Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT.

Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have "mismatch" lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

Evidence of Active Orbivirus Transmission in 2016 in Kansas and Nebraska.

Retrospective serological and case diagnostic data of endemic bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) provide evidence of viral transmission among livestock and wildlife from 2016 in Kansas and Nebraska. Serological testing of mature cattle in nine distinct regional zones of Kansas revealed 76% to 100% had detectable antibodies to BTV and/or EHDV. Specimens tested in the Kansas Veterinary Diagnostic Laboratory (55 submissions) were 51% test positive for antibodies to BTV and/or EHDV. Specimens tested in the Nebraska Veterinary Diagnostic Center (283 submissions) were 25% test positive for antibodies to BTV and/or EHDV. Low disease incidence in white-tailed deer and other susceptible wild ungulates was observed during 2016. However, there were no confirmed reports of disease in livestock in either state. The reasons for emergence of significant clinical disease in livestock and wildlife populations remain undefined.

Social determinants of health in uterine carcinosarcoma.

OBJECTIVE: UCS survival outcome disparities by race have been reported. We aimed to investigate social determinants of health (SDOH) and their relation to survival outcomes in women at two affiliated high-volume institutions serving a racially and economically diverse population. METHODS: Women diagnosed with stage I-IV UCS treated at St. Paul University Hospital, University of Texas Southwestern (UTSW) Zale Lipshy Pavilion-William P. Clements Jr. University Hospital, and Parkland Memorial Hospital between 1992 and 2022 were eligible. Patients were identified by the local tumor registries; a retrospective study was conducted. The Pearson chi-square test was utilized for categorical variables. OS and PFS were calculated using Kaplan-Meier estimates and compared with the log-rank test. Multivariate Cox models were used to identify independent prognostic factors. All statistical analyses were performed using SAS, version 9.4. RESULTS: Over half of the 218 patients with UCS were NHB. 35% of the patients had stage IV disease. Most HSP and NHB patients had a lower median household income* than Asian/Pacific Islander (API) or NHW (p < 0.001). Stage at diagnosis significantly affected OS (p < 0.001) but not PFS (p = 0.46) in univariate analyses. Accounting for age at diagnosis, insurance, income*, hospital, distance between hospital and home, months from diagnosis to first treatment, stage, and adjuvant therapy, race was significant for OS (p = 0.03) and PFS (p = 0.04). *Median household income by ZIP Code. CONCLUSIONS: Racial disparities were seen in median household income. Most SDOH independently analyzed in this study did not affect OS. The complex interaction between race and stage in UCS survival outcomes needs further investigation.

Examining the Intersection of Ethnoracial Disparities and HIV Status in Substance Use Risks among U.S. Adults.

Black/African American and Hispanic Americans experience significant HIV-related disparities. Substance use might be a contributing factor to these disparities, but there is limited research on this topic. This study investigated various substance use risks by HIV status and race/ethnicity (Black, Hispanic, White) among U.S. adults. We used data from the 2005-2019 National Survey on Drug Use and Health (N = 541,921). In each racial/ethnic group, the prevalence rates of past-year and past-month tobacco, alcohol, cannabis, and cocaine use, and past-year alcohol and illicit drug use disorders were estimated by HIV status. A series of logistic regressions with the interaction term of HIV x race/ethnicity were performed to examine race/ethnicity's moderating effect on the HIV-substance use associations, while controlling for sociodemographic factors and survey year. Moderation analysis showed that HIV status's association with the risks of past-year tobacco use (AOR = 1.67, 95% CI = 1.01-2.75), past-year cocaine use (AOR = 3.80, 95% CI = 1.91-7.57), past-month cocaine use (AOR = 5.34, 95% CI = 2.10-13.60), and past-year alcohol use disorder (AOR = 2.52, 95% CI = 1.29-4.92) differed significantly between Black and White adults. Between the Hispanic and White groups, HIV status's association with the risks of past-year alcohol use (AOR = 2.00, 95% CI = 1.09-3.69), past-year cocaine use (AOR = 2.40, 95% CI = 1.06-5.39), and past-month cocaine use (AOR = 3.69, 95% CI = 1.36-10.02) also differed significantly. It is well-established that individuals with HIV face an elevated risk of substance use. Our study added valuable insights by highlighting that this phenomenon is particularly more significant among Black and Hispanic adults for several substances when compared to White adults. Implications for practice are discussed.

Six-year cumulative treatment effect and treatment efficacy of a dual focus myopia control contact lens.

