African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Decoding the synergistic potential of MAZ-51 and zingerone as therapy for melanoma treatment in alignment with sustainable development goals.

Melanoma, an invasive class of skin cancer, originates from mutations in melanocytes, the pigment-producing cells. Globally, approximately 132,000 new cases are reported each year, and in South Africa, the incidence stands at 2.7 per 100,000 people, signifying a worrisome surge in melanoma rates. Therefore, there is a need to explore treatment modalities that will target melanoma's signalling pathways. Melanoma metastasis is aided by ligand activity of transforming growth factor-beta 1 (TGF-ß1), vascular endothelial growth factor-C (VEGF-C) and C-X-C chemokine ligand 12 (CXCL12) which bind to their receptors and promote tumour cell survival, lymphangiogenesis and chemotaxis. (3-(4-dimethylaminonaphthelen-1-ylmethylene)-1,3-dihydroindol-2-one) MAZ-51 is an indolinone-based molecule that inhibits VEGF-C induced phosphorylation of vascular endothelial growth factor receptor 3 (VEGFR-3). Despite the successful use of conventional cancer therapies, patients endure adverse side effects and cancer drug resistance. Moreover, conventional therapies are toxic to the environment and caregivers. The use of medicinal plants and their phytochemical constituents in cancer treatment strategies has become more widespread because of the rise in drug resistance and the development of unfavourable side effects. Zingerone, a phytochemical derived from ginger exhibits various pharmacological properties positioning it as a promising candidate for cancer treatment. This review provides an overview of melanoma biology and the intracellular signalling pathways promoting cell survival, proliferation and adhesion. There is a need to align health and environmental objectives within sustainable development goals 3 (good health and well-being), 13 (climate action) and 15 (life on land) to promote early detection of skin cancer, enhance sun-safe practices, mitigation of environmental factors and advancing the preservation of biodiversity, including medicinal plants. Thus, this review discusses the impact of cytostatic cancer drugs on patients and the environment and examines the potential use of phytochemicals as adjuvant therapy.

Household living conditions and individual behaviours associated with malaria risk: a community-based survey in the Limpopo River Valley, 2020, South Africa.

BACKGROUND: Over the past decade, implementation of multiple malaria control strategies in most countries has largely contributed to advance the global malaria elimination agenda. Nevertheless, in some regions, seasonal epidemics may adversely affect the health of local populations. In South Africa, Plasmodium falciparum malaria is still present, with the Vhembe District experiencing an incidence rate of 3.79 cases/1000 person-years in 2018, particularly in the Limpopo River Valley, bordering Zimbabwe. To elucidate the complexity of the mechanisms involved in local regular malaria outbreaks, a community-based survey was implemented in 2020 that focused on the relationship between housing conditions and malaria risky behaviours. METHODS: The community-based cross-sectional survey was conducted among the population of three study sites in the Vhembe District, which were selected based on malaria incidence rate, social and health characteristics of inhabitants. The household survey used a random sampling strategy, where data were collected through face-to-face questionnaires and field notes; to described the housing conditions (housing questionnaire), and focus on individual behaviours of household members. Statistical analyses were performed combining hierarchical classifications and logistic regressions. RESULTS: In this study, 398 households were described, covering a population of 1681 inhabitants of all ages, and 439 adults who participated in community-based survey. The analysis of situations at risk of malaria showed that the influence of contextual factors, particularly those defined by the type of habitat, was significant. Housing conditions and poor living environments were factors of malaria exposure and history, regardless of site of investigation, individual preventive behaviours and personal characteristics of inhabitants. Multivariate models showed that, considering all personal characteristics or behaviours of inhabitants, housing conditions such as overcrowding pressures were significantly associated with individual malaria risk. CONCLUSIONS: The results showed the overwhelming weight of social and contextual factors on risk situations. Considering the Fundamental Causes Theory, malaria control policies based on health behaviour prevention, should reinforce access to care or promoting health education actions. Overarching economic development interventions in targeted geographical areas and populations have to be implemented, so that malaria control and elimination strategies can be efficiently and effectively managed.

Cumulative Incidence of SARS-CoV-2 Infections Among Adults in Georgia, United States, August to December 2020.

