Smith–Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and ...sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Data show that Rai1+/− mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with Rai1+/− female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the Rai1+/− mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the Rai1+/− mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that Rai1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of Rai1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.
Retention in HIV pre-exposure prophylaxis (PrEP) care is critical for effective PrEP implementation. Few studies have reported long-term lost to follow-up (LTFU) and re-engagement in PrEP care in the ...United States. Medical record data for all cisgender patients presenting to the major Rhode Island PrEP clinic from 2013 to 2019 were included. LTFU was defined as no PrEP follow-up appointment within 98 days. Re-engagement in care was defined as individuals who were ever LTFU and later attended a follow-up appointment. Recurrent event survival analysis was performed to explore factors associated with PrEP retention over time. Of 654 PrEP patients, the median age was 31 years old interquartile range (IQR): 25, 43. The majority were male (96%), White (64%), non-Hispanic (82%), and insured (97%). Overall, 72% patients were ever LTFU and 27% of those ever LTFU re-engaged in care. Female patients were 1.37 times crude hazard ratio (cHR): 1.37; 95% confidence interval (CI): 0.86-2.18 more likely to be LTFU than male patients, and a 1-year increase in age was associated with a 1% lower hazard of being LTFU (cHR: 0.99; CI: 0.98-0.99). Being either heterosexual (aHR: 2.25, 95% (CI): 1.70-2.99 or bisexual (aHR: 2.35, 95% CI: 1.15-4.82) was associated with a higher hazard of loss to follow-up compared with having same-sex partners only. The majority of PrEP users were LTFU, especially at the first 6 months of PrEP initiation. Although a significant number were re-engaged in care, targeted interventions are needed to improve retention in PrEP care. This study characterized the natural projection of loss to follow-up and re-engagement in HIV PrEP care using a longitudinal clinic cohort data and explored associated factors for guiding future interventions to improve retention in PrEP care.
Adequate access to effective treatment and medication assisted therapies for opioid dependence has led to improved antiretroviral therapy adherence and decreases in morbidity among people who inject ...drugs (PWID), and can also address a broad range of social and public health problems. However, even with the success of syringe service programs and opioid substitution programs in European countries (and others) the US remains historically low in terms of coverage and access with regard to these programs. This manuscript investigates predictors of historical change in drug treatment coverage for PWID in 90 US metropolitan statistical areas (MSAs) during 1993-2007, a period in which, overall coverage did not change.
Drug treatment coverage was measured as the number of PWID in drug treatment, as calculated by treatment entry and census data, divided by numbers of PWID in each MSA. Variables suggested by the Theory of Community Action (i.e., need, resource availability, institutional opposition, organized support, and service symbiosis) were analyzed using mixed-effects multivariate models within dependent variables lagged in time to study predictors of later change in coverage.
Mean coverage was low in 1993 (6.7%; SD 3.7), and did not increase by 2007 (6.4%; SD 4.5). Multivariate results indicate that increases in baseline unemployment rate (β = 0.312; pseudo-p < 0.0002) predict significantly higher treatment coverage; baseline poverty rate (β = - 0.486; pseudo-p < 0.0001), and baseline size of public health and social work workforce (β = 0.425; pseudo-p < 0.0001) were predictors of later mean coverage levels, and baseline HIV prevalence among PWID predicted variation in treatment coverage trajectories over time (baseline HIV * Time: β = 0.039; pseudo-p < 0.001). Finally, increases in black/white poverty disparity from baseline predicted significantly higher treatment coverage in MSAs (β = 1.269; pseudo-p < 0.0001).
While harm reduction programs have historically been contested and difficult to implement in many US communities, and despite efforts to increase treatment coverage for PWID, coverage has not increased. Contrary to our hypothesis, epidemiologic need, seems not to be associated with change in treatment coverage over time. Resource availability and institutional opposition are important predictors of change over time in coverage. These findings suggest that new ways have to be found to increase drug treatment coverage in spite of economic changes and belt-tightening policy changes that will make this difficult.
Abstract
Objective: The aim of this systematic review was to identify literature examining associations between isometric strength and gait velocity following stroke.
Methods: An electronic search ...was performed using six online databases. Targeted searching of reference lists of included articles and three relevant journals was also performed. Two independent reviewers identified relevant articles, extracted data and assessed the methodological quality of included articles. Inclusion criteria involved studies that assessed univariate correlations between gait velocity and isometric strength of individual lower limb muscle groups in a stroke population.
Results: Twenty-one studies were included for review. The majority of included studies had a relatively small sample size. After accounting for sample size and methodological quality, the knee extensors showed poor-to-moderate correlations with gait velocity while the ankle dorsiflexors showed the strongest association with gait velocity.
Conclusions: Current evidence suggests that the strength of the ankle dorsiflexors has a stronger correlation to gait velocity compared with other lower limb muscle groups. Consequently, a focus on increasing ankle dorsiflexor strength to improve gait velocity following stroke may be beneficial. However, due to limitations of the research identified, further research is needed to determine the associations between lower limb strength and gait velocity following stroke.
While combinations of immune checkpoint (ICP) inhibitors and neo-adjuvant chemotherapy (NAC) have begun testing in patients with breast cancer (BC), the effects of chemotherapy on ICP expression in ...circulating T cells and within the tumor microenvironment are still unclear. This information could help with the design of future clinical trials by permitting the selection of the most appropriate ICP inhibitors for incorporation into NAC.
