Benthic sediment as stores and sources of bacteria and viruses in streams: A comparison of baseflow vs. stormflow longitudinal transport and residence times.

The presence of bacteria and viruses in freshwater represents a global health risk. The substantial spatial and temporal variability of microbes leads to difficulties in quantifying the risks associated with their presence in freshwater. Fine particles, including bacteria and viruses are transported and accumulated into shallow streambed (i.e., benthic) sediment, delaying the downstream transmission during baseflow conditions but contributing to their resuspension and transport downstream during stormflow events. Direct measurements of pathogen accumulation in benthic sediments are rare. Until now, the dynamic role of benthic sediment as both a store and source of microbes, has not been quantified. In this study, we analyze microbial abundance in benthic sediment along a 1 km reach of an intermittent Mediterranean stream receiving inputs from the effluent of a wastewater treatment plant, a known point source of microbes in streams. We sampled benthic sediment during a summer drought when the wastewater effluent constituted 100 % of the stream flow, and thus, large accumulation and persistence of pathogens along the streambed was expected. We measured the abundance of total bacteria, Escherichia coli (as a fecal indicator), and presence of enteric rotavirus (RoV) and norovirus (NoV). The abundance of E. coli, based on qPCR detection, was high (4.99∙102 gc /cm2) along the first 100 m downstream of the wastewater effluent input and in general decreased with distance from the source, with presence of RoV and NoV along the study reach. A particle tracking model was applied, that uses stream water velocity as an input, and accounts for microbial exchange into, immobilization, degradation, and resuspension out of benthic sediment during baseflow and stormflow. Rates of exchange into benthic sediment were 3 orders of magnitude higher during stormflow, but residence times were proportionately lower, resulting in increased longitudinal connectivity from up to downstream during stormflow. Model simulations demonstrated mechanistically how the rates of exchange into and out of the benthic sediment resulted in benthic sediment to act as a store during baseflow and a source during stormflow.

Understanding Gender-Based Violence Service Delivery in CDC-Supported Health Facilities: 15 Sub-Saharan African Countries, 2017-2021.

Gender-based violence (GBV) is a complex issue deeply rooted in social structures, making its eradication challenging. GBV increases the risk of HIV transmission and is a barrier to HIV testing, care, and treatment. Quality clinical services for GBV, which includes the provision of HIV postexposure prophylaxis (PEP), vary, and service delivery data are lacking. We describe GBV clinical service delivery in 15 countries supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control and Prevention. Through a descriptive statistical analysis of PEPFAR Monitoring, Evaluation, and Reporting (MER) data, we found a 252% increase in individuals receiving GBV clinical services, from 158,691 in 2017 to 558,251 in 2021. PEP completion was lowest (15%) among 15-19-year-olds. Understanding GBV service delivery is important for policy makers, program managers, and providers to guide interventions to improve the quality of service delivery and contribute to HIV epidemic control.

The natural history of cystic fibrosis liver disease a prospective cohort study.

BACKGROUND: Our understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. AIM: to determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). METHODS: The Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) RESULTS: 480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99-10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD. During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59-12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44-3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77-1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. CONCLUSION: The incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children.

Strengthening health system's capacity for linkage to HIV care for adolescent girls and young women and adolescent boys and young men in South Africa (SheS'Cap-Linkage): Protocol for a mixed methods study in KwaZulu-Natal, South Africa.

INTRODUCTION: Adolescent girls and young women (AGYW) aged 15-24 years and adolescent boys and young men (ABYM) aged 15-34 years represent one of the populations at highest risk for HIV-infection in South Africa. The National Department of Health adopted the universal test and treat (UTT) strategy in 2016, resulting in increases in same-day antiretroviral therapy initiations and linkage to care. Monitoring progress towards attainment of South Africa's 95-95-95 targets amongst AGYW and ABYM relies on high quality data to identify and address gaps in linkage to care. The aim of this study is to describe the current approaches for engaging AGYW and ABYM in the treatment continuum to generate knowledge that can guide efforts to improve linkage to, and retention in, HIV care among these populations in KwaZulu-Natal, South Africa. METHODS AND ANALYSIS: This is a mixed methods study, which will be conducted in uMgungundlovu district of KwaZulu-Natal, over a 24-month period, in 22 purposively selected HIV testing and treatment service delivery points (SDPs). For the quantitative component, a sample of 1100 AGYW aged 15-24 years and ABYM aged 15-35 years old will be recruited into the study, in addition to 231 healthcare providers (HCPs) involved in the implementation of the UTT program. The qualitative component will include 30 participating patients who were successfully linked to care, 30 who were not, and 30 who have never tested for HIV. Key informant interviews will also be conducted with 24 HCPs. Logistic regression will be used to model the primary outcomes on SDP types, while a time to event analysis will be conducted using a Cox regression model and adjusting the standard errors of the hazard ratio for the clustering of participants within SDPs. For qualitative data, a general inductive approach of analysis will be used. DISSEMINATION: Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer reviewed journal articles and research capacity building through research degrees.