BACKGROUND: Reported coronavirus disease 2019 (COVID-19) cases underestimate true severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Data on all infections, including asymptomatic infections, are needed. To minimize biases in estimates from reported cases and seroprevalence surveys, we conducted a household-based probability survey and estimated cumulative incidence of SARS-CoV-2 infections adjusted for antibody waning. METHODS: From August to December 2020, we mailed specimen collection kits (nasal swabs and blood spots) to a random sample of Georgia addresses. One household adult completed a survey and returned specimens for virus and antibody testing. We estimated cumulative incidence of SARS-CoV-2 infections adjusted for waning antibodies, reported fraction, and infection fatality ratio (IFR). Differences in seropositivity among demographic, geographic, and clinical subgroups were explored with weighted prevalence ratios (PR). RESULTS: Among 1370 participants, adjusted cumulative incidence of SARS-CoV-2 was 16.1% (95% credible interval [CrI], 13.5%-19.2%) as of 16 November 2020. The reported fraction was 26.6% and IFR was 0.78%. Non-Hispanic black (PR, 2.03; 95% confidence interval [CI], 1.0-4.1) and Hispanic adults (PR, 1.98; 95% CI, .74-5.31) were more likely than non-Hispanic white adults to be seropositive. CONCLUSIONS: As of mid-November 2020, 1 in 6 adults in Georgia had been infected with SARS-CoV-2. The COVID-19 epidemic in Georgia is likely substantially underestimated by reported cases.

Severe Acute Respiratory Syndrome Coronavirus 2 Cumulative Incidence, United States, August 2020-December 2020.

BACKGROUND: Reported coronavirus disease 2019 (COVID-19) cases underestimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We conducted a national probability survey of US households to estimate cumulative incidence adjusted for antibody waning. METHODS: From August-December 2020 a random sample of US addresses were mailed a survey and self-collected nasal swabs and dried blood spot cards. One adult household member completed the survey and mail specimens for viral detection and total (immunoglobulin [Ig] A, IgM, IgG) nucleocapsid antibody by a commercial, emergency use authorization-approved antigen capture assay. We estimated cumulative incidence of SARS-CoV-2 adjusted for waning antibodies and calculated reported fraction (RF) and infection fatality ratio (IFR). Differences in seropositivity among demographic, geographic, and clinical subgroups were explored. RESULTS: Among 39 500 sampled households, 4654 respondents provided responses. Cumulative incidence adjusted for waning was 11.9% (95% credible interval [CrI], 10.5%-13.5%) as of 30 October 2020. We estimated 30 332 842 (CrI, 26 703 753-34 335 338) total infections in the US adult population by 30 October 2020. RF was 22.3% and IFR was 0.85% among adults. Black non-Hispanics (Prevalence ratio (PR) 2.2) and Hispanics (PR, 3.1) were more likely than White non-Hispanics to be seropositive. CONCLUSIONS: One in 8 US adults had been infected with SARS-CoV-2 by October 2020; however, few had been accounted for in public health reporting. The COVID-19 pandemic is likely substantially underestimated by reported cases. Disparities in COVID-19 by race observed among reported cases cannot be attributed to differential diagnosis or reporting of infections in population subgroups.

What will it take to meet UNAIDS targets for preexposure prophylaxis users?

PURPOSE OF REVIEW: Preexposure prophylaxis (PrEP) is a critical strategy to curb new HIV infections globally. National and global targets have been set for people starting PrEP. However, global PrEP initiations fell short of UNAIDS 2020 targets, and reflection is needed on how we set and meet targets for PrEP use. RECENT FINDINGS: Recent literature documents challenges to meeting ambitious goals for PrEP coverage in multiple phases of PrEP: PrEP initiations are limited by gaps in the identification of those who might benefit from PrEP. Conversely, getting PrEP to those who need it most is threatened by inaccurate risk perception and HIV and PrEP stigma. Once people are on PrEP, a substantial number discontinue PrEP in the first year (the 'PrEP Cliff'), a finding that is robust across groups of PrEP users (e.g., women, men who have sex with men, transwomen) and across global prevention settings. Further, PrEP inequities - by which we refer to utilization of PrEP in a specific group that is not commensurate with their epidemic risk - threaten the overall population benefit of PrEP because those at highest risk of acquiring HIV are not adequately protected. SUMMARY: To realize global goals for PrEP utilization and impact, we must address multiple points of PrEP delivery programs that address not just PrEP starts, but also retention in PrEP and measurement and accountability to PrEP equity. We call for new approaches to better identify PrEP candidates, suggest additional research to address the known and consistent reasons for PrEP discontinuations, and advocate for metrics to measure and be accountable to PrEP equity.

