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The short physical performance battery and incident heart failure among older women: the OPACH study

Am J Prev Cardiol

2021 Chongzhi Di

Objective: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high. Methods: Women (n=5325; mean age 797 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0-3), low (4-6), medium (7-9), or high (10-12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time. Results: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34-3.66), 1.63 (1.11-2.38), 1.39 (1.00-1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR=1.41, absent HR=1.41), hypertension (present HR=1.45, absent HR=1.30), diabetes (present HR=1.32, absent HR=1.44), and lower accelerometer-measured MVPA (<45 min/day HR=1.29, 45min/day HR=1.60); all P-interaction>0.10. Conclusion: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

Acceptability of human papillomavirus (HPV) self-sampling among never- and under-screened Indigenous and other minority women: a randomised three-arm community trial in Aotearoa New Zealand

Lancet Reg Health West Pac

2021 John Potter

Background: Internationally, self-sampling for human papillomavirus (HPV) has been shown to increase participation in cervical-cancer screening. In Aotearoa New Zealand, there are long-standing ethnic inequalities in cervical-cancer screening, incidence, and mortality, particularly for indigenous Mori women, as well as Pacific and Asian women. Methods: We invited never- and markedly under-screened (5 years overdue) 30-69-year-old Mori, Pacific, and Asian women to participate in an open-label, three-arm, community-based, randomised controlled trial, with a nested sub-study. We aimed to assess whether two specific invitation methods for self-sampling improved screening participation over usual care among the least medically served populations. Women were individually randomised 3:3:1 to: clinic-based self-sampling (CLINIC - invited to take a self-sample at their usual general practice); home-based self-sampling (HOME - mailed a kit and invited to take a self-sample at home); and usual care (USUAL - invited to attend a clinic for collection of a standard cytology sample). Neither participants nor research staff could be blinded to the intervention. In a subset of general practices, women who did not participate within three months of invitation were opportunistically invited to take a self-sample, either next time they attended a clinic or by mail. Findings: We randomised 3,553 women: 1,574 to CLINIC, 1,467 to HOME, and 512 to USUAL. Participation was highest in HOME (14.6% among Mori, 8.8% among Pacific, and 18.5% among Asian) with CLINIC (7.0%, 5.3% and 6.9%, respectively) and USUAL (2.0%, 1.7% and 4.5%, respectively) being lower. In fully adjusted models, participation was statistically significantly more likely in HOME than USUAL: Mori OR=9.7, (95%CI 3.0-31.5); Pacific OR=6.0 (1.8-19.5); and Asian OR=5.1 (2.4-10.9). There were no adverse outcomes reported. After three months, 2,780 non-responding women were invited to participate in a non-randomised, opportunistic, follow-on substudy. After 6 months,192 (6.9%) additional women had taken a self-sample. Interpretation: Using recruitment methods that mimic usual practice, we provide critical evidence that self-sampling increases screening among the groups of women (never and under-screened) who experience the most barriers in Aotearoa New Zealand, although the absolute level of participation through this population approach was modest. Follow-up for most women was routine but a small proportion required intensive support. Trial registration: ANZCTR Identifier: ACTRN12618000367246 (date registered 12/3/2018) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371741&isReview=true; UTN: U1111-1189-0531. Funding: Health Research Council of New Zealand (HRC 16/405). Protocol: http://publichealth.massey.ac.nz/assets/Uploads/Study-protocol-V2.1Self-sampling-for-HPV-screening-a-community-trial.pdf.

An approximate quasi-likelihood approach for error-prone failure time outcomes and exposures

Stat Med

2021 Lesley Tinker

Measurement error arises commonly in clinical research settings that rely on data from electronic health records or large observational cohorts. In particular, self-reported outcomes are typical in cohort studies for chronic diseases such as diabetes in order to avoid the burden of expensive diagnostic tests. Dietary intake, which is also commonly collected by self-report and subject to measurement error, is a major factor linked to diabetes and other chronic diseases. These errors can bias exposure-disease associations that ultimately can mislead clinical decision-making. We have extended an existing semiparametric likelihood-based method for handling error-prone, discrete failure time outcomes to also address covariate error. We conduct an extensive numerical study to compare the proposed method to the naive approach that ignores measurement error in terms of bias and efficiency in the estimation of the regression parameter of interest. In all settings considered, the proposed method showed minimal bias and maintained coverage probability, thus outperforming the naive analysis which showed extreme bias and low coverage. This method is applied to data from the Women's Health Initiative to assess the association between energy and protein intake and the risk of incident diabetes mellitus. Our results show that correcting for errors in both the self-reported outcome and dietary exposures leads to considerably different hazard ratio estimates than those from analyses that ignore measurement error, which demonstrates the importance of correcting for both outcome and covariate error.