Use of Epidemiology Surge Support to Enhance Robustness and Expand Capacity of SARS-CoV-2 Pandemic Response, South Africa.

As COVID-19 cases increased during the first weeks of the pandemic in South Africa, the National Institute of Communicable Diseases requested assistance with epidemiologic and surveillance expertise from the US Centers for Disease Control and Prevention South Africa. By leveraging its existing relationship with the National Institute of Communicable Diseases for >2 months, the US Centers for Disease Control and Prevention South Africa supported data capture and file organization, data quality reviews, data analytics, laboratory strengthening, and the development and review of COVID-19 guidance This case study provides an account of the resources and the technical, logistical, and organizational capacity leveraged to support a rapid response to the COVID-19 pandemic in South Africa.

Stream Hydrology Controls the Longitudinal Bioreactive Footprint of Urban-Sourced Fine Particles.

The relevance of wastewater treatment plant (WWTP) effluents in fluvial networks is increasing as urbanization grows in catchments. Urban-sourced fine particles from WWTP effluents deposit and accumulate in the streambed sediment of receiving streams over time and can fuel respiration rates, which can thus potentially increase rates of biogeochemical reactions and CO2 emissions to the atmosphere. We aimed to provide a quantitative assessment of the influence of WWTP-sourced fine particles deposited in the streambed sediment on stream metabolic activity for 1 year in an intermittent Mediterranean stream. More nutrient-rich and metabolically active fine particle standing stocks were observed downstream of the WWTP, propagating to the end of the 820 m study reach, especially during the dry period (i.e., when the dilution capacity of the stream to WWTP inputs is <40%). Based on the longitudinal patterns of fine particle standing stocks and their metabolic activity, we estimated that the in-stream bioreactive capacity associated with these fine particles could potentially lead to substantial carbon dioxide emissions to the atmosphere (3.1 g C/m2/d). We show the importance of incorporating fine particle standing stocks downstream of point source inputs, particularly WWTPs in intermittent streams, into carbon budgets.

Strengthening health system's capacity for pre-exposure prophylaxis for adolescent girls and young women and adolescent boys and young men in South Africa (SHeS'Cap-PrEP): Protocol for a mixed methods study in KwaZulu-Natal, South Africa.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) is an effective prevention intervention that can be used to control HIV incidence especially among people who are at increased risk for HIV such as adolescent girls and young women (AGYW) and adolescent boys and young men (ABYM). In South Africa, various approaches of delivering PrEP have been adopted at different service delivery points (facility-based only, school-based only, community-based only and hybrid school-facility and community-facility models) to overcome challenges associated with individual, structural, and health systems related barriers that may hinder access to and uptake of PrEP among these populations. However, little is known about how to optimize PrEP implementation and operational strategies to achieve high sustained uptake of good quality services for AGYW and ABYM. This study aims to identify effective and feasible PrEP models of care for improving PrEP uptake, continuation, and adherence among AGYW and ABYM. METHODS AND ANALYSIS: A sequential explanatory mixed-methods study will be conducted in 22 service delivery points (SDPs) in uMgungundlovu district, KwaZulu-Natal, South Africa. We will recruit 600 HIV negative, sexually active, high risk, AGYW (aged 15-24 years) and ABYM (aged 15-35 years). Enrolled participants will be followed up at 1-, 4- and 7-months to determine continuation and adherence to PrEP. We will conduct two focus group discussions (with 8 participants in each group) across four groups (i. Initiated PrEP within 1 month, ii. Did not initiate PrEP within 1 month, iii. Continued PrEP at 4/7 months and iv. Did not continue PrEP at 4/7 months) and 48 in-depth interviews from each of the four groups (12 per group). Twelve key informant interviews with stakeholders working in HIV programs will also be conducted. Associations between demographic characteristics stratified by PrEP initiation and by various service-delivery models will be assessed using Chi-square/Fishers exact tests or t-test/Mann Whitney test. A general inductive approach will be used to analyze the qualitative data. ETHICS AND DISSEMINATION: The protocol was approved by the South African Medical Research Council Health Research Ethics Committee (EC051-11/2020). Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer-reviewed journal articles and research capacity building through research degrees.