Cross-sectional assessment of determinants of STIs among men who have sex with men and transgender women in Kigali, Rwanda.

BACKGROUND: STIs among men who have sex with men (MSM) and transgender women (TGW) continue to increase. In Rwanda, STI management relies on syndromic management with limited empirical data characterising the burden of specific STIs among MSM/TGW. This study evaluated the prevalence of syphilis, Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) and associated factors among MSM/TGW in Kigali. METHODS: From March to August 2018, 737 MSM/TGW >18 years were enrolled using respondent-driven sampling (RDS). Structured interviews and HIV/STI screening were conducted. Syphilis was screened with rapid plasma reagin confirmed by Treponema pallidum hemagglutination assay. CT/NG were tested by Cepheid GeneXpert. RDS-adjusted multivariable Poisson regression models with robust variance estimation were used to evaluate factors associated with any STI, and determinants of urethral and rectal STIs separately. RESULTS: Prevalence of any STI was 20% (RDS adjusted: 16.7% (95% CI: 13.2% to 20.2%)). Syphilis was 5.7% (RDS adjusted: 6.8% (95% CI: 4.3% to 9.4%)). CT was 9.1% (RDS adjusted: 6.1% (95% CI: 3.9% to 8.4%)) and NG was 8.8% (RDS adjusted: 7.1% (95% CI: 4.9% to 9.2%)). STIs were more common among older MSM and those with HIV (p<0.05). Of CT infections, 67% were urethral, 27% rectal and 6% were dual site. For NG infections, 52% were rectal, 29% urethral and 19% were dual site. Overall, 25.8% (23 of 89) of those with confirmed STI and returned for their results were symptomatic at time of testing.STI symptoms in the previous year (adjusted prevalence ratio (aPR): 1.94 (95% CI: 1.26 to 2.98)) were positively associated with any STI. Being circumcised was negatively associated with any STI (aPR: 0.47 (95% CI: 0.31 to 0.73)). HIV was positively associated with rectal STIs (aPR: 3.50 (95% CI: 1.09 to 11.21)) but negatively associated with urethral STIs. CONCLUSION: MSM/TGW, especially those living with HIV, are at high risk of STIs in Rwanda with the vast majority being asymptomatic. These data suggest the potential utility of active STI surveillance strategies using highly sensitive laboratory methods among those at high risk given the anatomical distribution and limited symptomatology of STIs observed among Rwandan MSM/TGW.

Behavioral Efficacy of a Sexual Health Mobile App for Men Who Have Sex With Men: Randomized Controlled Trial of Mobile Messaging for Men.

BACKGROUND: Gay, bisexual, and other men who have sex with men (GBMSM) face the highest burden of HIV in the United States, and there is a paucity of efficacious mobile health (mHealth) HIV prevention and care interventions tailored specifically for GBMSM. We tested a mobile app combining prevention messages and access to core prevention services for GBMSM. OBJECTIVE: This study aims to measure the efficacy of the Mobile Messaging for Men (M-cubed) app and related services to increase HIV prevention and care behaviors in diverse US GBMSM. METHODS: We conducted a randomized open-label study with a waitlist control group among GBMSM in 3 groups (low-risk HIV-negative group, high-risk HIV-negative group, and living-with-HIV [LWH] group) recruited online and in venues in Atlanta, Detroit, and New York City. Participants were randomly assigned to receive access to the app immediately or at 9 months after randomization. The app provided prevention messages in 6 domains of sexual health and offered ordering of at-home HIV and sexually transmitted infection test kits, receiving preexposure prophylaxis (PrEP) evaluations and navigation, and service locators. Serostatus- and risk-specific prevention outcomes were evaluated at baseline, at the end of the intervention period, and at 3, 6, and 9 months after the intervention period. RESULTS: In total, 1226 GBMSM were enrolled and randomized; of these 611 (49.84%) were assigned to the intervention group and 608 (99.51%) were analyzed, while 615 (50.16%) were assigned to the control group and 612 (99.51%) were analyzed. For high-risk GBMSM, allocation to the intervention arm was associated with higher odds of HIV testing during the intervention period (adjusted odds ratio [aOR] 2.02, 95% CI 1.11-3.66) and with higher odds of using PrEP in the 3 months after the intervention period (aOR 2.41, 95% CI 1.00-5.76, P<.05). No changes in HIV prevention or care were associated with allocation to the intervention arm for the low-risk HIV-negative and LWH groups. CONCLUSIONS: Access to the M-cubed app was associated with increased HIV testing and PrEP use among high-risk HIV-negative GBMSM in 3 US cities. The app could be made available through funded HIV prevention providers; additional efforts are needed to understand optimal strategies to implement the app outside of the research setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666247; https://clinicaltrials.gov/ct2/show/NCT03666247. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16439.

