Women Veterans with co-morbid medical and mental health conditions face persistent barriers accessing high-quality health care. Evidence-based quality improvement (EBQI) offers a systematic approach ...to implementing new care models that can address care gaps for women Veterans.
This study examines factors associated with the successful deployment of EBQI within integrated health systems to improve primary care for women Veterans with complex mental health needs.
Following a 12-site (8 EBQI, 4 control) cluster randomized study to evaluate EBQI effectiveness, we conducted an in-depth case study analysis of one women's health clinic that used EBQI to improve integrated primary care-mental health services for women Veterans.
Our study sample included providers, program managers, and clinic staff at a women Veteran's health clinic that, at the time of the study, had one Primary Care and Mental Health Integration team and one women's health primary care provider serving 800 women. We analyzed interviews conducted 12 months, 24 months, and 4 years post-implementation and call summaries between the clinic and support team.
We conducted qualitative thematic analysis of interview and call summary data to identify EBQI elements, clinic characteristics, and reported challenges and successes within project development and execution.
The clinic harnessed core EBQI elements (multi-level stakeholder engagement, data-driven progress-monitoring, PDSA cycles, sharing results) to accomplish pre-defined project goals, strengthen inter-disciplinary partnerships, and bolster team confidence. Clinic characteristics that facilitated implementation success included prior QI experience and an organizational culture responsive to innovation, while lack of pre-existing guidelines and limited access to centralized databases posed implementation challenges.
Successful practice transformation emerges through the interaction of evidence-based methods and site-specific characteristics. Examining how clinic characteristics support or impede EBQI adaptation can facilitate efforts to improve care within integrated health systems.
Delaying needed medical care contributes to greater health risks and higher long-term medical costs. Women Veterans with complex medical and mental health needs face increased barriers to timely care ...access.
In a sample of women Veterans with recent engagement in Veterans Administration (VA) primary care, we aimed to compare characteristics of women Veterans who delayed care in the past 6 months with those who did not and examine factors associated with self-reported delayed care. Our study aims to inform interventions focused on eliminating health care access disparities among women Veterans.
An innovation to improve women Veterans' engagement and retention in evidence-based health care for cardiovascular (CV) risk reduction (CV Toolkit) was implemented across five primary care sites within the VA. Women Veterans who were exposed to at least one CV Toolkit component participated in a mailed survey (
= 253). We used multivariate logistic regression to model factors associated with delaying care, including trust in VA providers, positive mental health screening (
, positive screen for either depression or anxiety), traumatic experience, self-rated health, and age.
Women with any mental health symptoms (odds ratio OR 2.42, 95% confidence interval CI: 1.23-4.74) and women who had experienced a traumatic event (OR 2.61, 95%CI: 1.11-6.14) were significantly more likely to report delaying care.
Our study identified high rates of delayed care-over one-third of respondents-among women Veterans with recent primary care engagement. Mental health symptoms were the most common reported reason for delay among those who delayed care. Clinical Trial registration: NCT02991534.
Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a ...multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.
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•hiPSC-derived neural rosettes carrying 15q11.2 CNV exhibit polarity defects•CYFIP1 haploinsufficiency causes polarity defects via WAVE complex destabilization•CYFIP1 and WAVE signaling regulate radial glia cells in the developing mouse cortex•CYFIP1 and ACTR2 interact epistatically to affect risk for schizophrenia
Yoon et al. show that 15q11.2 copy number variants, a risk factor for schizophrenia and autism, result in deficient CYFIP1 and WAVE signaling in cortical neural stem cells.
Summary Background In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse ...transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. Methods In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , NCT01641809. Findings Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 87% of 60, 51 85% of 60, and 53 87% of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77–88) patients in the cabotegravir groups (48 80%; 70–90, 48 80%; 70–90, and 53 87%; 78–95 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60–82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69–82) receiving cabotegravir (41 68%; 57–80, 45 75%; 64–86, and 51 84%; 74–93 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51–75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 47%, 32 53%, and 33 54% patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one 2%, one 2%, and four 7% patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. Interpretation Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. Funding ViiV Healthcare and Janssen Research and Development.
AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP ...is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1−/− mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC p.Asn490_Met495delins(40) and c.1743C>A p.Cys581∗) in the first individual, a homozygous variant (c.1320_1326del p.Arg440Serfs∗3) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.
Simplified treatment regimens for HIV-1 may have advantages. In this open-label, randomized, controlled trial, patients with HIV-1 infection who had not previously received antiretroviral therapy ...were given oral induction therapy, then treated with either monthly injections of long-acting cabotegravir and rilpivirine or standard treatment. At 48 weeks, similar viral suppression was observed with the two regimens.
BACKGROUND:Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1.
SETTING:ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, ...multicenter, multinational phase 3 studies.
METHODS:Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithmnoninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints.
RESULTS:The pooled intention-to-treat exposed population included 591 participants in each arm 28% women (sex at birth), 19% aged ≥50 years. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm.
CONCLUSION:This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.
How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn ...neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
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► DISC1 regulation of dendritic growth requires NKCC1 and depolarizing GABA signaling ► Early-postnatal and adult neurogenesis exhibit differential DISC1 dependency ► Stress synergizes with DISC1 in regulating early-postnatal hippocampal neurogenesis ► Epistatic interaction between DISC1 and NKCC1 affects risk for schizophrenia
Dendritic development in immature neurons depends on combined signals from DISC and the neurotransmitter GABA. SNPs in genes affecting both pathways interact to increase risk of schizophrenia, suggesting that signaling important for the timing of neuronal development is critical in disease manifestation.
Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) ...are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ~30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG: FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).
The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine versus daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three ...participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on
sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact
sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).
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