Shorter total sleep time is associated with lower CD4+/CD8+ T cell ratios in virally suppressed men with HIV.

Study Objectives: Although poor sleep quality is associated with lower CD4+ T cell counts among people living with HIV (PLWH), the association between objective sleep metrics and T lymphocyte subset counts is unknown. We evaluated the association between polysomnography (PSG) derived sleep metrics and T lymphocyte subpopulations in a cohort of men living with HIV. Methods: Virally suppressed men living with HIV participating in the Multicenter AIDS Cohort Study underwent home overnight PSG. We assessed the association of PSG parameters with CD4+ and CD8+ T cell counts and the CD4+/CD8+ T cell ratio. Results: Overall, 289 men with mean (±SD) age 55.3 ±â€…11.3 years and mean CD4+ T cell count 730 ±â€…308 cells/mm3 were evaluated. Total sleep time (TST) was significantly associated with CD8+ but not CD4+ T cell counts. After adjusting for age, race, depressive symptoms, antidepressant use, and non-nucleoside reverse transcriptase inhibitors use, every hour of shorter TST was associated with an additional 33 circulating CD8+ T cells/mm3 (p = 0.05) and a 5.6% (p = 0.0007) decline in CD4+/CD8+ T cell ratio. In adjusted models, every hour of shorter rapid eye movement (REM) sleep was associated with an additional 113 CD8+ T cells/mm3 (p = 0.02) and a 15.1% lower CD4+/CD8+ T cell ratio (p = 0.006). In contrast, measures of sleep efficiency and sleep-disordered breathing were not associated with differences in T lymphocyte subpopulations. Conclusions: Our findings suggest that shorter TST and REM sleep durations are associated with differences in T lymphocyte subpopulations among men living with HIV. Addressing sleep may reflect a novel opportunity to improve immune function in PLWH.

Incidence of VTE in Patients With OSA: A Cohort Study.

BACKGROUND: Previous studies suggesting that OSA may be an independent risk factor for VTE have been limited by reliance on administrative data and lack of adjustment for clinical variables, including obesity. RESEARCH QUESTION: Does OSA confer an independent risk of incident VTE among a large clinical cohort referred for sleep-disordered breathing evaluation? STUDY DESIGN AND METHODS: We analyzed the clinical outcomes of 31,309 patients undergoing overnight polysomnography within a large hospital system. We evaluated the association of OSA severity with incident VTE, using Cox proportional hazards modeling accounting for age, sex, BMI, and common comorbid conditions. RESULTS: Patients were of mean age 50.4 years, and 50.1% were female. There were 1,791 VTE events identified over a mean follow-up of 5.3 years. In age- and sex-adjusted analyses, each 10-event/h increase in the apnea-hypopnea index was associated with a 4% increase in incident VTE risk (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). After adjusting for BMI, this association disappeared (HR, 1.01; 95% CI, 0.99-1.03). In contrast, nocturnal hypoxemia had an independent association with incident VTE. Patients with > 50% sleep time spent with oxyhemoglobin saturation < 90% are at 48% increased VTE risk compared with those without nocturnal hypoxemia (HR, 1.48; 95% CI, 1.16-1.69). INTERPRETATION: In this large cohort, we found that patients with more severe OSA as measured by the apnea-hypopnea index are more likely to have incident VTE. Adjusted analyses suggest that this association is explained on the basis of confounding by obesity. However, severe nocturnal hypoxemia may be a mechanism by which OSA heightens VTE risk.

The Adenosine Pathway and Human Immunodeficiency Virus-Associated Inflammation.

Human immunodeficiency virus (HIV) is associated with an increased risk of age-associated comorbidities and mortality compared to people without HIV. This has been attributed to HIV-associated chronic inflammation and immune activation despite viral suppression. The adenosine pathway is an established mechanism by which the body regulates persistent inflammation to limit tissue damage associated with inflammatory conditions. However, HIV infection is associated with derangements in the adenosine pathway that limits its ability to control HIV-associated inflammation. This article reviews the function of purinergic signaling and the role of the adenosine signaling pathway in HIV-associated chronic inflammation. This review also discusses the beneficial and potential detrimental effects of pharmacotherapeutic strategies targeting this pathway among people with HIV.