A Data Visualization and Dissemination Resource to Support HIV Prevention and Care at the Local Level: Analysis and Uses of the AIDSVu Public Data Resource.

BACKGROUND: AIDSVu is a public resource for visualizing HIV surveillance data and other population-based information relevant to HIV prevention, care, policy, and impact assessment. OBJECTIVE: The site, AIDSVu.org, aims to make data about the US HIV epidemic widely available, easily accessible, and locally relevant to inform public health decision making. METHODS: AIDSVu develops visualizations, maps, and downloadable datasets using results from HIV surveillance systems, other population-based sources of information (eg, US Census and national probability surveys), and other data developed specifically for display and dissemination through the website (eg, pre-exposure prophylaxis [PrEP] prescriptions). Other types of content are developed to translate surveillance data into summarized content for diverse audiences using infographic panels, interactive maps, local and state fact sheets, and narrative blog posts. RESULTS: Over 10 years, AIDSVu.org has used an expanded number of data sources and has progressively provided HIV surveillance and related data at finer geographic levels, with current data resources providing HIV prevalence data down to the census tract level in many of the largest US cities. Data are available at the county level in 48 US states and at the ZIP Code level in more than 50 US cities. In 2019, over 500,000 unique users consumed AIDSVu data and resources, and HIV-related data and insights were disseminated through nearly 4,000,000 social media posts. Since AIDSVu's inception, at least 249 peer-reviewed publications have used AIDSVu data for analyses or referenced AIDSVu resources. Data uses have included targeting of HIV testing programs, identifying areas with inequitable PrEP uptake, including maps and data in academic and community grant applications, and strategically selecting locations for new HIV treatment and care facilities to serve high-need areas. CONCLUSIONS: Surveillance data should be actively used to guide and evaluate public health programs; AIDSVu translates high-quality, population-based data about the US HIV epidemic and makes that information available in formats that are not consistently available in surveillance reports. Bringing public health surveillance data to an online resource is a democratization of data, and presenting information about the HIV epidemic in more visual formats allows diverse stakeholders to engage with, understand, and use these important public health data to inform public health decision making.

Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men.

BACKGROUND: Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high-risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS: Here we reveal through metagenomic analysis of host-derived whole-genome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS: We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6-5.5; P = .0004-.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS: Our study provides suggestive evidence for the presence of a core, bacteria-rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non-African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially-driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.

TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: A focus on Africa.

BACKGROUND: The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce. METHODS: RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing. RESULTS: Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates. CONCLUSIONS: Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.

Diagnostic Accuracy and Financial Implications of Age-Adjusted D-Dimer Strategies for the Diagnosis of Deep Venous Thrombosis in the Emergency Department.

BACKGROUND: Multiple D-dimer cutoffs have been suggested for older patients to improve diagnostic specificity for venous thromboembolism. These approaches are better established for pulmonary embolism. OBJECTIVES: We evaluated the diagnostic performance and compared the health system cost for previously suggested cutoffs and a new D-dimer cutoff for low-risk emergency department (ED) deep venous thrombosis (DVT) patients. METHODS: We conducted a retrospective cohort study in two large EDs involving patients aged > 50 years who had low pretest probability for DVT and had a D-dimer performed. The outcome was a diagnosis of DVT at 30 days. We evaluated the diagnostic accuracy and estimated the difference in cost for cutoffs of 500 ng/mL and the age-adjusted (age × 10) rule. A derived cutoff of 1000 ng/mL was also assessed. RESULTS: Nine hundred and seventy-two patients were included (median age 66 years; 59.5% female); 63 (6.5%) patients were diagnosed with DVT. The conventional cutoff of < 500 ng/mL demonstrated a sensitivity of 100% (95% confidence interval [CI] 94.3-100%) and a specificity of 35.6% (95% CI 32.5-38.8%). The age-adjusted approach increased specificity while maintaining high sensitivity. A new cutoff of 1000 ng/mL demonstrated improved performance: sensitivity 100% (95% CI 94.3-00%) and specificity 66.3% (95% CI 63.2-69.4%). Compared to the conventional approach, both the 1000 ng/mL cutoff and the age-adjusted cutoffs could save healthcare dollars. A cutoff of 1000 ng/mL could have saved 310 ED length of stay hours and $166,909 (Canadian dollars) in our cohort, or an average savings of 0.32 h and $172 per patient. CONCLUSIONS: Among patients aged > 50 years with suspected DVT, the age-adjusted D-dimer and a cutoff of 1000 ng/mL improved specificity without compromising sensitivity, and lowered the health care system cost compared to that for the conventional approach.