PURPOSE: Accumulated axial growth observed during a 6-year clinical trial of a dual focus myopia control contact lens was used to explore different approaches to assess treatment efficacy. METHODS: Axial length measurements from 170 eyes in a 6-year clinical trial of a dual focus myopia control lens (MiSight 1 day, CooperVision) were analysed. Treatment groups comprised one having undergone 6 years of treatment and the other (the initial control group) having 3 years of treatment after 3 years of wearing a single vision control lens. Efficacy was assessed by comparing accumulated ocular growth during treatment to that expected of untreated myopic and emmetropic eyes. The impact of treatment on delaying axial growth was quantified by comparing the increased time required to reach criterion growths for treated eyes and survivor analysis approaches. RESULTS: When compared to the predicted accumulated growth of untreated eyes, 6 years of treatment reduced growth by 0.52 mm, while 3 years of treatment initiated 3 years later reduced growth by 0.19 mm. Accumulated differences between the growth of treated and untreated myopic eyes ranged between 67% and 52% of the untreated myopic growth, and between 112% and 86% of the predicted difference in growth between untreated myopic and age-matched emmetropic eyes. Treated eyes took almost 4 years longer to reach their final accumulated growth than untreated eyes. Treatment increased the time to reach criterion growths by 2.3-2.7 times. CONCLUSION: Estimated growth of age-matched emmetropic and untreated myopic eyes provided evidence of an accumulated slowing in axial elongation of 0.52 mm over 6 years, and the treated growth remained close to that expected of emmetropic eyes. Six years of dual focus myopia control delayed the time to reach the final growth level by almost 4 years.

Bioinspired polymeric heart valves: A combined in vitro and in silico approach.

Background: Polymeric heart valves (PHVs) may address the limitations of mechanical and tissue valves in the treatment of valvular heart disease. In this study, a bioinspired valve was designed, assessed in silico, and validated by an in vitro model to develop a valve with optimum function for pediatric applications. Methods: A bioinspired heart valve was created computationally with leaflet curvature derived from native valve anatomies. A valve diameter of 18 mm was chosen to approach sizes suitable for younger patients. Valves of different thicknesses were fabricated via dip-coating with siloxane-based polyurethane and tested in a pulse duplicator for their hydrodynamic function. The same valves were tested computationally using an arbitrary Lagrangian-Eulerian plus immersed solid approach, in which the fluid-structure interaction between the valves and fluid passing through them was studied and compared with experimental data. Results: Computational analysis showed that valves of 110 to 200 µm thickness had effective orifice areas (EOAs) of 1.20 to 1.30 cm2, with thinner valves exhibiting larger openings. In vitro tests demonstrated that PHVs of similar thickness had EOAs of 1.05 to 1.35 cm2 and regurgitant fractions (RFs) <7%. Valves with thinner leaflets exhibited optimal systolic performance, whereas thicker valves had lower RFs. Conclusions: Bioinspired PHVs demonstrated good hydrodynamic performance that exceeded ISO 5840-2 standards. Both methods of analysis showed similar correlations between leaflet thickness and valve systolic function. Further development of this PHV may lead to enhanced durability and thus a more reliable heart valve replacement than contemporary options.

Immunotherapy response in patients with cutaneous squamous cell carcinoma of head and neck with cranial nerve involvement.

BACKGROUND: Metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) can be treated with immunotherapy (IO). Cranial nerve involvement (CNI) is uncommon in cSCC and is a poor prognostic factor. Our aim is to describe how patients with CNI respond to IO monotherapy and/or as an adjunct to RT. METHODS: Under an IRB approved protocol, patients with histologically proven cSCC of the head and neck with CNI treated with IO were retrospectively reviewed. RESULTS: Twelve patients were included and received cemiplimab or pembrolizumab. Eight patients had CNI at diagnosis, and 4 at time of recurrence after non-IO therapy. Best responses were complete response (1), partial response (7), stable disease (1), progressive disease (2), and pending response (1). Nine patients are alive, 6 of which remain on IO. CONCLUSIONS: In this cohort, IO showed clinical response in 83% of patients, indicating IO can be an effective monotherapy, reserving RT for instances of local failure after IO.

Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician's Choice.