Dengue and Zika virus infections in children elicit cross-reactive protective and enhancing antibodies that persist long term

Sci Transl Med

2021 M. Elizabeth Halloran

[Figure: see text].

Self-Identity, Beliefs, and Behavior Among Men Who Have Sex with Transgender Women: Implications for HIV Research and Interventions

Arch Sex Behav

2021 Ann Duerr; Michele Andrasik

While transgender women have been identified as a global priority population for HIV prevention and treatment, little is known about the cisgender male partners of transgender women, including their sexual behavior and HIV prevalence. Previous research has suggested that these male partners have varied identities and sexual behavior, which make identifying and engaging them in research difficult. This paper describes interviews conducted with fifteen cisgender men who reported recent sexual activity with transgender women in Lima, Peru. The purpose of this research was to explore how these men reported their identities and sexual behavior, to better understand how they would interact with HIV outreach, research, and care. The major themes were sexual orientation and identity; view of transgender partners; social ties to transgender women and other men with transgender women partners; disclosure of relationships; HIV knowledge and risk perception; and attitudes toward interventions. We found that language used to assess sexual orientation was problematic in this population, due to lack of consistency between orientation and reported behavior, and unfamiliarity with terms used to describe sexual orientation. In addition, stigma, lack of knowledge of HIV prevention methods, and fear of disclosure of sexual behavior were identified as barriers that could impact engagement in HIV research, prevention, and care. However, participants reported social relationships with both transgender women and other men who have transgender partners, presenting possible avenues for recruitment into HIV research and healthcare services.

Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA)

J Neurooncol

2021 Christina Lockwood; James Olson; J Geyer; Sarah Leary

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p=0.001), with leptomeningeal metastasis (p=0.001), and was associated with decreased probability of gross total resection (GTR; p=0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR=0.058; p=0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR=3.27; p=0.025). Deep tumor location (HR=2.93; p=0.001) and chemotherapy administration (HR=2.02; p=0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer

Proc Natl Acad Sci U S A

2021 Peter Nelson; Taranjit Gujral; Thomas Bello

Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.

Attenuation of apoptotic cell detection triggers thymic regeneration after damage

Cell Rep

2021 Kirsten Cooper; Jarrod Dudakov; Cindy Evandy; David Granadier; Kayla Hopwo; Lorenzo Iovino; Sinéad Kinsella; Colton Smith; Paul deRoos

The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.

Comparative analysis of infectious complications with outpatient vs. inpatient care for adults with high-risk myeloid neoplasm receiving intensive induction chemotherapy

Leuk Lymphoma

2021 Paul Hendrie; Elihu Estey; Mary-Elizabeth Percival; Roland Walter; Nicholas Howard; Anna Halpern; Megan Othus

We recently reported an early hospital discharge (EHD) care strategy following intensive acute myeloid leukemia (AML)-like chemotherapy is safe. To evaluate its impact on infectious outcomes, we compared all adults treated from 8/1/2014 to 7/31/2018 discharging within 72 h of completing chemotherapy (EHD) with hospitalized patients (controls) across 354 induction and 259 post-remission cycles. While overall outcomes were similar, gram-positive bacteremias were more common in EHD patients than control (p<.001), although they received fewer days of IV antimicrobials (p< .001). Notably, cumulative infection risks in EHD patients were similar after induction and post-remission therapy. In multivariable analysis, only EHD status was independently associated with risk for gram-positive bacteremia (p= .01), whereas the only independent risk factor for fungal infection was fluconazole (vs. posaconazole) use (p< .001). The observation of increased rates of gram-positive bacteremias with EHD identifies improvements in catheter management as one area to further increase the safety of this care approach.

Anticoagulation Targeting Membrane-Bound Anionic Phospholipids Improved Outcomes of Traumatic Brain Injury in Mice

Blood

2021 Teri Blevins; Amanda Koehne

Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. Phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared to EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.

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