Estimated Number of Injection-Involved Overdose Deaths in US States From 2000 to 2020: Secondary Analysis of Surveillance Data.

BACKGROUND: In the United States, both drug overdose mortality and injection-involved drug overdose mortality have increased nationally over the past 25 years. Despite documented geographic differences in overdose mortality and substances implicated in overdose mortality trends, injection-involved overdose mortality has not been summarized at a subnational level. OBJECTIVE: We aimed to estimate the annual number of injection-involved overdose deaths in each US state from 2000 to 2020. METHODS: We conducted a stratified analysis that used data from drug treatment admissions (Treatment Episodes Data Set-Admissions; TEDS-A) and the National Vital Statistics System (NVSS) to estimate state-specific percentages of reported drug overdose deaths that were injection-involved from 2000 to 2020. TEDS-A collects data on the route of administration and the type of substance used upon treatment admission. We used these data to calculate the percentage of reported injections for each drug type by demographic group (race or ethnicity, sex, and age group), year, and state. Additionally, using NVSS mortality data, the annual number of overdose deaths involving selected drug types was identified by the following specific multiple-cause-of-death codes: heroin or synthetic opioids other than methadone (T40.1, T40.4), natural or semisynthetic opioids and methadone (T40.2, T40.3), cocaine (T40.5), psychostimulants with abuse potential (T43.6), sedatives (T42.3, T42.4), and others (T36-T59.0). We used the probabilities of injection with the annual number of overdose deaths, by year, primary substance, and demographic groups to estimate the number of overdose deaths that were injection-involved. RESULTS: In 2020, there were 91,071 overdose deaths among adults recorded in the United States, and 93.1% (84,753/91,071) occurred in the 46 jurisdictions that reported data to TEDS-A. Slightly less than half (38,253/84,753, 45.1%; 95% CI 41.1%-49.8%) of those overdose deaths were estimated to be injection-involved, translating to 38,253 (95% CI 34,839-42,181) injection-involved overdose deaths in 2020. There was large variation among states in the estimated injection-involved overdose death rate (median 14.72, range 5.45-31.77 per 100,000 people). The national injection-involved overdose death rate increased by 323% (95% CI 255%-391%) from 2010 (3.78, 95% CI 3.33-4.31) to 2020 (15.97, 95% CI 14.55-17.61). States in which the estimated injection-involved overdose death rate increased faster than the national average were disproportionately concentrated in the Northeast region. CONCLUSIONS: Although overdose mortality and injection-involved overdose mortality have increased dramatically across the country, these trends have been more pronounced in some regions. A better understanding of state-level trends in injection-involved mortality can inform the prioritization of public health strategies that aim to reduce overdose mortality and prevent downstream consequences of injection drug use.

AIDSVu Cities' Progress Toward HIV Care Continuum Goals: Cross-Sectional Study.

BACKGROUND: Public health surveillance data are critical to understanding the current state of the HIV and AIDS epidemics. Surveillance data provide significant insight into patterns within and progress toward achieving targets for each of the steps in the HIV care continuum. Such targets include those outlined in the National HIV/AIDS Strategy (NHAS) goals. If these data are disseminated, they can be used to prioritize certain steps in the continuum, geographic locations, and groups of people. OBJECTIVE: We sought to develop and report indicators of progress toward the NHAS goals for US cities and to characterize progress toward those goals with categorical metrics. METHODS: Health departments used standardized SAS code to calculate care continuum indicators from their HIV surveillance data to ensure comparability across jurisdictions. We report 2018 descriptive statistics for continuum steps (timely diagnosis, linkage to medical care, receipt of medical care, and HIV viral load suppression) for 36 US cities and their progress toward 2020 NHAS goals as of 2018. Indicators are reported categorically as met or surpassed the goal, within 25% of attaining the goal, or further than 25% from achieving the goal. RESULTS: Cities were closest to meeting NHAS goals for timely diagnosis compared to the goals for linkage to care, receipt of care, and viral load suppression, with all cities (n=36, 100%) within 25% of meeting the goal for timely diagnosis. Only 8% (n=3) of cities were >25% from achieving the goal for receipt of care, but 69% (n=25) of cities were >25% from achieving the goal for viral suppression. CONCLUSIONS: Display of progress with graphical indicators enables communication of progress to stakeholders. AIDSVu analyses of HIV surveillance data facilitate cities' ability to benchmark their progress against that of other cities with similar characteristics. By identifying peer cities (eg, cities with analogous populations or similar NHAS goal concerns), the public display of indicators can promote dialogue between cities with comparable challenges and opportunities.