PURPOSE: Lenvatinib and pembrolizumab (LEN+PEMBRO) demonstrated clinically meaningful and statistically significant improvements in efficacy versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer (aEC) in the phase 3 Study 309/KEYNOTE-775. Health-related quality-of-life (HRQoL) is reported. PATIENTS AND METHODS: Patients were randomly assigned to receive LEN+PEMBRO (n = 411; LEN 20 mg/day; PEMBRO 200 mg Q3W) or TPC (n = 416; doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 [weekly, 3 weeks on/1 week off]). Impact of treatment on HRQoL assessed by the global health status/quality of life (GHS/QoL) score of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) was a secondary objective; other scales of the Quality-of-Life Questionnaire (QLQ-C30), EORTC QLQ-Endometrial, 24 questions (EORTC QLQ-EN24), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) were exploratory objectives. HRQoL was assessed on day 1 of each cycle. Completion/compliance, change from baseline, time to first and definitive deterioration were assessed. No multiplicity adjustments were applied for HRQoL endpoints. RESULTS: The latest timepoint at which the predefined rates of completion (≥60%) and compliance (≥80%) were met was week 12. HRQoL at week 12 between treatment groups was generally similar. Time to first deterioration symptom scales favoured LEN+PEMBRO for QLQ-C30 dyspnoea, and QLQ-EN24 for poor body image, tingling/numbness, and hair loss; and TPC was favoured for QLQ-C30 pain, appetite loss, and diarrhoea, and QLQ-EN24 muscular pain. While the QLQ-C30 physical functional scale favoured TPC, other functional scales were generally similar between arms. Time to definitive deterioration favoured LEN+PEMBRO on most scales. CONCLUSION: HRQoL data from Study 309/KEYNOTE-775, with previously published efficacy and safety results, indicate that LEN+PEMBRO has an overall favourable benefit/risk profile versus TPC for the treatment of patients with aEC. CLINICALTRIALS: GOV: NCT03517449.

Log-Spectral Matching GAN: PPG-based Atrial Fibrillation Detection can be Enhanced by GAN-based Data Augmentation with Integration of Spectral Loss.

Photoplethysmography (PPG) is a ubiquitous physiological measurement that detects beat-to-beat pulsatile blood volume changes and hence has a potential for monitoring cardiovascular conditions, particularly in ambulatory settings. A PPG dataset that is created for a particular use case is often imbalanced, due to a low prevalence of the pathological condition it targets to predict and the paroxysmal nature of the condition as well. To tackle this problem, we propose log-spectral matching GAN (LSM-GAN), a generative model that can be used as a data augmentation technique to alleviate the class imbalance in a PPG dataset to train a classifier. LSM-GAN utilizes a novel generator that generates a synthetic signal without a up-sampling process of input white noises, as well as adds the mismatch between real and synthetic signals in frequency domain to the conventional adversarial loss. In this study, experiments are designed focusing on examining how the influence of LSM-GAN as a data augmentation technique on one specific classification task - atrial fibrillation (AF) detection using PPG. We show that by taking spectral information into consideration, LSM-GAN as a data augmentation solution can generate more realistic PPG signals.

Exercise as therapy for neurodevelopmental and cognitive dysfunction in people with a Fontan circulation: A narrative review.

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended.

Tumor Treating Fields (TTFields) Therapy Concomitant with Taxanes for Cancer Treatment.

Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes; however, implementation is limited by additive toxicities and potential drug-drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patient's skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers.

From Scan to Simulation-A Novel Workflow for Developing Bioinspired Heart Valves.

Current heart valve replacements lack durability and prolonged performance, especially in pediatric patients. In part, these problems may be attributed to the materials chosen for these constructs, but another important contributing factor is the design of the valve, as this dictates hemodynamic performance and impacts leaflet stresses which may accelerate structural valve deterioration. Most current era bioprosthetic valves adhere to a fundamental design where flat leaflets are supported by commissural posts, secured to a sewing ring. This overall design strategy is effective, but functionality and durability can be improved by incorporating features of the native valve geometry. This paper presents a novel workflow for developing and analyzing bio-inspired valve designs computationally. The leaflet curvature was defined using a mathematical equation whose parameters were derived from the three-dimensional model of a native sheep pulmonary valve obtained via microcomputed tomography. Finite element analysis was used to screen the various valve designs proposed in this study by assessing the effect of leaflet thickness, Young's modulus, and height/curvature on snap-through (where leaflets bend against their original curvature), geometric orifice area (GOA) and the stress in the leaflets. This workflow demonstrated benefits for valve designs with leaflet thicknesses between 0.1 and 0.3 mm, Young's moduli less than 50 MPa, and elongated leaflets with higher curvatures. The proposed workflow brings substantial efficiency gains at the design stage, minimizing manufacturing and animal testing during iterative improvements, and offers a bridge between in vitro and more complex in silico studies in the future.