Peripheral blood samples and/or tumor specimens before and after NAC were obtained from 24 women with operable BC. The expression of CTLA4, PD-1, Lag3, OX40, and Tim3 on circulating T lymphocytes before and at the end of NAC were measured using flow cytometry. Furthermore, using multi-color immunohistochemistry (IHC), the expression of immune checkpoint molecules by stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells, and tumor cells was determined before and after NAC. Differences in the percentage of CD4+ and CD8+ T cells expressing various checkpoint receptors were determined by a paired Student's t-test.
This analysis showed decreased ICP expression by circulating CD4+ T cells after NAC, including significant decreases in CTLA4, Lag3, OX40, and PD-1 (all p values < 0.01). In comparison, circulating CD8+ T cells showed a significant increase in CTLA4, Lag3, and OX40 (all p values < 0.01). Within tumor samples, TILs, CD8+ T cells, and PD-L1/PD-1 expression decreased after NAC. Additionally, fewer tumor specimens were considered to be PD-L1/PD-1 positive post-NAC as compared to pre-NAC biopsy samples using a cutoff of 1% expression.
This work revealed that NAC treatment can substantially downregulate CD4+ and upregulate CD8+ T cell ICP expression as well as deplete the amount of TILs and CD8+ T cells found in breast tumor samples. These findings provide a starting point to study the biological significance of these changes in BC patients.
NCT04022616.
Recruiting participants into cancer survivorship research remains a significant challenge. Few studies have tested and compared the relative use of non-clinical online recruitment methods, especially ...in samples of adult cancer survivors. This paper reports on the feasibility of recruiting a representative cohort of cancer survivors using online social media. Two hundred participants with cancer diagnosis within the past 12 months were recruited via social media (Facebook, Twitter and Reddit) into a longitudinal questionnaire study. Different methods of online recruitment proved to be more effective than others over time. Paid Facebook boosting, Reddit posts and Twitter advertisements placed by existing cancer charities proved most helpful in reaching our recruitment target (contributing 27%, 22% and 32%, respectively). Recruiting online achieved a more demographically and clinically representative sample for our study: our subject was younger, less heteronormative, including those with a range of clinical diagnoses, primary and recurrence illness, and patients who had both completed and were still receiving treatment. This was certainly not a quick method of sample recruitment but that could have been optimised by focussing only on the three most effective methods described earlier. While we found that online recruitment is significantly lower in cost than traditional recruitment methods, and can reduce some biases, there still remains the potential for some biases (e.g. excluding much older participants) and ethical/methodological issues (e.g. excluding those without access to Internet). We outline our recruitment strategy, retention rates and a cost breakdown in order to guide other researchers considering such methods for future research in cancer survivorship.
Abstract Background Palliative care provision should be driven by high quality research evidence. However, there are barriers to conducting research. Most research attention focuses on potential ...patient barriers; staff and organisational issues that affect research involvement are underexplored. The aim of this research is to understand professional and organisational facilitators and barriers to conducting palliative care research. Methods A mixed methods study, using an open cross-sectional online survey, followed by working groups using nominal group techniques. Participants were professionals interested in palliative care research, working as generalist/specialist palliative care providers, or palliative care research staff across areas of North West England. Recruitment was via local health organisations, personal networks, and social media in 2022. Data were examined using descriptive statistics and content analysis. Results Participants (survey n = 293, working groups n = 20) were mainly from clinical settings (71%) with 45% nurses and 45% working more than 10 years in palliative care. 75% were not active in research but 73% indicated a desire to increase research involvement. Key barriers included lack of organisational research culture and capacity (including prioritisation and available time); research knowledge (including skills/expertise and funding opportunities); research infrastructure (including collaborative opportunities across multiple organisations and governance challenges); and patient and public perceptions of research (including vulnerabilities and burdens). Key facilitators included dedicated research staff, and active research groups, collaborations, and networking opportunities. Conclusions Professionals working in palliative care are keen to be research active, but lack time, skills, and support to build research capabilities and collaborations. A shift in organisational culture is needed to enhance palliative care research capacity and collaborative opportunities across clinical and research settings.
Studies suggest that among children, adverse childhood experiences increase the risk of developing behavioral challenges in and out of the school environment. Rooted in distributed leadership, ...trauma-leadership teams (TLTs) are a novel systems-based intervention in which a team of educators deepens knowledge and works to implement trauma-responsive policies and practices within the school community. The current study used a consensual qualitative research design to (a) understand the ways TLTs are created, (b) describe educators' perceived benefits and outcomes of these teams, and (c) describe how TLTs are applied in schools to improve trauma-informed care practices. Additionally, the study highlights growth areas for TLT implementation. Domains from interviews include (1) Formation of TLTs; (2) Benefits and Outcomes of TLTs; (3) Trauma-Responsive Competency; and (4) Growth Areas of TLT. Results suggest that TLT members view TLTs positively, offer insight into how TLTs are formed, and see benefits from TLTs within their school communities. Results also suggest areas for growth for TLTs.
Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability, but it has not been reported if or how these variants disrupt Kirrel3 ...function. Previously, we studied Kirrel3 loss of function using KO mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse
Here, we developed an
, gain-of-function assay for Kirrel3 using neuron cultures prepared from male and female mice and rats. We find that WT Kirrel3 induces synapse formation selectively between Kirrel3-expressing neurons via homophilic, transcellular binding. We tested six disease-associated Kirrel3 missense variants and found that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to WT Kirrel3. Two tested variants lack homophilic transcellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating that Kirrel3 transcellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to the mechanism of Kirrel3 function and the consequences of missense variants associated with autism and intellectual disability.
Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 transcellular interactions mediate target recognition and signaling to promote synapse development. Moreover, this study tests the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, increases understanding of the complex etiology of neurodevelopmental disorders arising from rare missense variants in synaptic genes.
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