The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome-a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men.

BACKGROUND: The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) accumulates in marine mammals and fish. DDT and p,p'-DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome. OBJECTIVES: The objective of this study was to assess the sperm epigenome in relation to p,p'-DDE serum levels between geographically diverse populations. METHODS: In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of p,p'-DDE serum levels (mean=870.734±134.030 ng/mL). We assessed the sperm epigenome in relation to serum p,p'-DDE levels using MethylC-Capture-sequencing (MCC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. RESULTS: Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression. DISCUSSION: These findings suggest that DDT and p,p'-DDE exposure impacts the sperm epigenome in a dose-response-like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013.

Alterations in the Epigenetic Machinery Associated with Prostate Cancer Health Disparities.

Prostate cancer is driven by acquired genetic alterations, including those impacting the epigenetic machinery. With African ancestry as a significant risk factor for aggressive disease, we hypothesize that dysregulation among the roughly 656 epigenetic genes may contribute to prostate cancer health disparities. Investigating prostate tumor genomic data from 109 men of southern African and 56 men of European Australian ancestry, we found that African-derived tumors present with a longer tail of epigenetic driver gene candidates (72 versus 10). Biased towards African-specific drivers (63 versus 9 shared), many are novel to prostate cancer (18/63), including several putative therapeutic targets (CHD7, DPF3, POLR1B, SETD1B, UBTF, and VPS72). Through clustering of all variant types and copy number alterations, we describe two epigenetic PCa taxonomies capable of differentiating patients by ancestry and predicted clinical outcomes. We identified the top genes in African- and European-derived tumors representing a multifunctional "generic machinery", the alteration of which may be instrumental in epigenetic dysregulation and prostate tumorigenesis. In conclusion, numerous somatic alterations in the epigenetic machinery drive prostate carcinogenesis, but African-derived tumors appear to achieve this state with greater diversity among such alterations. The greater novelty observed in African-derived tumors illustrates the significant clinical benefit to be derived from a much needed African-tailored approach to prostate cancer healthcare aimed at reducing prostate cancer health disparities.

Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods.

BACKGROUND: HIV incidence estimates are published each year for all Ending the HIV Epidemic (EHE) counties, but they are not stratified by the demographic variables highly associated with risk of infection. Regularly updated estimates of HIV incident diagnoses available at local levels are required to monitor the epidemic in the United States over time and could contribute to background incidence rate estimates for alternative clinical trial designs for new HIV prevention products. OBJECTIVE: We describe methods using existing, robust data sources within areas in the United States to reliably estimate longitudinal HIV incident diagnoses stratified by race and age categories among men who have sex with other men (MSM) eligible for pre-exposure prophylaxis (PrEP) but not taking it. METHODS: This is a secondary analysis of existing data sources to develop new estimates of incident HIV diagnoses in MSM. We reviewed past methods used to estimate incident diagnoses and explored opportunities to improve these estimates. We will use existing surveillance data sources and population sizes of HIV PrEP-eligible MSM estimated from population-based data sources (eg, US Census data and pharmaceutical prescription databases) to develop metropolitan statistical area-level estimates of new HIV diagnoses among PrEP-eligible MSM. Required parameters are number of new diagnoses among MSM, estimates of MSM with an indication for PrEP, and prevalent PrEP use including median duration of use; these parameters will be stratified by jurisdiction and age group or race or ethnicity. Preliminary outputs will be available in 2023, and updated estimates will be produced annually thereafter. RESULTS: Data to parameterize new HIV diagnoses among PrEP-eligible MSM are available with varying levels of public availability and timeliness. In early 2023, the most recent available data on new HIV diagnoses were from the 2020 HIV surveillance report, which reports 30,689 new HIV infections in 2020, and 24,724 of them occurred in an MSA with a population of ≥500,000. Updated estimates for PrEP coverage based on commercial pharmacy claims data through February 2023 will be generated. The rate of new HIV diagnoses among MSM can be estimated from new diagnoses within each demographic group (numerator) and the total person-time at risk of diagnosis for each group (denominator) by metropolitan statistical area and year. To estimate time at risk, the person-time of individuals on PrEP or person-time after incident HIV infection but before diagnosis should be removed from stratified population size estimates of the total number of person-years with indications for PrEP. CONCLUSIONS: Reliable, serial, cross-sectional estimates for rates of new HIV diagnoses for MSM with PrEP indications can serve as benchmark community estimates of failures of HIV prevention and opportunities to improve services and will support public health epidemic monitoring and alternative clinical trial designs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42267.

