HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer incidence and mortality rates in the United States are declining, but this decrease may not be observed in rural areas where residents are more likely to live in poverty, smoke, and forego ...cancer screening. However, there is limited research exploring national rural-urban differences in cancer incidence and trends.
We analyzed data from the North American Association of Central Cancer Registries' public use dataset, which includes population-based cancer incidence data from 46 states. We calculated age-adjusted incidence rates, rate ratios, and annual percentage change (APC) for: all cancers combined, selected individual cancers, and cancers associated with tobacco use and human papillomavirus (HPV). Rural-urban comparisons were made by demographic, geographic, and socioeconomic characteristics for 2009 to 2013. Trends were analyzed for 1995 to 2013.
Combined cancers incidence rates were generally higher in urban populations, except for the South, although the urban decline in incidence rate was greater than in rural populations (10.2% vs. 4.8%, respectively). Rural cancer disparities included higher rates of tobacco-associated, HPV-associated, lung and bronchus, cervical, and colorectal cancers across most population groups. Furthermore, HPV-associated cancer incidence rates increased in rural areas (APC = 0.724,
< 0.05), while temporal trends remained stable in urban areas.
Cancer rates associated with modifiable risks-tobacco, HPV, and some preventive screening modalities (e.g., colorectal and cervical cancers)-were higher in rural compared with urban populations.
Population-based, clinical, and/or policy strategies and interventions that address these modifiable risk factors could help reduce cancer disparities experienced in rural populations.
AbstractColorectal cancer (CRC) is a leading cause of cancer-related death in the United States. Despite evidence that screening reduces CRC incidence and mortality, only about 60% of age-eligible ...adults are up-to-date on CRC screening. This analysis aims to identify self-reported barriers to CRC screening among patients in a safety-net healthcare setting.Participants were recruited from safety-net primary care sites that were participating in a trial to increase CRC screening. At baseline, patients (n = 483) completed self-report surveys that assessed demographics, healthcare and CRC screening. Barriers to CRC screening were assessed through an open-ended question. Using a basic text analysis, data were coded and organized into key topics.Overall, 65.2% ever had CRC screening; 46.4% were up-to-date. Of those who described barriers (n = 198), 22.9% said they were not due for screening or their provider had not recommended it. Other common barriers included fear or worry about the procedure or outcome, financial challenges such as lack of insurance or cost of testing, and logistic challenges such as transportation and time. Fewer said that screening was of low importance or mentioned discomfort with the procedure or colonoscopy preparation.In this safety-net setting, CRC screening rates were lower than national rates. These qualitative results are similar to quantitative findings reported in the literature but the qualitative data add to our understanding of patient-reported concerns and challenges faced by safety-net patients. These results may be applied to developing targeting communication or intervention strategies to improve CRC screening rates within safety-net health centers.
