Challenges with Delivering Gender-Specific and Comprehensive Primary Care to Women Veterans

Background The growing presence of women veterans in Veterans Administration (VA) settings has prompted the need for greater attention to clinical proficiency related to women's health (WH) primary care needs. Instead of making appointments for multiple visits or referring patients to a WH clinic or alternate site for gender-specific care, a comprehensive primary care model now allows for women veteran patients be seen by primary care providers (PCPs) who have WH training/experience and can see patients for both primary and WH care in the context of a single visit. However, little is currently known about the barriers and facilitators WH-PCPs face in using this approach to incorporate gender-specific services into women veterans' primary care services. Methods We conducted qualitative in-depth interviews with 22 WH-PCPs at one Midwestern VA Medical Center. All participants were members of one of four outpatient primary care clinics within the main medical center, one off-site satellite clinic, or two off-site community-based outpatient clinics. Results Inductive thematic analysis identified six themes: 1) Time constraints, 2) importance of staff support, 3) necessity of sufficient space and equipment/supplies, 4) perceptions of discomfort among patients with trauma histories, 5) lack of education/training, and 6) challenges with scheduling/logistics. Conclusion Although adequate staff was a key facilitator, the findings suggest that there may be barriers that undermine the ability of VA WH-PCPs to provide high-quality, comprehensive primary and gender-specific care. The nature of these barriers is multifactorial and multilevel in nature, and may therefore require special policy and practice action

The association of HIV-related stigma and psychosocial factors and HIV treatment outcomes among people living with HIV in the Volta region of Ghana:A mixed-methods study

Stigma and discrimination have been identified as significant barriers to HIV treatment among people living with HIV (PLWH). HIV stigma affects decision to seek HIV testing and early treatment. Evidence shows that HIV stigma undermines antiretroviral therapy (ART) adherence by affecting the psychological process such as adjusting and coping with social support. In Ghana, stigma toward PLWH occurs in many ways including rejection by their communities and family members, ostracism, and refusal to engage in social interactions such as eating, sharing a bed, or shaking hands. Therefore. we examined PLWH's experiences with different forms of HIV-related stigma and the impact on HIV treatment outcome in the Volta region of Ghana. We employed a convergent mixedmethod approach consisting of a survey with 181 PLWH, four focus group discussions with 24 survey respondents, and in-depth interviews with six providers. We performed independent samples t-test, ANOVA, and chi-square test to test associations in bivariate analysis and analyzed qualitative data using thematic analysis. In all, 49% of survey respondents reported experiencing high internalized stigma, which was associated with high social support and depression (p&lt;0.001). In qualitative interviews, anticipated stigma was the most salient concern of PLWH, followed by internalized and enacted stigma, which all negatively impacted HIV treatment and care. Stigma was experienced on multiple levels and affected psychosocial and treatment outcomes. Findings suggest urgent need for HIV-stigma reduction intervention among PLWH and their family, providers, and community members.</p

Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34&lt;sup&gt;+&lt;/sup&gt;38&lt;sup&gt;lo/−&lt;/sup&gt;), are significantly lower than in CML progenitor cells (total CD34&lt;sup&gt;+&lt;/sup&gt;) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34&lt;sup&gt;+&lt;/sup&gt; and primitive CD34&lt;sup&gt;+&lt;/sup&gt;38&lt;sup&gt;lo/−&lt;/sup&gt; cells accumulated significantly higher levels of sLDL when compared with non-CML CD34&lt;sup&gt;+&lt;/sup&gt; cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication

Activated PI3K Delta Syndrome-1 mutations cause neutrophilia in zebrafish larvae

People with Activated PI3 Kinase Delta Syndrome 1 (APDS1) suffer from immune deficiency and severe bronchiectasis. APDS1 is caused by dominant activating mutations of the PIK3CD gene that encodes the PI3 kinase delta (PI3Kδ) catalytic subunit. Despite the importance of innate immunity defects in bronchiectasis, there has been limited investigation of neutrophils or macrophages in APDS1 patients or mouse models. Zebrafish embryos provide an ideal system to study neutrophils and macrophages. Previous studies of zebrafish with strongly hyperactivated PI3 kinase activity due to Pten deficiency, revealed excessive production of immature neutrophils that fail to mature. We used CRISPR-Cas9 and CRISPR-Cpf1, with oligo-nucleotide directed homologous repair, to engineer zebrafish equivalents of the two most prevalent human APDS1 disease mutations. These zebrafish pik3cd alleles dominantly cause excessive neutrophilic inflammation in a tail-fin injury model. They also exhibit total body neutrophilia in the absence of any inflammatory stimulus but have normal numbers of macrophages. Exposure to the PI3Kδ inhibitor CAL-101 reverses the total body neutrophilia. There is no apparent defect in neutrophil maturation or migration and tail-fin regeneration is unimpaired

