Conceptualizing the Risks of Coronary Heart Disease and Heart Failure Among People Aging with HIV: Sex-Specific Considerations.

Cardiovascular disease (CVD) is emerging as a major threat to healthy aging among people with HIV (PHIV). PHIV face heightened risks for coronary heart disease (CHD)/myocardial infarction (MI) and heart failure (HF), fueled by systemic immune activation and by metabolic dysregulation. Women with HIV (WHIV) evidence unique patterns of vascular and myocardial pathology as compared to men with HIV (MHIV). These patterns include a predilection to microvascular dysfunction and type II MI, as well as a penchant for diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). Investigations are underway to understand how advanced reproductive aging among WHIV influences systemic immune activation and metabolic dysregulation en route to these CVD phenotypes. A key goal is to identify targeted CVD prevention strategies relevant to WHIV, particularly as efficacious treatment approaches to type II MI and HFpEF are lacking.

Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases.

During macroautophagy/autophagy, mammalian Atg8-family proteins undergo 2 proteolytic processing events. The first exposes a COOH-terminal glycine used in the conjugation of these proteins to lipids on the phagophore, the precursor to the autophagosome, whereas the second releases the lipid. The ATG4 family of proteases drives both cleavages, but how ATG4 proteins distinguish between soluble and lipid-anchored Atg8 proteins is not well understood. In a fully reconstituted delipidation assay, we establish that the physical anchoring of mammalian Atg8-family proteins in the membrane dramatically shifts the way ATG4 proteases recognize these substrates. Thus, while ATG4B is orders of magnitude faster at processing a soluble unprimed protein, all 4 ATG4 proteases can be activated to similar enzymatic activities on lipid-attached substrates. The recognition of lipidated but not soluble substrates is sensitive to a COOH-terminal LIR motif both in vitro and in cells. We suggest a model whereby ATG4B drives very fast priming of mammalian Atg8 proteins, whereas delipidation is inherently slow and regulated by all ATG4 homologs.

Association of Rideshare-Based Transportation Services and Missed Primary Care Appointments: A Clinical Trial.

Importance: Transportation barriers contribute to missed primary care appointments for patients with Medicaid. Rideshare services have been proposed as alternatives to nonemergency medical transportation programs because of convenience and lower costs. Objective: To evaluate the association between rideshare-based medical transportation and missed primary care appointments among Medicaid patients. Design, Setting, and Participants: In a prospective clinical trial, 786 Medicaid beneficiaries who resided in West Philadelphia and were established primary care patients at 1 of 2 academic internal medicine practices located within the same building were included. Participants were allocated to being offered complimentary ride-sharing services (intervention arm) or usual care (control arm) based on the prescheduled day of their primary care appointment reminder. Those scheduled on even-numbered weekdays were in the intervention arm and on odd-numbered weekdays, the control arm. The primary study outcome was the rate of missed appointments, estimated using an intent-to-treat approach. All individuals receiving a phone call reminder were included in the study sample, regardless of whether they answered their phone. The study was conducted between October 24, 2016, and April 20, 2017. Interventions: A model of providing rideshare-based transportation was designed. As part of usual care, patients assigned to both arms received automated appointment phone call reminders. As part of the study protocol, patients assigned to both arms received up to 3 additional appointment reminder phone calls from research staff 2 days before their scheduled appointment. During these calls, patients in the intervention arm were offered a complimentary ridesharing service. Research staff prescheduled rides for those interested in the service. After their appointment, patients phoned research staff to initiate a return trip home. Main Outcomes and Measures: Missed appointment rate (no shows and same-day cancellations) in the intervention compared with control arm. Results: Of the 786 patients allocated to the intervention or control arm, 566 (72.0%) were women; mean (SD) age was 46.0. (12.5) years. Within the intervention arm, 85 among 288 (26.0%) participants who answered the phone call used ridesharing. The missed appointment rate was 36.5% (144 of 394) for the intervention arm and 36.7% (144 of 392) for the control arm (P = .96). Conclusions and Relevance: The uptake of ridesharing was low and did not decrease missed primary care appointments. Future studies trying to reduce missed appointments should explore alternative delivery models or targeting populations with stronger transportation needs. Trial Registration: clinicaltrials.gov Identifier: NCT02955433.

Rideshare-Based Medical Transportation for Medicaid Patients and Primary Care Show Rates: A Difference-in-Difference Analysis of a Pilot Program.

BACKGROUND: Transportation to primary care is a well-documented barrier for patients with Medicaid, despite access to non-emergency medical transportation (NEMT) benefits. Rideshare services, which offer greater convenience and lower cost, have been proposed as an NEMT alternative. OBJECTIVE: To evaluate the impact of rideshare-based medical transportation on the proportion of Medicaid patients attending scheduled primary care appointments. DESIGN: In one of two similar practices, all eligible Medicaid patients were offered rideshare-based transportation ("rideshare practice"). A difference-in-difference analytical approach using logistic regression with robust standard errors was employed to compare show rate changes between the rideshare practice and the practice where rideshare was not offered ("control practice"). PARTICIPANTS: Our study population included residents of West Philadelphia who were insured by Medicaid and were established patients at two academic general internal medicine practices located in the same building. INTERVENTION: We designed a rideshare-based transportation pilot intervention. Patients were offered the service during their reminder call 2 days before the appointment, and rides were prescheduled by research staff. Patients then called research staff to schedule their return trip home. MAIN MEASURES: We assessed the effect of offering rideshare-based transportation on appointment show rates by comparing the change in the average show rate for the rideshare practice, from the baseline period to the intervention period, with the change at the control practice. KEY RESULTS: At the control practice, the show rate declined from 60% (146/245) to 51% (34/67). At the rideshare practice, the show rate improved from 54% (72/134) to 68% (41/60). In the adjusted model, controlling for patient demographics and provider type, the odds of showing up for an appointment before and after the intervention increased 2.57 (1.10-6.00) times more in the rideshare practice than in the control practice. CONCLUSIONS: Results of this pilot program suggest that offering a rideshare-based transportation service can increase show rates to primary care for Medicaid patients.

Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-ß, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation.

Eukaryotic cells can use the autophagy pathway to defend against microbes that gain access to the cytosol or reside in pathogen-modified vacuoles. It remains unclear if pathogens have evolved specific mechanisms to manipulate autophagy. Here, we found that the intracellular pathogen Legionella pneumophila could interfere with autophagy by using the bacterial effector protein RavZ to directly uncouple Atg8 proteins attached to phosphatidylethanolamine on autophagosome membranes. RavZ hydrolyzed the amide bond between the carboxyl-terminal glycine residue and an adjacent aromatic residue in Atg8 proteins, producing an Atg8 protein that could not be reconjugated by Atg7 and Atg3. Thus, intracellular pathogens can inhibit autophagy by irreversibly inactivating Atg8 proteins during infection.