostication remains challenging despite available prognostic models. We investigated whether a biomarker panel improves the predictive performance of established prognostic scores. METHODS: We investigated the improvement in discrimination, calibration, and overall performance by adding five biomarkers (procalcitonin, copeptin, cortisol, mid-regional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) to the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and age/NIHSS scores using data from two prospective cohort studies (SICFAIL, PREDICT) and one clinical trial (STRAWINSKI). Poor outcome was defined as mRS > 2 at 12 (SICFAIL, derivation dataset) or 3 months (PREDICT/STRAWINSKI, pooled external validation dataset). RESULTS: Among 412 SICFAIL participants (median age 70 years, quartiles 59-78; 63% male; median NIHSS score 3, quartiles 1-5), 29% had a poor outcome. Area under the curve of the ASTRAL and age/NIHSS were 0.76 (95% CI 0.71-0.81) and 0.77 (95% CI 0.73-0.82), respectively. Copeptin (0.79, 95% CI 0.74-0.84), NT-proBNP (0.80, 95% CI 0.76-0.84), and MR-proANP (0.79, 95% CI 0.75-0.84) significantly improved ASTRAL score's discrimination, calibration, and overall performance. Copeptin improved age/NIHSS model's discrimination, copeptin, MR-proANP, and NT-proBNP improved its calibration and overall performance. In the validation dataset (450 patients, median age 73 years, quartiles 66-81; 54% men; median NIHSS score 8, quartiles 3-14), copeptin was independently associated with various definitions of poor outcome and also mortality. Copeptin did not increase model's discrimination but it did improve calibration and overall model performance. DISCUSSION: Copeptin, NT-proBNP, and MR-proANP improved modest but consistently the predictive performance of established prognostic scores in patients with mild AIS. Copeptin was most consistently associated with poor outcome in patients with moderate to severe AIS, although its added prognostic value was less obvious.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Family dementia caregivers with suicidal ideation improve with mentalizing imagery therapy: Results from a pilot study.

Background: Family caregivers of persons living with dementia often experience increased depression and suicidal ideation (SI). However, the feasibility and impact of therapies on caregiver SI has remained largely unexplored. Mentalizing imagery therapy (MIT) helps reduce psychological symptoms through mindfulness and guided imagery. This pilot study examined the feasibility of participation by caregivers with SI in a randomized controlled trial (RCT) of MIT versus a psychosocial support group (SG), and the respective impact of group on SI, depression, and secondary outcomes. Methods: A secondary analysis of data from an RCT of 4-week MIT or SG for caregivers (n = 46) was performed, identifying SI (n = 23) and non-SI (n = 23) cohorts. Group attendance and home practice were compared between cohorts. In the SI cohort (total n = 23, MIT n = 11, SG n = 12), group differences in SI, depression, and secondary outcomes were evaluated post-group and at 4-month follow-up. Results: Attendance in both groups and home practice in MIT were similar between SI and non-SI cohorts. In the SI cohort, MIT evinced greater improvements relative to SG in SI (p=.02) and depression (p=.02) post-group, and other secondary outcomes at follow-up. Limitations: Limitations include small sample size and single-item assessments of SI from validated depression rating scales. Conclusions: Participation in an RCT was feasible for caregivers with SI. MIT resulted in important benefits for SI and depression, while SG showed no acute SI benefit. The role of MIT in improving SI should be confirmed with adequately powered trials, as effective therapies to address caregiver SI are critical.

Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick.

Infections frequently cause behavioral changes, known as sickness behavior. In a recent study,1 Yipp and collaborators discovered a sensory circuit that is activated by a bacterial lipopolysaccharide during lung infection and drives sickness behaviors independent of inflammation. Biofilm-producing bacteria, however, avoid activating this lung-brain circuit, resulting in infection without sickness behavior.

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Global arthropod beta-diversity is spatially and temporally structured by latitude.