Microplastic accumulation in riverbed sediment via hyporheic exchange from headwaters to mainstems.

In rivers, small and lightweight microplastics are transported downstream, but they are also found frequently in riverbed sediment, demonstrating long-term retention. To better understand microplastic dynamics in global rivers from headwaters to mainstems, we developed a model that includes hyporheic exchange processes, i.e., transport between surface water and riverbed sediment, where microplastic retention is facilitated. Our simulations indicate that the longest microplastic residence times occur in headwaters, the most abundant stream classification. In headwaters, residence times averaged 5 hours/km but increased to 7 years/km during low-flow conditions. Long-term accumulation for all stream classifications averaged ~5% of microplastic inputs per river kilometer. Our estimates isolated the impact of hyporheic exchange processes, which are known to influence dynamics of naturally occurring particles in streams, but rarely applied to microplastics. The identified mechanisms and time scales for small and lightweight microplastic accumulation in riverbed sediment reveal that these often-unaccounted components are likely a pollution legacy that is crucial to include in global assessments.

Impact of comorbidities on atrial fibrillation and sudden cardiac death in hypertrophic cardiomyopathy.

BACKGROUND: The impact of comorbid disease states on the development of atrial and ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) remains unresolved. OBJECTIVE: Evaluate the association of comorbidities linked to arrhythmias in other cardiovascular diseases (e.g., obesity, systemic hypertension, diabetes, obstructive sleep apnea, renal disorders, tobacco, and alcohol use) to atrial fibrillation (AF) and sudden cardiac death (SCD) events in a large cohort of HCM patients. METHODS: A total  of 2269 patients, 54 ± 15 years of age, 1392 males, were evaluated at the Tufts HCM Institute between 2004 and 2018 and followed for an average of 4 ± 3 years for new-onset clinical AF and SCD events (appropriate defibrillation for ventricular tachyarrhythmias, resuscitated cardiac arrest, or SCD). RESULTS: One or more comorbidity was present in 75% of HCM patients, including 50% with ≥2 comorbidities, most commonly obesity (body mass index [BMI] ≥ 30 kg/m2 ) in 43%. New-onset atrial fibrillation developed in 11% of our cohort (2.6%/year). On univariate analysis, obesity was associated with a 1.7-fold increased risk for AF (p = .03) with 12% of obese patients developing AF (3.3%/year) as compared to 7% of patients with BMI < 25 kg/m2 (1.6%/year; p = .006). On multivariate analysis, age and LA transverse dimension emerged as the only variables predictive of AF. Comorbidities, including obesity, were not independently associated with AF development (p > .10 for each). SCD events occurred in 3.3% of patients (0.8%/year) and neither obesity nor other comorbidities were associated with increased risk for SCD (p > .10 for each). CONCLUSIONS: In adult HCM patients comorbidities do not appear to impact AF or SCD risk. Therefore, for most patients with HCM, adverse disease related events of AF and SCD appear to be primarily driven by underlying left ventricular and atrial myopathy as opposed to comorbidities.

Development and Validation of a Clinical Predictive Model for Identifying Hypertrophic Cardiomyopathy Patients at Risk for Atrial Fibrillation: The HCM-AF Score.

[Figure: see text].

Gathering at the top? Environmental controls of microplastic uptake and biomagnification in freshwater food webs.