Type 2 Diabetes Mellitus and Sarcopenia as Comorbid Chronic Diseases in Older Adults: Established and Emerging Treatments and Therapies

Type 2 diabetes mellitus (T2DM) and sarcopenia (low skeletal muscle mass and function) share a bidirectional relationship. The prevalence of these diseases increases with age and they share common risk factors. Skeletal muscle fat infiltration, commonly referred to as myosteatosis, may be a major contributor to both T2DM and sarcopenia in older adults via independent effects on insulin resistance and muscle health. Many strategies to manage T2DM result in energy restriction and subsequent weight loss, and this can lead to significant declines in muscle mass in the absence of resistance exercise, which is also a first-line treatment for sarcopenia. In this review, we highlight recent evidence on established treatments and emerging therapies targeting weight loss and muscle mass and function improvements in older adults with, or at risk of, T2DM and/or sarcopenia. This includes dietary, physical activity and exercise interventions, new generation incretin-based agonists and myostatin-based antagonists, and endoscopic bariatric therapies. We also highlight how digital health technologies and health literacy interventions can increase uptake of, and adherence to, established and emerging treatments and therapies in older adults with T2DM and/or sarcopenia.

Direct Medical Costs and Healthcare Resource Utilization of Treating Patients With Two Clinical Subtypes of Axial Spondyloarthritis in Colombia.

OBJECTIVES: This study aimed to calculate the healthcare resource utilization and direct medical costs in patients with 2 subtypes of axial spondyloarthritis (axSpA) in a rheumatic care center in Colombia. METHODS: This is a retrospective cost-of-illness study. Patients with at least 1 medical consultation associated with an axSpA diagnosis between October 2018 and October 2019 were identified. Patients were classified as having radiographic (r-axSpA) or nonradiographic axSpA (nr-axSpA). Direct medical costs were calculated in Colombian pesos and expressed in American dollars using an exchange rate of 3263 Colombian pesos = 1 US dollar ($). Predictors of total direct costs were identified using a generalized linear model with gamma distribution and log-link. RESULTS: A total of 162 patients with a mean age of 49.6 years (± 13.7) were included in the study. Among these, 147 (90.7%) were considered as having r-axSpA and 15 (9.3%) nr-axSpA, with mean costs of $6600 (± 6203) and $843 (± 1135), respectively (P < .001). The total direct mean cost was calculated at $6067 (± 6144) per patient. Medication costs were the main driver of total costs (97.6%, $5921), with biologic disease-modifying antirheumatic drugs accounting for nearly 92.0% ($5582) of these costs. Rheumatologist (100%) and physiatrist (64.2%) visits were the most frequently used medical service. CONCLUSIONS: The economic burden associated with axSpA in the Colombian setting is substantial. There is a significant difference in direct medical costs between the r-axSpA and the nr-axSpA. Health policies aimed at the comprehensive management of nr-axSpA would have an important role in the reduction of the associated direct medical costs.

Fluorotrithiophosphate Abstraction from the Difluoropentathiodiphosphate Dianion: d8 and d6 Complexes of [η2-S3PF]2.

Coordinative heterolysis of the difluoropentathiodiphosphate dianion [S5P2F2]2- results in the formal elimination of [S2PF] by complexes of the group 10 divalent metals nickel, palladium, and platinum. The remaining fragment of this cleavage, [S3PF]2- coordinates as an η2-ligand. Several complexes with this novel fluorotrithiophosphate were characterized structurally and spectroscopically with X-ray diffraction (XRD), infrared (IR) spectroscopy, and 31P and 19F nuclear magnetic resonance (NMR). In addition to mononuclear η2 chelate complexes, bridging complexes with η2-µ2-S3PF configurations result in binuclear nickel and ruthenium adducts. Facile methylation with methyl triflate of the uncoordinated sulfur atom leads to a complex with the methylthiofluorodithiophosphate ligand in a cationic complex, which hydrolyses with loss of fluoride to give complexed [S2P(O)SMe]2-. Alternatively hydrolysis can also lead to a binuclear Ni2(dppe)2(S3PF)(S2POF) complex. Divalent ruthenium π-aryl's form fluorotrithiophosphate complexes rapidly at room temperature to give bridged dimers with complete chloride substitution.

The Sulfur Rich Fluorothiophosphate Dianions [S5 P2 F2 ]2- and [S3 PF]2- : Cluster and Chelation Control of P-S Heterolysis.

