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Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13 , FOXA1 and NKX3-1 . Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression. Analyses of epigenomic datasets spanning transitions from normal prostate epithelium to localized prostate cancer to metastases show that latent developmental programs are reactivated in metastatic disease and that prostate lineage-specific regulatory elements are strongly enriched for prostate cancer risk heritability.

Private messaging platforms provide strong protection against platform eavesdropping, but malicious users can use privacy as cover for spreading abuse and misinformation. In response, researchers have proposed mechanisms to trace back the source of a user-reported message (CCS ’19,’21). Unfortunately, the threat model considered by initial proposals allowed a single user to compromise the privacy of another user whose legitimate content the reporting user did not like. Recent work has attempted to mitigate this side effect by requiring a threshold number of users to report a message before its origins can be identified (NDSS ’22). However, the state of the art scheme requires the introduction of probabilistic data structures and only achieves a “fuzzy” threshold guarantee.This paper introduces a new threshold source tracking technique and accompanying efficient implementation that allows a private messaging platform, with the cooperation of a third-party moderator, to operate a threshold reporting scheme with exact thresholds.

Background: Genome-wide association studies of prostate cancer have identified >250 significant risk loci, but the causal variants and mechanisms for these loci remain largely unknown. Here, we sought to identify and characterize risk harboring regulatory elements by integrating epigenomes from primary prostate tumor and normal tissues of 27 patients across the H3K27ac, H3K4me3, and H3K4me2 histone marks and FOXA1 and HOXB13 transcription factors. Results: We identified 7,371 peaks with significant allele-specificity (asQTL peaks). Showcasing their relevance to prostate cancer risk, H3K27ac T-asQTL peaks were the single annotation most enriched for prostate cancer GWAS heritability (40x), significantly higher than corresponding non-asQTL H3K27ac peaks (14x) or coding regions (14x). Surprisingly, fine-mapped GWAS risk variants were most significantly enriched for asQTL peaks observed in tumors, including asQTL peaks that were differentially imbalanced with respect to tumor-normal states. These data pinpointed putative causal regulatory elements at 20 GWAS loci, of which 11 were detected only in the tumor samples. More broadly, tumor-specific asQTLs were enriched for expression QTLs in benign tissues as well as accessible regions found in stem cells, supporting a hypothesis where some germline variants become reactivated during/after transformation and can be captured by epigenomic profiling of the tumor. Conclusion: Our study demonstrates the power of allele-specificity in chromatin signals to uncover GWAS mechanisms, highlights the relevance of tumor-specific regulation in the context of cancer risk, and prioritizes multiple loci for experimental follow-up. Competing Interest Statement The authors have declared no competing interest.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional ‘surges’ in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and is an independent risk factor for all-cause in-hospital death in patients with COVID-19. This Consensus Statement from the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI and for areas of future research, with the aim of improving understanding of the underlying processes and outcomes for patients with COVID-19 AKI.

Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1). In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes and ceramides. The proteolytic enzyme cathepsin D (CTSD) had impaired maturation. A large proportion of lysosomes were galectin-3 (Lgals3) positive, suggesting cytotoxic lysosomal membrane permeabilization. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.

MicroRNAs may act as diagnostic and prognostic biomarkers of chronic kidney disease and are functionally important in disease pathogenesis. To identify novel microRNA biomarkers, we performed small RNA-sequencing on plasma from individuals with type 2 diabetes, with and without chronic kidney disease. MiR-190a-5p abundance was significantly lower in the circulation of type 2 diabetic patients with reduced function compared to those with normal kidney function. In an independent cohort of patients with chronic kidney disease of diverse aetiology, miR-190a-5p abundance predicted disease progression in individuals with no or moderate albuminuria ( < 300 mg/mmol). miR-190a-5p expression in kidney biopsy tissue correlated with the level of miR-190a-5p in the circulation and with estimated glomerular filtration rate, tubular mass and negatively with histological fibrosis. Administration of a miR-190a-5p mimic in a murine ischaemia-reperfusion injury model in male mice reduced tubular injury and fibrosis and increased expression of genes associated with tubular health. Our analyses suggest that miR-190a-5p is a biomarker of tubular cell health, low circulating levels may predict chronic kidney disease progression independent of existing risk factors and strategies to preserve miR-190a-5p may be an effective treatment for restoring tubular cell health following kidney injury. Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.

Recent research highlights the dynamics of suicide risk, resulting in a shift toward real-time methodologies, such as ecological momentary assessment (EMA), to improve suicide risk identification. However, EMA's reliance on active self-reporting introduces challenges, including participant burden and reduced response rates during crises. This study explores the potential of Screenomics-a passive digital phenotyping method that captures intensive, real-time smartphone screenshots-to detect suicide risk through text-based analysis. Seventy-nine participants with past-month suicidal ideation or behavior completed daily EMA prompts and provided smartphone data over 28 days, resulting in approximately 7.5 million screenshots. Text from screenshots was analyzed using a validated dictionary encompassing suicide-related and general risk language. Results indicated significant associations between passive and active suicidal ideation and suicide planning with specific language patterns. Detection of words related to suicidal thoughts and general risk-related words strongly correlated with self-reported suicide risk, with distinct between- and within-person effects highlighting the dynamic nature of suicide risk factors. This study demonstrates the feasibility of leveraging smartphone text data for real-time suicide risk detection, offering a scalable, low-burden alternative to traditional methods. Findings suggest that dynamic, individualized monitoring via passive data collection could enhance suicide prevention efforts by enabling timely, tailored interventions. Future research should refine language models and explore diverse populations to extend the generalizability of this innovative approach.

