Defining species-specific and conserved interactions of apical membrane protein 1 during erythrocyte invasion in malaria to inform multi-species vaccines.

Plasmodium falciparum and P. vivax are the major causes of human malaria, and P. knowlesi is an important additional cause in SE Asia. Binding of apical membrane antigen 1 (AMA1) to rhoptry neck protein 2 (RON2) was thought to be essential for merozoite invasion of erythrocytes by Plasmodium spp. Our findings reveal that P. falciparum and P. vivax have diverged and show species-specific binding of AMA1 to RON2, determined by a ß-hairpin loop in RON2 and specific residues in AMA1 Loop1E. In contrast, cross-species binding of AMA1 to RON2 is retained between P. vivax and P. knowlesi. Mutation of specific amino acids in AMA1 Loop1E in P. falciparum or P. vivax ablated RON2 binding without impacting erythrocyte invasion. This indicates that the AMA1-RON2-loop interaction is not essential for invasion and additional AMA1 interactions are involved. Mutations in AMA1 that disrupt RON2 binding also enable escape of invasion inhibitory antibodies. Therefore, vaccines and therapeutics will need to be broader than targeting only the AMA1-RON2 interaction. Antibodies targeting AMA1 domain 3 had greater invasion-inhibitory activity when RON2-loop binding was ablated, suggesting this domain is a promising additional target for vaccine development. Targeting multiple AMA1 interactions involved in invasion may enable vaccines that generate more potent inhibitory antibodies and address the capacity for immune evasion. Findings on specific residues for invasion function and species divergence and conservation can inform novel vaccines and therapeutics against malaria caused by three species, including the potential for cross-species vaccines.

Sexually transmitted disease clinics in the United States: Understanding the needs of patients and the capabilities of providers.

Reports of bacterial sexually transmitted infections are at the highest levels ever reported in the United States, and state and local budgetary issues are placing specialized sexually transmitted disease (STD) care at risk. This study collected information from 4138 patients seeking care at 26 STD clinics in large metropolitan areas across the United States with high levels of reported STDs to determine patient needs and clinic capabilities. Surveys were provided to patients attending these STD clinics to assess their demographic information as well as reasons for coming to the clinic and surveys were also provided to clinic administrators to determine their operational capacities and services provided by the clinic. For this initial study, we conducted univariate analyses to report all data collected from these surveys. Patients attending STD clinics across the country indicated that they do so because of the relative ease of getting an appointment; including walk-in and same-day appointments as well as the welcoming environment and expertise of the staff at the clinic. Additionally, STD clinics provide specialized care to patients; including HIV testing and counseling as well as on-site, injectable medications for the treatment of gonorrhea and syphilis in an environment that helps to reduce the role of stigma in seeking this kind of care. Sexually transmitted disease clinics continue to play an important role in helping to curb the rising epidemic of sexually transmitted infections.

Extent and sufficiency of STD/HIV disease intervention specialists in the United States of America, 2016.

Disease intervention specialists (DIS) conduct partner notification for STD and HIV to interrupt the transmission of STD/HIV. In 2016, we collected information from health departments in the United States of America to determine the number of DIS and whether this number was sufficient for STD/HIV prevention. We identified 1610 STD/HIV DIS positions in the USA and 379 DIS supervisory positions. Of DIS positions, 85% were filled indicating potential issues with turnover. Using nationally reportable data from 2016, we found that states with more primary and secondary syphilis cases had more DIS. DIS participated in public health emergencies in 57% of states. Most USA states indicated that the DIS workforce was not sufficient for STD/HIV prevention. Knowledge of information about DIS workload (e.g. number of STD/HIV cases assigned per DIS) would be helpful.

Functional Conservation of the AMA1 Host-Cell Invasion Ligand Between P. falciparum and P. vivax: A Novel Platform to Accelerate Vaccine and Drug Development.

Plasmodium vivax and P. falciparum malaria species have diverged significantly in receptor-ligand interactions and host-cell invasion. One protein common to both is the merozoite invasion ligand AMA1. While the general structure of AMA1 is similar between species, their sequences are divergent. Surprisingly, it was possible to genetically replace PfAMA1 with PvAMA1 in P. falciparum parasites. PvAMA1 complemented PfAMA1 function and supported invasion of erythrocytes by P. falciparum. Genetically modified P. falciparum expressing PvAMA1 evaded the invasion inhibitory effects of antibodies to PfAMA1, demonstrating species specificity of functional antibodies. We generated antibodies to recombinant PvAMA1 that effectively inhibited invasion, confirming the function of PvAMA1 in genetically modified parasites. Results indicate significant molecular flexibility in AMA1 enabling conserved function despite substantial sequence divergence across species. This provides powerful new tools to quantify the inhibitory activities of antibodies or drugs targeting PvAMA1, opening new opportunities for vaccine and therapeutic development against P. vivax.

