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 β-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.
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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria vaccine candidate AMA1 of Plasmodium vivax complements P. falciparum AMA1 erythrocyte invasion. P. falciparum expressing PvAMA1 provides a new platform for quantifying the invasion-inhibitory ...capacity of antibodies and small molecules to accelerate development of vaccines and therapeutics for malaria.
Abstract
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.
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.
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.
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).
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.
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.
We examined the infrastructure for US public sexually transmitted disease (STD) clinical services.
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.
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.
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.
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.
•STD clinics are key to stemming the tide of rising STD rates in the United States.•STD clinics play a role in the provision of PrEP and can help end the HIV epidemic.•Care is sought at STD clinics due to appointment availability and confidentiality.•Most clinics in high morbidity areas are affiliated with the public health system.
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.
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