The sulfur rich difluoropentathiodiphosphate dianion [S5 P2 F2 ]2- , from fluoride addition to P4 S10 , has a somewhat checkered history and proves to be the main product of the reaction in acetonitrile. Its optimized synthesis, and structural characterization, as either a tetraphenylphosphonium or a tetrapropylammonium salt, [Nn Pr4 ]2 [S5 P2 F2 ] allows for the first coordination chemistry for this dianion. Reactions of [S5 P2 F2 ]2- with d10 metal ions of zinc(II), and cadmium(II), and d9 copper(II) resulted in a surprising diverse array of binding modes and structural motifs. In addition to the simple bis-chelate coordination of [S5 P2 F2 ]2- with zinc, cleavage of the P-S bond resulted in complexes with the unusual [S3 PF]2- fluorotrithiophosphate dianion. This was observed in two cluster complexes: a trinuclear cadmium complex with mixed [S5 P2 F2 ]2- /[S3 PF]2- ligands, [Cd3 (S5 P2 F2 )3 (S3 PF)2 ]4- as well as an octanuclear copper cluster, [Cu8 (S3 PF)6 ]4- which form rapidly at room temperature. These new metal/sulfur/ligand clusters are of relevance to understanding multimetal binding to metallothionines, and to potential capping strategies for the condensed nanoparticulate cadmium chalcogenide semiconductors CdS and CdSe.

Transcatheter mitral valve repair in patient with atrial functional mitral regurgitation using novel DragonFly™ device.

We report the first case of transcatheter mitral valve repair with the novel DragonFly™ device, a transcatheter edge-to-edge mitral regurgitation (MR) repair device, in a patient with severe, symptomatic MR due to annular dilation from atrial functional disease (Carpentier type I). The patient had experienced multiple heart failure events and was unsuitable for surgery due to pulmonary dysfunction and obesity.

Glacial isostatic adjustment directed incision of the Channeled Scabland by Ice Age megafloods.

During the last deglaciation, dozens of glacial outburst floods-among the largest known floods on Earth-scoured the Channeled Scabland landscape of eastern Washington. Over this same period, deformation of the Earth's crust in response to the growth and decay of ice sheets changed the topography by hundreds of meters. Here, we investigated whether glacial isostatic adjustment affected routing of the Missoula floods and incision of the Channeled Scabland from an impounded, glacial Lake Columbia. We used modern topography corrected for glacial isostatic adjustment as an input to flood models that solved the depth-averaged, shallow water equations and compared the results to erosion constraints. Results showed that floods could have traversed and eroded parts of two major tracts of the Channeled Scabland-Telford-Crab Creek and Cheney-Palouse-near 18 ka, whereas glacial isostatic adjustment limited flow into the Cheney-Palouse tract at 15.5 ka. Partitioning of flow between tracts was governed by tilting of the landscape, which affected the filling and overspill of glacial Lake Columbia directly upstream of the tracts. These results highlight the impact of glacial isostatic adjustment on megaflood routing and landscape evolution.

Impact of baseline renal dysfunction on cardiac outcomes and end-stage renal disease in heart failure patients with mitral regurgitation: the COAPT trial.

AIMS: Baseline renal dysfunction (RD) adversely impacts outcomes among patients with heart failure (HF) and severe secondary mitral regurgitation (MR). Heart failure and MR, in turn, accelerate progression to end-stage renal disease (ESRD), worsening prognosis. We sought to determine the impact of RD in HF patients with severe MR and the impact of transcatheter mitral valve repair (TMVr) on new-onset ESRD and the need for renal replacement therapy (RRT). METHODS AND RESULTS: The COAPT trial randomized 614 patients with HF and severe MR to MitraClip plus guideline-directed medical therapy (GDMT) vs. GDMT alone. Patients were stratified into three RD subgroups based on baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): none (≥60), moderate (30-60), and severe (<30). End-stage renal disease was defined as eGFR <15 mL/min/1.73 m2 or RRT. The 2-year rates of all-cause death or HF hospitalization (HFH), new-onset ESRD, and RRT according to RD and treatment were assessed. Baseline RD was present in 77.0% of patients, including 23.8% severe RD, 6.0% ESRD, and 5.2% RRT. Worse RD was associated with greater 2-year risk of death or HFH (none 45.3%; moderate 53.9%; severe 69.2%; P < 0.0001). MitraClip vs. GDMT alone improved outcomes regardless of RD (Pinteraction = 0.62) and reduced new-onset ESRD [2.9 vs. 8.1%, hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.15-0.76, P = 0.008] and the need for new RRT (2.5 vs. 7.4%, HR 0.33, 95% CI 0.14-0.78, P = 0.011). CONCLUSION: Baseline RD was common in the HF patients with severe MR enrolled in COAPT and strongly predicted 2-year death and HFH. MitraClip treatment reduced new-onset ESRD and the need for RRT, contributing to the improved prognosis after TMVr.