Global biodiversity gradients are generally expected to reflect greater species replacement closer to the equator. However, empirical validation of global biodiversity gradients largely relies on vertebrates, plants, and other less diverse taxa. Here we assess the temporal and spatial dynamics of global arthropod biodiversity dynamics using a beta-diversity framework. Sampling includes 129 sampling sites whereby malaise traps are deployed to monitor temporal changes in arthropod communities. Overall, we encountered more than 150,000 unique barcode index numbers (BINs) (i.e. species proxies). We assess between site differences in community diversity using beta-diversity and the partitioned components of species replacement and richness difference. Global total beta-diversity (dissimilarity) increases with decreasing latitude, greater spatial distance and greater temporal distance. Species replacement and richness difference patterns vary across biogeographic regions. Our findings support long-standing, general expectations of global biodiversity patterns. However, we also show that the underlying processes driving patterns may be regionally linked.

Superimposition of virtual models using palatal rugae and maximum habitual intercuspation.

INTRODUCTION: The superimposition of 3 dimensions (3D) digital models has been increasingly used for evaluating dental changes resulting from orthodontic treatment, and different superimposition techniques have been described. Although the maxilla has areas with greater stability for superimposition, such as the palatal rugae, there is still no reliable method for superimposing models of the lower arch. OBJECTIVE: Therefore, this article aims to describe a technique for superimposing virtual models. METHODS: To evaluate pre- and post-orthodontic treatment changes, the Geomagic Qualify 2013 software (3D Systems®, Rock Hill, South Carolina, USA) was used, with reference points in the maxilla, including the rugae and a reference area in the palate and midpalatal raphe. The lower arch was superimposed using the maximum habitual intercuspation (MHI) model as reference. RESULTS AND CONCLUSION: 3D models superimposition using palatal rugae and MHI occlusion seems to offer satisfactory results in the interpretation of clinical changes at different follow-up moments in terms of development and/or orthodontic treatment.

First record of mercury concentrations and stable isotopes (13C & 15N) in albacore (Thunnus alalunga) from the Western Equatorial Atlantic Ocean.

This paper reports the first record of total mercury (THg) concentrations in albacore (Thunnus alalunga), one of the main tuna species caught from the Western Equatorial Atlantic Ocean and presents a preliminary comparison with other regions and tuna species. Mean, standard deviation and range of concentrations in T. alalunga (515 ± 145 ng g-1 ww; 294-930 ng g-1 ww) with 92 % being of methyl-Hg, are higher than in albacore from other Atlantic Ocean subregions despite their smaller body size. These concentrations are similar to those from the Pacific and Indian oceans, but lower than in the Mediterranean. Compared to other sympatric tuna species, concentrations are higher than those in T. albacares and similar to T. obesus. These results are discussed considering the potential differences in stable isotope values (13C and 15N) of T. alalunga populations from multiple oceanic areas and compared to other tuna species worldwide.

Confirmation of the invasive American mink (Neogale vison) as carrier of Mycobacterium bovis in southern Chile.

Bovine tuberculosis (bTB) is a chronic infectious-contagious disease with worldwide distribution, caused by the zoonotic pathogen Mycobacterium bovis. It is believed that the existence of wild cycles may hamper the success of bTB control strategies worldwide, where wildlife species could be reservoirs of this bacterial agent across their native (e.g., European badgers, wild boars) or non-indigenous (e.g., brushtail possum in New Zealand) ranges. However, further studies are required to understand the potential risk posed by non-native wildlife in becoming carriers of M. bovis in other neglected latitudes, such as the Southern Cone of South America. In this study, we performed a specific M. bovis-RD4 real-time PCR (qPCR) assay to detect bacterial DNA in tissues from the invasive American mink (Neogale vison) in Los Ríos region, Chile. We detected M. bovis DNA in blood samples collected from 13 out of 186 (7 %) minks with known sex and age. We did not find any significant differences in bacterial DNA detection according to mink sex and age. We found that 92 % (12/13) of specimens were positive in lung, 39 % (5/13) in mediastinal lymph node, and 15 % (2/13) in mesenteric lymph node, which suggest that both respiratory and digestive pathways as possible routes of transmission between infected hosts and minks. Our study is the first report on M. bovis molecular detection in invasive minks in an area where the largest cattle population in the country is located. Furthermore, this area is characterized by a low within-herd prevalence of M. bovis infection in cattle, with a relatively low number of infected herds, and so far, no attempts at eradicating the disease have been successful.

Breathing Air and Living Underwater: Molecular Evolution of Genes Related to Antioxidant Response in Cetaceans and Pinnipeds.