Pre-exposure prophylaxis (PrEP) is effective in preventing HIV infections among men who have sex with men (MSM). PrEP uptake and adherence remain low and product preferences are unknown, especially ...among young African American MSM who are most at-risk. We conducted 26 qualitative interviews from 2014-2016 among young adult HIV-negative African American MSM regarding PrEP product preferences in Missouri. While the pill and injectable were most liked of all modalities, about a quarter preferred rectal products or patches. Most participants preferred a long-acting injectable (LAI) to daily oral pills due to better medication adherence and a dislike for taking pills. Many participants preferred daily oral pills to on-demand oral PrEP due to the inability to predict sex and the perception that insufficient time or medication would not achieve HIV protection with on-demand. A fear of needles and the perception that there would not be therapeutic levels for a long duration were concerns with injectable PrEP. Study findings highlight the need for a range of prevention options for African American MSM and can inform PrEP product development as well as dissemination and implementation efforts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Structures of power and inequality shape day-to-day life for individuals who are poor, imposing waiting in multiple forms and for a variety of services, including for healthcare (Andaya, 2018a; ...Auyero, 2012; Strathmann and Hay, 2009). Constraints, such as the age requirements for Medicare, losing employer-provided health insurance, or the bureaucracy involved in filing for disability often require people to wait to follow recommendations for medical treatments. In 2016–2017, we conducted 52 narrative interviews in St. Louis, a city with significant racial and economic health inequities and without Medicaid expansion. We interviewed people with one or more chronic illnesses for which they were prescribed medication and who identified as having difficulties affording their prescriptions. Throughout the interviews, participants frequently recounted 1) experiences of waiting for care, along with other services, and 2) the range of strategies they utilized to manage the waiting. In this article, we develop the concept of active waiting to describe both the lived experiences of waiting for care and the responses that people devise to navigate, shorten, or otherwise endure waiting. Waiting is structured into healthcare and other social services at various scales in ways that reinforce feelings of marginalization, and also that require work on the part of those who wait. While much medical and public health research focuses on issues of diagnostic or treatment delay, we conclude that this conceptualization of active waiting provides a far more productive frame for accurately understanding the emotional and physical experiences of individuals who are disproportionately poor and made to wait for their care. Only with such understanding can we hope to build more just and compassionate social systems.
•Poor and chronically ill people wait to receive medical care and social services.•People wait actively, making decisions to manage the repercussions of waiting.•The idea of delaying care is inadequate to explain realities of illness and poverty.•Waiting broadens and deepens structural vulnerability for marginalized people.
Abstract
Microbial ecology provides insights into the ecological and evolutionary dynamics of microbial communities underpinning every ecosystem on Earth. Microbial communities can now be ...investigated in unprecedented detail, although there is still a wealth of open questions to be tackled. Here we identify 50 research questions of fundamental importance to the science or application of microbial ecology, with the intention of summarising the field and bringing focus to new research avenues. Questions are categorised into seven themes: host–microbiome interactions; health and infectious diseases; human health and food security; microbial ecology in a changing world; environmental processes; functional diversity; and evolutionary processes. Many questions recognise that microbes provide an extraordinary array of functional diversity that can be harnessed to solve real-world problems. Our limited knowledge of spatial and temporal variation in microbial diversity and function is also reflected, as is the need to integrate micro- and macro-ecological concepts, and knowledge derived from studies with humans and other diverse organisms. Although not exhaustive, the questions presented are intended to stimulate discussion and provide focus for researchers, funders and policy makers, informing the future research agenda in microbial ecology.
We identify research questions in the field of microbial ecology, with emerging themes that recognise vast microbial functions that could benefit humanity, and the need to integrate knowledge across organisms.
Environmental heterogeneity resulting from human-modified landscapes can increase intraspecific trait variation. However, less known is whether such phenotypic variation is driven by plastic or ...adaptive responses to local environments. Here, we study five bumble bee (Apidae: Bombus) species across an urban gradient in the greater Saint Louis, Missouri region in the North American Midwest and ask: (1) Can urban environments induce intraspecific spatial structuring of body size, an ecologically consequential functional trait? And, if so, (2) is this body size structure the result of plasticity or adaptation? We additionally estimate genetic diversity, inbreeding, and colony density of these species-three factors that affect extinction risk. Using ≥ 10 polymorphic microsatellite loci per species and measurements of body size, we find that two of these species (Bombus impatiens, Bombus pensylvanicus) exhibit body size clines across the urban gradient, despite a lack of population genetic structure. We also reaffirm reports of low genetic diversity in B. pensylvanicus and find evidence that Bombus griseocollis, a species thought to be thriving in North America, is inbred in the greater Saint Louis region. Collectively, our results have implications for conservation in urban environments and suggest that plasticity can cause phenotypic clines across human-modified landscapes.
Gestational diabetes mellitus (GDM) is increasing in the United States, with higher rates among minoritized racial and ethnic populations and lower income populations. GDM increases risk for type 2 ...diabetes (T2DM), and postpartum diabetes screening and prevention are imperative. This qualitative study examines barriers and facilitators to postpartum T2DM screening and prevention among non-privately insured individuals with a history of GDM in a state prior to Medicaid expansion.