Geo-epidemiology of malaria incidence in the Vhembe District to guide targeted elimination strategies, South-Africa, 2015-2018: a local resurgence.

In South Africa, the population at risk of malaria is 10% (around six million inhabitants) and concern only three provinces of which Limpopo Province is the most affected, particularly in Vhembe District. As the elimination approaches, a finer scale analysis is needed to accelerate the results. Therefore, in the process of refining local malaria control and elimination strategies, the aim of this study was to identify and describe malaria incidence patterns at the locality scale in the Vhembe District, Limpopo Province, South Africa. The study area comprised 474 localities in Vhembe District for which smoothed malaria incidence curve were fitted with functional data method based on their weekly observed malaria incidence from July 2015 to June 2018. Then, hierarchical clustering algorithm was carried out considering different distances to classify the 474 smoothed malaria incidence curves. Thereafter, validity indices were used to determine the number of malaria incidence patterns. The cumulative malaria incidence of the study area was 4.1 cases/1000 person-years. Four distinct patterns of malaria incidence were identified: high, intermediate, low and very low with varying characteristics. Malaria incidence increased across transmission seasons and patterns. The localities in the two highest incidence patterns were mainly located around farms, and along the rivers. Some unusual malaria phenomena in Vhembe District were also highlighted as resurgence. Four distinct malaria incidence patterns were found in Vhembe District with varying characteristics. Findings show also unusual malaria phenomena in Vhembe District that hinder malaria elimination in South Africa. Assessing the factors associated with these unusual malaria phenome would be helpful on building innovative strategies that lead South Africa on malaria elimination.

Prostate cancer genetic risk and associated aggressive disease in men of African ancestry.

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.

Health Information on Pre-Exposure Prophylaxis From Search Engines and Twitter: Readability Analysis.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is proven to prevent HIV infection. However, PrEP uptake to date has been limited and inequitable. Analyzing the readability of existing PrEP-related information is important to understand the potential impact of available PrEP information on PrEP uptake and identify opportunities to improve PrEP-related education and communication. OBJECTIVE: We examined the readability of web-based PrEP information identified using search engines and on Twitter. We investigated the readability of web-based PrEP documents, stratified by how the PrEP document was obtained on the web, information source, document format and communication method, PrEP modality, and intended audience. METHODS: Web-based PrEP information in English was systematically identified using search engines and the Twitter API. We manually verified and categorized results and described the method used to obtain information, information source, document format and communication method, PrEP modality, and intended audience. Documents were converted to plain text for the analysis and readability of the collected documents was assessed using 4 readability indices. We conducted pairwise comparisons of readability based on how the PrEP document was obtained on the web, information source, document format, communication method, PrEP modality, and intended audience, then adjusted for multiple comparisons. RESULTS: A total of 463 documents were identified. Overall, the readability of web-based PrEP information was at a higher level (10.2-grade reading level) than what is recommended for health information provided to the general public (ninth-grade reading level, as suggested by the Department of Health and Human Services). Brochures (n=33, 7% of all identified resources) were the only type of PrEP materials that achieved the target of ninth-grade reading level. CONCLUSIONS: Web-based PrEP information is often written at a complex level for potential and current PrEP users to understand. This may hinder PrEP uptake for some people who would benefit from it. The readability of PrEP-related information found on the web should be improved to align more closely with health communication guidelines for reading level to improve access to this important health information, facilitate informed decisions by those with a need for PrEP, and realize national prevention goals for PrEP uptake and reducing new HIV infections in the United States.