Cetaceans and pinnipeds are lineages of mammals that have independently returned to the aquatic environment, acquiring varying degrees of dependence on it while sharing adaptations for underwater living. Here, we focused on one critical adaptation from both groups, their ability to withstand the ischemia and reperfusion experienced during apnea diving, which can lead to the production of reactive oxygen species (ROS) and subsequent oxidative damage. Previous studies have shown that cetaceans and pinnipeds possess efficient antioxidant enzymes that protect against ROS. In this study, we investigated the molecular evolution of key antioxidant enzyme genes (CAT, GPX3, GSR, PRDX1, PRDX3, and SOD1) and the ROS-producing gene XDH, in cetaceans and pinnipeds lineages. We used the ratio of non-synonymous (dN) to synonymous (dS) substitutions as a measure to identify signatures of adaptive molecular evolution in these genes within and between the two lineages. Additionally, we performed protein modeling and variant impact analyzes to assess the functional consequences of observed mutations. Our findings revealed distinct selective regimes between aquatic and terrestrial mammals in five of the examined genes, including divergences within cetacean and pinniped lineages, between ancestral and recent lineages and between crowns groups. We identified specific sites under positive selection unique to Cetacea and Pinnipedia, with one site showing evidence of convergent evolution in species known for their long and deep-diving capacities. Notably, many sites under adaptive selection exhibited radical changes in amino acid properties, with some being damaging mutations in human variations, but with no apparent detrimental impacts on aquatic mammals. In conclusion, our study provides insights into the adaptive changes that have occurred in the antioxidant systems of aquatic mammals throughout their evolutionary history. We observed both distinctive features within each group of Cetacea and Pinnipedia and instances of convergence. These findings highlight the dynamic nature of the antioxidant system in response to challenges of the aquatic environment and provide a foundation for further investigations into the molecular mechanisms underlying these adaptations.

Modulation of host immunity by sensory neurons.

Recent studies have uncovered a new role for sensory neurons in influencing mammalian host immunity, challenging conventional notions of the nervous and immune systems as separate entities. In this review we delve into this groundbreaking paradigm of neuroimmunology and discuss recent scientific evidence for the impact of sensory neurons on host responses against a wide range of pathogens and diseases, encompassing microbial infections and cancers. These valuable insights enhance our understanding of the interactions between the nervous and immune systems, and also pave the way for developing candidate innovative therapeutic interventions in immune-mediated diseases highlighting the importance of this interdisciplinary research field.

Progression or Aging? A Deep Learning Approach for Distinguishing Glaucoma Progression From Age-Related Changes in OCT Scans.

PURPOSE: To develop deep learning (DL) algorithm to detect glaucoma progression using optical coherence tomography (OCT) images, in the absence of a reference standard. DESIGN: Retrospective cohort study. METHODS: Glaucomatous and healthy eyes with ≥5 reliable peripapillary OCT (Spectralis, Heidelberg Engineering) circle scans were included. A weakly supervised time-series learning model, called noise positive-unlabeled (Noise-PU) DL was developed to classify whether sequences of OCT B-scans showed glaucoma progression. The model used 2 learning schemes, one to identify age-related changes by differentiating test sequences from glaucoma vs healthy eyes, and the other to identify test-retest variability based on scrambled OCTs of glaucoma eyes. Both models' bases were convolutional neural networks (CNN) and long short-term memory (LSTM) networks which were combined to form a CNN-LSTM model. Model features were combined and jointly trained to identify glaucoma progression, accounting for age-related loss. The DL model's outcomes were compared with ordinary least squares (OLS) regression of retinal nerve fiber layer (RNFL) thickness over time, matched for specificity. The hit ratio was used as a proxy for sensitivity. RESULTS: Eight thousand seven hundred eighty-five follow-up sequences of 5 consecutive OCT tests from 3253 eyes (1859 subjects) were included in the study. The mean follow-up time was 3.5 ± 1.6 years. In the test sample, the hit ratios of the DL and OLS methods were 0.498 (95%CI: 0.470-0.526) and 0.284 (95%CI: 0.258-0.309) respectively (P < .001) when the specificities were equalized to 95%. CONCLUSION: A DL model was able to identify longitudinal glaucomatous structural changes in OCT B-scans using a surrogate reference standard for progression.