Microplastics are ubiquitous in the environment, with high concentrations being detected now also in river corridors and sediments globally. Whilst there has been increasing field evidence of microplastics accumulation in the guts and tissues of freshwater and marine aquatic species, the uptake mechanisms of microplastics into freshwater food webs, and the physical and geological controls on pathway-specific exposures to microplastics, are not well understood. This knowledge gap is hampering the assessment of exposure risks, and potential ecotoxicological and public health impacts from microplastics. This review provides a comprehensive synthesis of key research challenges in analysing the environmental fate and transport of microplastics in freshwater ecosystems, including the identification of hydrological, sedimentological and particle property controls on microplastic accumulation in aquatic ecosystems. This mechanistic analysis outlines the dominant pathways for exposure to microplastics in freshwater ecosystems and identifies potentially critical uptake mechanisms and entry pathways for microplastics and associated contaminants into aquatic food webs as well as their risk to accumulate and biomagnify. We identify seven key research challenges that, if overcome, will permit the advancement beyond current conceptual limitations and provide the mechanistic process understanding required to assess microplastic exposure, uptake, hazard, and overall risk to aquatic systems and humans, and provide key insights into the priority impact pathways in freshwater ecosystems to support environmental management decision making.

Diagnostic and treatment utility of echocardiography in the management of the cardiac patient.

BACKGROUND: Echocardiograms are an incredibly useful diagnostic tool due to their lack of harmful radiation, the relative ease and speed with which they can be performed, and their almost ubiquitous availability. Unfortunately, the advantages that support the use of echocardiography can also lead to the overuse of this technology. We sought to evaluate the physician perceived impact echocardiography has on patient management. AIM: To evaluate the physician perceived impact echocardiography has on patient management. METHODS: Surveys were distributed to the ordering physician for echocardiograms performed at our institution over a 10-wk period. Only transthoracic echocardiograms performed on the inpatient service were included. Surveys were distributed to either the attending physician or the resident physician listed on the echocardiogram order. The information requested in the survey focused on the indication for the study and the perceived importance and effect of the study. Observational statistical analysis was performed on all of the answers from the collected surveys. RESULTS: A total of 103 surveys were obtained and analyzed. The internal medicine (57%) and cardiology (37%) specialties ordered the most echocardiograms. The most common reason for ordering an echocardiogram was to rule out a diagnosis (38.2%). Only 27.5% of physicians reported that the echocardiogram significantly affected patient care, with 18.6% reporting a moderate effect, and 30.4% reporting a mild effect. A total of 19.6% of physicians stated that there was no effect on patient management. Additionally, 43.1% of physicians reported that they made changes in patient management due to no change having occurred in the disease, 11.8% reported that changes in management were based on the recommendation of a specialist, and only 9.8% reported that further imaging was ordered due to the results of the echocardiogram. The majority of physicians (67.6%) considered an echocardiogram to be "somewhat essential" in the management of adult inpatients, with only 15.7% considering it "essential". CONCLUSION: The majority of physicians surveyed report the echocardiogram had only a mild effect on management with only 27.5% reporting a significant effect. However, the majority of physicians (83.3%) perceived an echocardiogram to be somewhat or entirely essential for management. Only 9.8% reported the echo led to further imaging. These insights into ordering physician reasoning should help guide better definition of the optimal and ideal use of echocardiography.

Repeatability of transient elastography in children.

BACKGROUND: Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children. METHODS: TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination. RESULTS: The normal range of TE was 2.88-6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from -0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups. CONCLUSIONS: This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements. IMPACT: The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted. TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease. This study demonstrates that TE does not have adequate precision in children. This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

Wastewater treatment plant effluent inputs induce large biogeochemical changes during low flows in an intermittent stream but small changes in day-night patterns.

Wastewater treatment plant (WWTP) effluents alter stream water chemistry and metabolic activity. Yet, essential aspects influencing the biogeochemical response of receiving streams such as hydrology and diel oscillations of light and temperature remain largely unexplored. We measured day vs night water chemistry and in-stream net nutrient uptake velocity (Vf) in an intermittent forested stream, upstream and downstream of a WWTP effluent under contrasting hydrological conditions. The WWTP effluent negatively influenced stream water chemistry, especially during the dry period. Despite large diel oscillations in light inputs, day-night differences in nutrient and oxygen concentrations were small, suggesting that heterotrophic respiration drove stream metabolism with a minor contribution of gross primary production. The magnitude of Vf was similar between day and night at the two reaches. Yet, at the downstream reach, in-stream net DIN uptake occurred more often at night, and values of Vf for ammonia and nitrite indicated enhanced in-stream nitrification. The two reaches showed a small capacity to retain DIN and soluble reactive phosphorus from the water column. Positive values of in-stream net nutrient uptake (i.e. uptake > release) occurred mostly during the dry period, highlighting that in-stream biogeochemical processing can contribute to improve water quality in streams receiving point-sources effluents in regions with low water availability.