Thirty-six non-privately insured women with a history of GDM completed semi-structured interviews. Four focus groups and seven interviews were conducted with 30 nurse practitioners, physicians, physician assistants, nurses and registered dietitians from Federally Qualified Health Centers in St. Louis, MO. Interviews and focus groups were audio-recorded and transcribed. Data were analyzed using an integrative thematic analysis informed by the socio-ecological model.
Barriers and facilitators to T2DM screening and prevention occur across multiple environments (society, healthcare system, interpersonal, and individual). Societal barriers include insurance issues, unemployment, and lack of transportation, childcare, safe housing, and healthy food access, while facilitators include government sponsored programs and community organizations. Healthcare system barriers include care fragmentation, scheduling policies and time constraints while facilitators include care coordination, pregnancy support groups, and education materials. Interpersonal barriers include negative care experiences, cultural differences, communication challenges, competing priorities, and lack of a social support network, while facilitators include family and friend support and positive care experiences. Individual barriers include health complications and unhealthy food and exercise patterns, while facilitators include child wellbeing, empowered attitudes and healthy food and exercise patterns.
The socioecological model highlights the societal and systemic determinants that encompass individual and interpersonal factors affecting postpartum T2DM screening and prevention. This framework can inform multi-level interventions to increase postpartum T2DM screening and prevention in this high-risk population, including policy changes to alleviate higher-level barriers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cluster randomized trial design may raise financial concerns because the cost to recruit an additional cluster is much higher than to enroll an additional subject in subject-level randomized trials. ...Therefore, it is desirable to develop an optimal design. For local optimal designs, optimization means the minimum variance of the estimated treatment effect under the total budget. The local optimal design derived from the variance needs the input of an association parameter
ρ
in terms of a “working” correlation structure
R
(
ρ
)
in the generalized estimating equation models. When the range of
ρ
instead of an exact value is available, the parameter space is defined as the range of
ρ
and the design space is defined as enrollment feasibility, for example, the number of clusters or cluster size. For any value
ρ
within the range, the optimal design and relative efficiency for each design in the design space is obtained. Then, for each design in the design space, the minimum relative efficiency within the parameter space is calculated. MaxiMin design is the optimal design that maximizes the minimum relative efficiency among all designs in the design space. Our contributions are threefold. First, for three common measures (risk difference, risk ratio, and odds ratio), we summarize all available local optimal designs and MaxiMin designs utilizing generalized estimating equation models when the group allocation proportion is predetermined for two-level and three-level parallel cluster randomized trials. We then propose the local optimal designs and MaxiMin designs using the same models when the group allocation proportion is undecided. Second, for partially nested designs, we develop the optimal designs for three common measures under the setting of equal number of subjects per cluster and exchangeable working correlation structure in the intervention group. Third, we create three new Statistical Analysis System (SAS) macros and update two existing SAS macros for all the optimal designs. We provide two examples to illustrate our methods.
To examine systematically the literature on the effect of geographical location variation on breast cancer stage at diagnosis, race/ethnicity, and socioeconomic status.
Eight electronic databases ...were searched using combination of key words. Of the 312 articles retrieved from the search, 36 studies from 12 countries were considered eligible for inclusion.
This review identified 17 (47%) of 36 studies in which breast cancer patients residing in geographically remote/rural areas had more late-stage diagnosis than urban women. Ten (28%) studies reported higher proportions of women diagnosed with breast cancer resided in urban than rural counties. Nine (25%) studies reported no statistically significant association between place of residence and stage at diagnosis for breast cancer patients residing in rural and urban areas.
Cancer patients residing in rural and disadvantaged areas were more likely to be diagnosed with distant breast metastasis. Efforts to reduce these inequalities and subsequent mortality are needed.
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