Contemporary Assessment of Energy Degeneracy in Orbital Mixing with Tetravalent f-Block Compounds.

The f block is a comparatively understudied group of elements that find applications in many areas. Continued development of technologies involving the lanthanides (Ln) and actinides (An) requires a better fundamental understanding of their chemistry. Specifically, characterizing the electronic structure of the f elements presents a significant challenge due to the spatially core-like but energetically valence-like nature of the f orbitals. This duality led f-block scientists to hypothesize for decades that f-block chemistry is dominated by ionic metal-ligand interactions with little covalency because canonical covalent interactions require both spatial orbital overlap and orbital energy degeneracy. Recent studies on An compounds have suggested that An ions can engage in appreciable orbital mixing between An 5f and ligand orbitals, which was attributed to "energy-degeneracy-driven covalency". This model of bonding has since been a topic of debate because different computational methods have yielded results that support and refute the energy-degeneracy-driven covalency model. In this Viewpoint, literatures concerning the metal- and ligand-edge X-ray absorption near-edge structure (XANES) of five tetravalent f-block systems─MO2 (M = Ln, An), LnF4, MCl62-, and [Ln(NP(pip)3)4]─are compiled and discussed to explore metal-ligand bonding in f-block compounds through experimental metrics. Based on spectral assignments from a variety of theoretical models, covalency is seen to decrease from CeO2 and PrO2 to TbO2 through weaker ligand-to-metal charge-transfer (LMCT) interactions, while these LMCT interactions are not observed in the trivalent Ln sesquixodes until Yb. In comparison, while XANES characterization of AnO2 compounds is scarce, computational modeling of available X-ray absorption spectra suggests that covalency among AnO2 reaches a maximum between Am and Cm. Moreover, a decrease in covalency is observed upon changing ligands while maintaining an isostructural coordination environment from CeO2 to CeF4. These results could allude to the importance of orbital energy degeneracy in f-block bonding, but there are a variety of data gaps and conflicting results from different modeling techniques that need to be addressed before broad conclusions can be drawn.

Derivation and Validation of Generalized Sepsis-induced Acute Respiratory Failure Phenotypes Among Critically Ill Patients: A Retrospective Study.

Background: Septic patients who develop acute respiratory failure (ARF) requiring mechanical ventilation represent a heterogenous subgroup of critically ill patients with widely variable clinical characteristics. Identifying distinct phenotypes of these patients may reveal insights about the broader heterogeneity in the clinical course of sepsis. We aimed to derive novel phenotypes of sepsis-induced ARF using observational clinical data and investigate their generalizability across multi-ICU specialties, considering multi-organ dynamics. Methods: We performed a multi-center retrospective study of ICU patients with sepsis who required mechanical ventilation for ≥24 hours. Data from two different high-volume academic hospital systems were used as a derivation set with N=3,225 medical ICU (MICU) patients and a validation set with N=848 MICU patients. For the multi-ICU validation, we utilized retrospective data from two surgical ICUs at the same hospitals (N=1,577). Clinical data from 24 hours preceding intubation was used to derive distinct phenotypes using an explainable machine learning-based clustering model interpreted by clinical experts. Results: Four distinct ARF phenotypes were identified: A (severe multi-organ dysfunction (MOD) with a high likelihood of kidney injury and heart failure), B (severe hypoxemic respiratory failure [median P/F=123]), C (mild hypoxia [median P/F=240]), and D (severe MOD with a high likelihood of hepatic injury, coagulopathy, and lactic acidosis). Patients in each phenotype showed differences in clinical course and mortality rates despite similarities in demographics and admission co-morbidities. The phenotypes were reproduced in external validation utilizing an external MICU from second hospital and SICUs from both centers. Kaplan-Meier analysis showed significant difference in 28-day mortality across the phenotypes (p<0.01) and consistent across both centers. The phenotypes demonstrated differences in treatment effects associated with high positive end-expiratory pressure (PEEP) strategy. Conclusion: The phenotypes demonstrated unique patterns of organ injury and differences in clinical outcomes, which may help inform future research and clinical trial design for tailored management strategies.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.