US Public Sexually Transmitted Disease Clinical Services in an Era of Declining Public Health Funding: 2013-14.

BACKGROUND: We examined the infrastructure for US public sexually transmitted disease (STD) clinical services. METHODS: In 2013 to 2014, we surveyed 331 of 1225 local health departments (LHDs) who either reported providing STD testing/treatment in the 2010 National Profile of Local Health Departments survey or were the 50 local areas with the highest STD cases or rates. The sample was stratified by jurisdiction population size. We examined the primary referral clinics for STDs, the services offered and the impact of budget cuts (limited to government funding only). Data were analyzed using SAS, and analyses were weighted for nonresponse. RESULTS: Twenty-two percent of LHDs cited a specialty STD clinic as their primary referral for STD services; this increased to 53.5% of LHDs when combination STD-family planning clinics were included. The majority of LHDs (62.8%) referred to clinics providing same-day services. Sexually transmitted disease clinics more frequently offered extragenital testing for chlamydia and/or gonorrhea (74.7%) and gonorrhea culture (68.5%) than other clinics (52.9%, 46.2%, respectively; P < 0.05). The majority of LHDs (61.5%) reported recent budget cuts. Of those with decreased budgets, the most common impacts were fewer clinic hours (42.8%; 95% confidence interval [CI], 24.4-61.2), reduced routine screening (40.2%; 95% CI, 21.7-58.8) and reductions in partner services (42.1%; 95% CI, 23.6-60.7). One quarter of those with reduced STD budgets increased fees or copays for clients. CONCLUSIONS: Findings demonstrate gaps and reductions in US public STD services including clinical services that play an important role in reducing disease transmission. Furthermore, STD clinics tended to offer more specialized STD services than other public clinics.

Acceptability and preliminary efficacy of a tailored online HIV/STI testing intervention for young men who have sex with men: the Get Connected! program.

Southeast Michigan accounts for over 70 % of all HIV/STI cases in the state, with young men who have sex with men (YMSM) between the ages of 13 and 24 encumbering the largest burden in HIV/STI incidence. Using community-based participatory research principles, we developed and pilot tested a web-based, randomized control trial seeking to promote HIV/STI testing ("Get Connected!") among YMSM (N = 130; ages 15-24). Randomized participants completed a baseline assessment and shown a test-locator condition (control) or a tailored, personalized site (treatment). At 30-day follow-up, we found high acceptability among YMSM in both conditions, yet higher credibility of intervention content among YMSM in the treatment group (d = .55). Furthermore, 30 participants reported testing by following, with the majority of these participants (73.3 %; n = 22) completing the treatment condition, a clinically meaningful effect (d = .34) suggesting preliminary efficacy for the intervention. These results demonstrate the potential of the intervention, and suggest that a larger efficacy trial may be warranted.

Obesity accelerates acute promyelocytic leukemia in mice and reduces sex differences in latency and penetrance.

OBJECTIVE: Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL). METHODS: Male and female C57BL/6J.mCG+/PR mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high-fat diet (HFD) or a low-fat diet (LFD) for up to 500 days. RESULTS: Relative to LFD-fed mice, HFD-fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet-responsive sex difference in APL penetrance and incidence was identified, with LFD-fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD-fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding. CONCLUSIONS: Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance.

Availability of Safety-net Sexually Transmitted Disease Clinical Services in the U.S., 2018.

INTRODUCTION: Safety-net sexually transmitted disease services can prevent transmission of sexually transmitted disease. This study assesses the availability of safety-net sexually transmitted disease clinical services across the U.S. METHODS: A 2018 survey of U.S. local health departments examined the availability of safety-net providers and the availability of specific sexually transmitted disease clinical services, including point-of-care testing and treatment. In 2019, Rao-Scott chi-square tests were used to compare service availability by clinic type (sexually transmitted disease clinic versus other clinics). RESULTS: A total of 326 local health departments completed the survey (49% response rate). Of respondents, 64.4% reported that a clinic in their jurisdiction provided safety-net sexually transmitted disease services. Having a safety-net clinic that provided sexually transmitted disease services was more common in medium and large jurisdictions. Sexually transmitted disease clinics were the primary provider in 40.5% of jurisdictions. A wide range of specific sexually transmitted disease services was offered at the primary safety-net clinic for sexually transmitted diseases. Most clinics offered human papillomavirus vaccination and appropriate point-of-care treatment for gonorrhea and syphilis. Fewer than one-quarter of clinics offered point-of-care rapid plasma reagin or darkfield microscopy syphilis testing. Compared with other clinics, services more commonly offered at sexually transmitted disease clinics included same-day services, hepatitis B vaccination, rapid plasma reagin testing (syphilis), any point-of-care testing for gonorrhea, point-of-care trichomonas testing, and extragenital chlamydia or gonorrhea testing. CONCLUSIONS: One-third of local health departments reported no safety-net sexually transmitted disease services or were not aware of the services, and availability of specific services varied. Without an expansion of resources, local health departments might explore collaborations with healthcare systems and innovations in testing to expand sexually transmitted disease services.