Neighborhoods with Greater Prevalence of Minority Residents Have Lower Continuous Positive Airway Pressure Adherence.

Rationale: Limited data suggest racial disparities in continuous positive airway pressure (CPAP) adherence exist.Objectives: To assess whether CPAP adherence varies by neighborhood racial composition at a national scale.Methods: Telemonitoring data from a CPAP manufacturer database were used to assess adherence in adult patients initiating CPAP therapy between November 2015 and October 2018. Mapping ZIP code to ZIP code tabulation areas, age- and sex-adjusted CPAP adherence data at a neighborhood level was computed as a function of neighborhood racial composition. Secondary analyses adjusted for neighborhood education and poverty.Measurements and Main Results: Among 787,236 patients living in 26,180 ZIP code tabulation areas, the prevalence of CPAP adherence was 1.3% (95% confidence interval [CI], 1.0-1.6%) lower in neighborhoods with high (⩾25%) versus low (<1%) percentages of Black residents and 1.2% (95% CI, 0.9-1.5%) lower in neighborhoods with high versus low percentages of Hispanic residents (P < 0.001 for both), even after adjusting for neighborhood differences in poverty and education. Mean CPAP usage was similar across neighborhoods for the first 2 days, but by 90 days, differences in CPAP usage increased to 22 minutes (95% CI, 18-27 min) between neighborhoods with high versus low percentages of Black residents and 22 minutes (95% CI 17-27 min) between neighborhoods with high versus low percentages of Hispanic residents (P < 0.001 for both).Conclusions: CPAP adherence is lower in neighborhoods with greater proportions of Black and Hispanic residents, independent of education or poverty. These differences lead to a lower likelihood of meeting insurance coverage requirements for CPAP therapy, potentially exacerbating sleep health disparities.

Non-REM Apnea and Hypopnea Duration Varies across Population Groups and Physiologic Traits.

Rationale: Symptoms and morbidities associated with obstructive sleep apnea (OSA) vary across individuals and are not predicted by the apnea-hypopnea index (AHI). Respiratory event duration is a heritable trait associated with mortality that may further characterize OSA.Objectives: We evaluated how hypopnea and apnea durations in non-REM (NREM) sleep vary across demographic groups and quantified their associations with physiological traits (loop gain, arousal threshold, circulatory delay, and pharyngeal collapsibility).Methods: Data were analyzed from 1,546 participants from the Multi-Ethnic Study of Atherosclerosis with an AHI ≥5. Physiological traits were derived using a validated model fit to the polysomnographic airflow signal. Multiple linear regression models were used to evaluate associations of event duration with demographic and physiological factors.Measurements and Main Results: Participants had a mean age ± SD of 68.9 ± 9.2 years, mean NREM hypopnea duration of 21.73 ± 5.60, and mean NREM apnea duration of 23.87 ± 7.44 seconds. In adjusted analyses, shorter events were associated with younger age, female sex, higher body mass index (P < 0.01, all), and Black race (P < 0.05). Longer events were associated with Asian race (P < 0.01). Shorter event durations were associated with lower circulatory delay (2.53 ± 0.13 s, P < 0.01), lower arousal threshold (1.39 ± 0.15 s, P < 0.01), reduced collapsibility (-0.71 ± 0.16 s, P < 0.01), and higher loop gain (-0.27 ± 0.11 s, P < 0.05) per SD change. Adjustment for physiological traits attenuated age, sex, and obesity associations and eliminated racial differences in event duration.Conclusions: Average event duration varies across population groups and provides information on ventilatory features and airway collapsibility not captured by the AHI.

Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in the Multi-Ethnic Study of Atherosclerosis (MESA).