The method controls the story - Sampling method impacts on the detection of pore-water nitrogen concentrations in streambeds.

Biogeochemical gradients in streambeds are steep and can vary over short distances often making adequate characterisation of sediment biogeochemical processes challenging. This paper provides an overview and comparison of streambed pore-water sampling methods, highlighting their capacity to address gaps in our understanding of streambed biogeochemical processes. This work reviews and critiques available pore-water sampling techniques to characterise streambed biogeochemical conditions, including their characteristic spatial and temporal resolutions, and associated advantages and limitations. A field study comparing three commonly-used pore-water sampling techniques (multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gels) was conducted to assess differences in observed nitrate and ammonium concentration profiles. Pore-water nitrate concentrations did not differ significantly between sampling methods (p-value = 0.54) with mean concentrations of 2.53, 4.08 and 4.02 mg l-1 observed with the multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gel samplers, respectively. Pore-water ammonium concentrations, however, were significantly higher in pore-water extracted by multilevel mini-piezometers (3.83 mg l-1) and significantly lower where sampled with miniature drivepoint samplers (1.05 mg l-1, p-values <0.01). Differences in observed pore-water ammonium concentration profiles between active (suction: multilevel mini-piezometers) and passive (equilibrium; diffusive equilibrium in thin-film gels) samplers were further explored under laboratory conditions. Measured pore-water ammonium concentrations were significantly greater when sampled by diffusive equilibrium in thin-film gels than with multilevel mini-piezometers (all p-values ≤0.02). The findings of this study have critical implications for the interpretation of field-based research on hyporheic zone biogeochemical cycling and highlight the need for more systematic testing of sampling protocols. For the first time, the impact of different active and passive pore-water sampling methods is addressed systematically here, highlighting to what degree the choice of pore-water sampling methods affects research outcomes, with relevance for the interpretation of previously published work as well as future studies.

Cervical cancer data and data systems in limited-resource settings: Challenges and opportunities.

Appropriate collection and use of health information is critical to the planning, scaling up, and improvement of cervical cancer programs. The health information systems implementation landscape is unique to each country; however, systems serving cervical cancer programs in low-resource settings share characteristics that present common challenges. In response, many programs have taken innovative approaches to generating the quality information needed for decision making. Recent advances in health information technology also provide feasible solutions to challenges. This article draws from the experiences of the authors and from current literature to describe outstanding challenges and promising practices in the implementation of cervical cancer data systems, and to make recommendations for next steps. Recommendations include engaging all stakeholders-including providers, program managers, implementing partners, and donors-in promoting national, district, and community information systems; building on existing systems and processes, as well as introducing new technologies; and evolving data collection and data systems as programs advance.

Parenting for the promotion of adolescent mental health: a scoping review of programmes targeting ethnoculturally diverse families.

A scoping review of the literature on parenting programmes that target the promotion of adolescent mental health was conducted to examine the quality of the studies and unique content of programmes for parents from ethnoculturally diverse communities. PsycINFO and Web of Science were searched in April, 2011 (for all publications prior to that date) and again in August, 2015 (for publications from April, 2011 to August, 2015) using specific keywords and inclusion criteria. A hand search was also conducted. Overall, 107 studies met inclusion criteria for final data extraction and included evaluations of interventions targeted at substance use, early/risky sexual activity and behavioural problems. Eighteen of the 107 studies described programmes targeting parents of adolescents from diverse ethnocultural communities; the quality of these 18 studies was assessed using a marginally modified version of the Downs and Black Checklist (Downs & Black 1998). Their average quality assessment score was 16 out of 28. In addition, two key themes reflected in successful interventions emerged: strengthening parent-adolescent relationship through communication, and importance of community engagement in designing and implementing the intervention. Findings indicate gaps in service delivery to parents of adolescents from ethnoculturally diverse communities; there are a limited number of studies on programmes targeting ethnoculturally diverse parents of adolescents, and the quality of studies that do exist is overall low. Given increasing diversity, more emphasis should be placed on developing and modifying programmes to meet the needs of ethnoculturally diverse communities. More rigorous, standardised efforts should be made to evaluate programmes that do exist.

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.