PrEP implementation by local health departments in US cities and counties: Findings from a 2015 assessment of local health departments.

OBJECTIVE: The United States Public Health Service released clinical practice guidelines for daily oral preexposure prophylaxis (PrEP) in May 2014. Local health departments (LHDs) are expected to play a critical role in PrEP implementation. We surveyed LHDs to assess awareness of and interest in supporting PrEP implementation, what roles they were taking, or believed they should take, in supporting PrEP, and what resources would be required to do so. METHODS: LHDs were surveyed in 2015 to assess their engagement in PrEP implementation (n = 500). The study employed a cross-sectional survey design with a randomly selected stratified sample. RESULTS: Among responding LHDs (n = 284), 109 (29%, weighted proportion) reported engagement in PrEP implementation. LHDs serving large jurisdictions (population 500,000+) and located in the West were more likely to be engaged in PrEP implementation. Making referrals for PrEP (74%) and conducting education and outreach to community members (51%) were the activities most frequently reported by LHDs engaged in PrEP implementation; 45% anticipated expanding their level of engagement. Among LHDs not engaged in PrEP implementation, 13% expected to become engaged over the next four years, 46% were undecided, and 41% reported it was unlikely. Information about PrEP for health care providers and information about PrEP for health department staff were the most frequently reported resource needs for LHDs engaged and not engaged in PrEP implementation, respectively. CONCLUSIONS: PrEP implementation by LHDs was limited in 2015, three years after Food and Drug Administration approval and one year after the U.S. Public Health Service issued clinical practice guidelines. PrEP is a recently available intervention that is requiring LHDs to adjust existing HIV prevention efforts and service delivery models. Additional resources and implementation research is needed to effectively support PrEP scale-up by LHDs. Efforts must also be undertaken to increase PrEP awareness, knowledge, and implementation capacity among LHDs.

A role for the Saccharomyces cerevisiae regulation of Ace2 and polarized morphogenesis signaling network in cell integrity.

Saccharomyces cerevisiae RAM is a conserved signaling network that regulates maintenance of polarized growth and daughter-cell-specific transcription, the latter of which is critical for septum degradation. Consequently, cells defective in RAM function (designated ramDelta) are round in morphology, form feeble mating projections, and fail to separate following cytokinesis. It was recently demonstrated that RAM genes are essential in strains containing functional SSD1 (SSD1-v), which encodes a protein of unknown function that binds the RAM Cbk1p kinase. Here we investigated the essential function of RAM in SSD1-v strains and identified two functional groups of dosage suppressors for ramDelta lethality. We establish that all ramDelta mutants exhibit cell integrity defects and cell lysis. All dosage suppressors rescue the lysis but not the cell polarity or cell separation defects of ramDelta cells. One class of dosage suppressors is composed of genes encoding cell wall proteins, indicating that alterations in cell wall structure can rescue the cell lysis in ramDelta cells. Another class of ramDelta dosage suppressors is composed of ZRG8 and SRL1, which encode two unrelated proteins of unknown function. We establish that ZRG8 and SRL1 share similar genetic interactions and phenotypes. Significantly, Zrg8p coprecipitates with Ssd1p, localizes similarly to RAM proteins, and is dependent on RAM for localization. Collectively, these data indicate that RAM and Ssd1p function cooperatively to control cell integrity and suggest that Zrg8p and Srl1p function as nonessential inhibitors of Ssd1p.

Using a Handheld Device for Patient Data Collection: A Pilot for Medical Countermeasures Surveillance.

Medical countermeasures (MCMs) are medical products used during public health emergencies. This study, conducted within the Mini-Sentinel Initiative, sought to develop the patient identification and matching processes necessary to assess safety outcomes for MCMs. A handheld device was used to collect identifying information (e.g., name, birthdate, and sex) from the driver's licenses of 421 individuals presenting for routine care at their primary care medical office. Overall, 374 individuals (88.8%) could be linked to their electronic health data using driver's license information. The device was also pilot-tested at a seasonal influenza immunization clinic: detailed vaccine information (e.g., lot number and manufacturer) was captured with a high degree of accuracy. This investigation demonstrated that a handheld device is a feasible means of collecting patient identity and medical product receipt data. This capacity should be useful for safety surveillance of MCMs, particularly when dispensed in settings outside the traditional health-care delivery system.