RATIONALE: Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia. OBJECTIVES: To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling. METHODS: We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomographic imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) by polysomnography and high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) by computed tomography. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders. RESULTS: The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI was 8.4 events/h, and 32% had an oAHI greater than 15. After adjusting for demographics, smoking, and center, an oAHI greater than 15 was associated with a 4.0% HAA increment (95% confidence interval [CI], 1.4-6.8%; P = 0.003) and 35% increased odds of ILA (95% CI, 13-61%; P = 0.001). However, there was evidence that these associations varied by body mass index (BMI) (P for interaction = 0.08 and 0.04, respectively). Among those with a BMI less than 25 kg/m2, an oAHI greater than 15 was associated with a 6.1% HAA increment (95% CI, 0.5-12%; P = 0.03) and 2.3-fold increased odds of ILA (95% CI, 1.3-4.1; P = 0.005). Among those with a BMI greater than 30 kg/m2, an oAHI greater than 15 was associated with 1.8-fold greater odds of ILA (95% CI, 1.1-2.9; P = 0.01) but was not associated with HAA. There were no meaningful associations detected among those with a BMI of 25-30 kg/m2. Greater oAHI was associated higher serum SP-A and MMP-7 levels, particularly among those with a BMI less than 25 kg/m2. CONCLUSIONS: Moderate to severe OSA is associated with subclinical ILD and with evidence of alveolar epithelial injury and extracellular matrix remodeling in community-dwelling adults, an association that is strongest among normal-weight individuals. These findings support the hypothesis that OSA might contribute to early ILD.

Arrangement of subunits in functional NMDA receptors.

Ionotropic glutamate receptors (iGluRs), including the NMDA receptor subtype, are ligand-gated ion channels critical to fast signaling in the CNS. NMDA receptors are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. However, the arrangement of GluN subunits in functional receptors-whether like subunits are adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another-remains unclear. Recently, a crystal structure of a homomeric AMPA receptor revealed that the four identical subunits adopt two distinct and subunit-specific conformations termed A/C and B/D with subunits of like conformations (e.g., A/C) diagonal to one another. In the structure, the two conformers were notable at the level of the linkers (S1-M1, M3-S2, and S2-M4) that join the ligand-binding domain to the transmembrane ion channel with the M3-S2 linker positioned more proximal to the central axis of the channel pore in the A/C conformation and S2-M4 more proximal in the B/D conformation. Using immunoblots and functional assays, we show that introduced cysteines in the M3/M3-S2 linker of GluN1, but not GluN2, show dimer formation and oxidation-induced changes in current amplitudes predictive of the A/C conformation. Conversely, introduced cysteines in the S2-M4 linker of GluN2, but not GluN1, showed similar functional effects, suggesting that the GluN2 subunit adopts the B/D conformation. Thus, we show that NMDA receptors, like AMPA receptors, possess distinct subunit-specific conformations with GluN1 approximating the A/C and GluN2 the B/D conformation. GluN subunits are therefore positioned in a N1/N2/N1/N2 arrangement in functional NMDA receptors.

Specific sites within the ligand-binding domain and ion channel linkers modulate NMDA receptor gating.

Gating in the NMDA receptor is initiated in the extracellular ligand-binding domain (LBD) and is ultimately propagated via three linkers-S1-M1, M3-S2, and S2-M4-to the ion channel. M3-S2 directly couples LBD movements into channel gating, but the functional and structural contributions of S1-M1 and S2-M4 to the overall gating process are unknown. A scan of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4 with a bulky cysteine-reactive reagent identified numerous positions that showed potentiation of glutamate-activated as well as leak currents. As indexed by MK801 (dizocilpine hydrogen maleate), an open channel blocker, this potentiation was attributable to an increase in open probability, an interpretation confirmed for a subset of positions with single-channel recordings. The magnitude of this gating effect, acting through S1-M1 or S2-M4, was dependent on the intrinsic gating properties of the NMDA receptors, being more effective in the inherently low open probability GluN2C- than the higher open probability GluN2A-subunit-containing receptors. For the majority of these potentiation positions, we propose that alteration of gating arises from steric destabilization of contact interfaces where close apposition of the contacting partners is necessary for efficient channel closure. Our results therefore indicate that the NMDA receptor S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the overall energetics of this process. Furthermore, the results conceptualize a mechanistic, as well as a possible structural, framework for pharmacologically targeting the linkers through noncompetitive and subunit-specific modes of action.