In contrast, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) found no effect of screening on prostate cancer mortal- ity (RR 1.09, 95% Cl 0.87-1.36; 0 deaths from prostate cancer prevented per 10 000 invited for screening).21 Participants in the PLCO trial had a high rate of pretrial PSA testing (52%), but sensi- tivity analysis found no effect of pretrial PSA testing on the results. High rates of opportunistic PSA screening were observed in the control group, however, which decreased the opportunity to show a beneficial effect of screening. There- fore, although the lack of benefit observed in the PLCO trial reduces confidence that PSA screen- ing truly does reduce prostate cancer mortality, the task force placed relatively more weight on the findings of the ERSPC study. Because of recent efforts to encourage screening for prostate cancer, some men may be interested in PSA screening despite the current recoimnen- dations. Evidence suggests that a patient's per- ceived vulnerability to the disease, as a result of family history or otherwise, and physician rec- oimnendation are both associated with patient re- quest for screening with the PSA test.50 Although high-quality evidence on the best way to facili- tate informed decision-making about prostate cancer screening is lacking, such discussions should ahn to elicit the knowledge, preferences and values of patients who ask about PSA screening.51,52 Many men view screening posi- tively but are unaware of the potential harms.55 In addition to a focus on the patient's values and preferences, informed decision-making requires practitioners to distinguish between the benefits and harms of screening, subsequent investiga- tions and treatment, including an overview of diagnostic and therapeutic options in the event that the PSA test result is abnormal. Future research may be best focused on finding alternatives to the PSA test for prostate cancer screening and reducing inappropriate PSA test- ing. It has been suggested that baseline PSA testing could help to assess the future risk of death or metastasis from prostate cancer (which could support risk-based screening67 68), but more work is needed before this approach could be recoimnended. Magnetic resonance hnaging and clinical decision rules are also promising approaches to hnproving the risk:benefit ratio of screening, but they have not been tested in rig- orous randomized trials. Future research should also develop methods to identify the subset of men with prostate cancer in whom clinically rel- evant disease would develop (in the absence of treatment). Altering PSA thresholds or screen- ing intervals, as well as uncoupling screening from treatment (because some men may opt for watchful waiting or active surveillance instead of active treatment), may favourably change the risk:benefit ratio of PSA screening; however, more research is needed to test this hypothesis. Trials investigating the benefits of PSA screen- ing among men with a family history of prostate cancer or men of black race would be helpful to determine whether screening in these high-risk populations is warranted. Finally, randomized trials should compare watchful waiting or active surveillance, or both, with treatment with a curative intent.

Rotator cuff tears are common in individuals over 40, and physical therapy is often prescribed post-surgery. However, access can be limited by cost, convenience, and insurance coverage. CuffLink is a telehealth rehabilitation system that integrates the Strengthening and Stabilization System mechanical exerciser with the interACTION mobile health platform. The system includes a triple-axis accelerometer (LSM6DSOX + LIS3MDL FeatherWing), a rotary encoder, a VL530X time-of-flight sensor, and two wearable BioMech Health IMUs to capture upper-limb motion. CuffLink is designed to facilitate controlled, home-based exercise while enabling clinicians to remotely monitor joint function. Concurrent validity and test–retest reliability were used to assess device accuracy and repeatability. The results showed moderate to good validity for shoulder rotation (ICC = 0.81), device rotation (ICC = 0.94), and linear tracking (from zero: ICC = 0.75 and RMSE = 2.41; from start: ICC = 0.88 and RMSE = 2.02) and good reliability (e.g., RMSEs as low as 1.66 cm), with greater consistency in linear tracking compared to angular measures. Shoulder rotation and abduction exhibited higher variability in both validity and reliability measures. Future improvements will focus on manufacturability, signal stability, and force sensing. CuffLink supports accessible, data-driven rehabilitation and holds promise for advancing digital health in orthopedic recovery.

Proper rehabilitation following rotator cuff repair (RCR) is necessary for successful postoperative outcomes, though the average course of physical therapy (PT) is lengthy and costly. The goals of this study were to (1) develop exercise programs for the CuffLink mHealth system and (2) evaluate early prototype efforts at meeting the needs of RCR clients. A panel of 24 clinicians participated in a Delphi study to identify consensus in rehabilitation, key informatic needs, and appropriate interface modalities for client usage. Utilizing the Delphi findings, the iA CuffLink mHealth system was developed, and a pilot evaluation assessed the feasibility and usability of CuffLink through the mHealth App Usability Questionnaire (MAUQ). During the pilot evaluation, the overall MAUQ score was 6.14. All participants (n = 18) viewed messaging the care team and a real time rep counter as “important” or “very important”. All participants either agreed or strongly agreed that quantifying progress would help motivate them to be compliant, and that the app helped them achieve their recovery outcomes compared to the shoulder device alone. Participants were generally pleased with the ease of use, information arrangement, and usefulness of CuffLink. These findings can advance our understanding of the informatics and usability needs in telerehabilitation systems.