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

Introducing an automated high content confocal imaging approach for Organs-on-Chips

Organ-Chips are micro-engineered systems that aim to recapitulate the organ microenvironment. Implementation of Organ-Chips within the pharmaceutical industry aims to improve the probability of success of drugs reaching late stage clinical trial by generating models for drug discovery that are of human origin and have disease relevance. We are adopting the use of Organ-Chips for enhancing pre-clinical efficacy and toxicity evaluation and prediction. Whilst capturing cellular phenotype via imaging in response to drug exposure is a useful readout in these models, application has been limited due to difficulties in imaging the chips at scale. Here we created an end-to-end, automated workflow to capture and analyse confocal images of multicellular Organ-Chips to assess detailed cellular phenotype across large batches of chips. By automating this process, we not only reduced acquisition time, but we also minimised process variability and user bias. This enabled us to establish, for the first time, a framework of statistical best practice for Organ-Chip imaging, creating the capability of using Organ-Chips and imaging for routine testing in drug discovery applications that rely on quantitative image data for decision making. We tested our approach using benzbromarone, whose mechanism of toxicity has been linked to mitochondrial damage with subsequent induction of apoptosis and necrosis, and staurosporine, a tool inducer of apoptosis. We also applied this workflow to assess the hepatotoxic effect of an active AstraZeneca drug candidate illustrating its applicability in drug safety assessment beyond testing tool compounds. Finally, we have demonstrated that this approach could be adapted to Organ-Chips of different shapes and sizes through application to a Kidney-Chip.</p

Quantitative analysis of powder mixtures by raman spectrometry : the influence of particle size and its correction

Particle size distribution and compactness have significant confounding effects on Raman signals of powder mixtures, which cannot be effectively modeled or corrected by traditional multivariate linear calibration methods such as partial least-squares (PLS), and therefore greatly deteriorate the predictive abilities of Raman calibration models for powder mixtures. The ability to obtain directly quantitative information from Raman signals of powder mixtures with varying particle size distribution and compactness is, therefore, of considerable interest In this study, an advanced quantitative Raman calibration model was developed to explicitly account for the confounding effects of particle size distribution and compactness on Raman signals of powder mixtures. Under the theoretical guidance of the proposed Raman calibration model, an advanced dual calibration strategy was adopted to separate the Raman contributions caused by the changes in mass fractions of the constituents in powder mixtures from those induced by the variations in the physical properties of samples, and hence achieve accurate quantitative determination for powder mixture samples. The proposed Raman calibration model was applied to the quantitative analysis of backscatter Raman measurements of a proof-of-concept model system of powder mixtures consisting of barium nitrate and potassium chromate. The average relative prediction error of prediction obtained by the proposed Raman calibration model was less than one-third of the corresponding value of the best performing PLS model for mass fractions of barium nitrate in powder mixtures with variations in particle size distribution, as well as compactness

Behavioural modification interventions for medically unexplained symptoms in primary care: Systematic reviews and economic evaluation

Background: The term 'medically unexplained symptoms' is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms. Objectives: An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis. Data sources: Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria - for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019. Participants: Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes. Interventions: Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution. Evidence synthesis: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (< 6 months since the end of treatment) and long-term follow-up (= 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities. Economic evaluation: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes. Results: Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive-behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive-behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/ stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/ stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000. Limitations: Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points. Conclusions: Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner-patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study). © Queen's Printer and Controller of HMSO 2020

Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model

Beta-amyloid (Aβ) oligomers contribute to the pathophysiology of Alzheimer disease (AD), and metabotropic glutamate receptor 5 (mGluR5) has been shown to act as a receptor for both Aβ oligomers and cellular prion proteins. Furthermore, the genetic deletion of mGluR5 in an APPswe/PS1δE9 mouse model of AD improves cognitive function and reduces Aβ plaques and Aβ oligomer concentrations. Here, we show that chronic administration of the orally bioavailable mGluR5-selective negative allosteric modulator CTEP, which is similar in structure, potency, and selectivity to Basimglurant (RO4917523), which is currently in phase II clinical development for major depressive disorder and fragile X syndrome, reverses cognitive decline in APPswe/PS1δE9 mice and reduces Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1δE9 and 3xTg-AD male mice. These findings suggest that CTEP or its analogue Basimglutant might potentially be an effective therapeutic for the treatment of AD patients