Provider Types and Outcomes in Obstructive Sleep Apnea Case Finding and Treatment: A Systematic Review.

Background: Obstructive sleep apnea (OSA) diagnosis and care models rely on sleep specialist physicians (SSPs) and can be expensive and inefficient. Purpose: To assess OSA case-finding accuracy and comparative effectiveness of care by non-sleep specialists (NSSs) and SSPs. Data Sources: MEDLINE and CINAHL from January 2000 through July 2017. Study Selection: English-language trials or observational studies comparing case finding or care by SSPs versus providers not specifically trained as SSPs (NSSs) for adults with suspected or diagnosed OSA. Data Extraction: One investigator extracted data and assessed risk of bias and strength of evidence, with confirmation by a second investigator. Primary outcomes were patient-centered (mortality, access to care, quality of life, patient satisfaction, adherence, symptom scores, and adverse events). Intermediate outcomes included resource use, costs, time to initiation of treatment, and case finding. Data Synthesis: Four observational studies (n = 580; mean age, 52 years; 77% male) reported good agreement between NSSs and SSPs on appropriate diagnostic testing and classification of OSA severity (low-strength evidence). Five randomized trials and 3 observational studies (n = 1515; mean age, 52 years; 68% male) found that care provided by NSSs and SSPs resulted in similar quality of life, adherence, and symptom scores (low-strength evidence). Evidence was insufficient for access to care and adverse events. Limitations: Many outcomes were reported infrequently or not at all. Many NSSs had extensive training or experience in sleep medicine, which limits generalizability of findings to providers with less experience. Conclusion: Care by NSSs and SSPs resulted in similar outcomes in adults with known or suspected OSA. Studies are needed to determine care model implementation and reproducibility of results in nonacademic settings and among less experienced NSSs. Primary Funding Source: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016036810 [full Veterans Affairs Evidence-based Synthesis Program report]).

Pathologic Regulation of Collagen I by an Aberrant Protein Phosphatase 2A/Histone Deacetylase C4/MicroRNA-29 Signal Axis in Idiopathic Pulmonary Fibrosis Fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless expansion of fibroblasts depositing type I collagen within the alveolar wall and obliterating the alveolar airspace. MicroRNA (miR)-29 is a potent regulator of collagen expression. In IPF, miR-29 levels are low, whereas type I collagen expression is high. However, the mechanism for suppression of miR-29 and increased type I collagen expression in IPF remains unclear. Here we show that when IPF fibroblasts are seeded on polymerized type I collagen, miR-29c levels are suppressed and type I collagen expression is high. In contrast, miR-29c is high and type I collagen expression is low in control fibroblasts. We demonstrate that the mechanism for suppression of miR-29 during IPF fibroblast interaction with polymerized collagen involves inappropriately low protein phosphatase (PP) 2A function, leading to histone deacetylase (HDA) C4 phosphorylation and decreased nuclear translocation of HDAC4. We demonstrate that overexpression of HDAC4 in IPF fibroblasts restored miR-29c levels and decreased type I collagen expression, whereas knocking down HDAC4 in control fibroblasts suppressed miR-29c levels and increased type I collagen expression. Our data indicate that IPF fibroblast interaction with polymerized type I collagen results in an aberrant PP2A/HDAC4 axis, which suppresses miR-29, causing a pathologic increase in type I collagen expression.

miR-210 promotes IPF fibroblast proliferation in response to hypoxia.

Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless spread of fibroblasts from scarred alveoli into adjacent alveolar units, resulting in progressive hypoxia and death by asphyxiation. Although hypoxia is a prominent clinical feature of IPF, the role of hypoxia as a driver of the progressive fibrotic nature of the disease has not been explored. Here, we demonstrate that hypoxia robustly stimulates the proliferation of IPF fibroblasts. We found that miR-210 expression markedly increases in IPF fibroblasts in response to hypoxia and that knockdown of miR-210 decreases hypoxia-induced IPF fibroblast proliferation. Silencing hypoxia-inducible factor (HIF)-2α inhibits the hypoxia-mediated increase in miR-210 expression and blocks IPF fibroblast proliferation, indicating that HIF-2α is upstream of miR-210. We demonstrate that the miR-210 downstream target MNT is repressed in hypoxic IPF fibroblasts and that knockdown of miR-210 increases MNT expression. Overexpression of MNT inhibits hypoxia-induced IPF fibroblast proliferation. Together, these data indicate that hypoxia potently stimulates miR-210 expression via HIF-2α, and high miR-210 expression drives fibroblast proliferation by repressing the c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates miR-210 expression in a similar distribution with HIF-2α and the hypoxic marker carbonic anhydrase-IX in cells within the IPF fibrotic reticulum. Our results raise the possibility that a pathological feed-forward loop exists in the IPF lung, in which hypoxia promotes IPF fibroblast proliferation via stimulation of miR-210 expression, which in turn worsens hypoxia.

Initial recovery and rebound of type f intestinal colonization botulism after administration of investigational heptavalent botulinum antitoxin.

Investigational heptavalent botulinum antitoxin (HBAT) is now the primary antitoxin for US noninfant botulism patients. HBAT consists of equine Fab/F(ab')2 IgG fragments, which are cleared from circulation faster than whole immunoglobulins. Rebound botulism after antitoxin administration is not previously documented but occurred in our patient 10 days after HBAT administration.

Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies. Fibroblasts isolated from IPF patients display pathological activation of PI3K/Akt caused by low PTEN phosphatase activity. This enables these cells to escape the negative proliferative properties of polymerized collagen. The mechanism underlying low PTEN activity in IPF fibroblasts is unclear, but our prior studies indicate that membrane-associated PTEN expression is decreased in these cells. Caveolin-1 is an integral membrane protein whose expression is decreased in IPF lung tissue, but how low caveolin-1 contributes to pathological fibrosis is incompletely understood. The objective of this study was to examine the hypothesis that caveolin-1 regulates PTEN function in IPF fibroblasts. Here we demonstrate that caveolin-1 expression is a determinant of membrane PTEN levels and show that PTEN interacts with caveolin-1 via its caveolin-1-binding sequence. We demonstrate that caveolin-1 expression is low in IPF fibroblasts and that this correlates with low membrane PTEN levels, whereas overexpression of caveolin-1 restores membrane PTEN levels, inhibits Akt phosphorylation, and suppresses proliferation. We demonstrate that caveolin-1 and PTEN expression are low in myofibroblasts within IPF fibroblastic foci. These data indicate that IPF fibroblasts display low caveolin-1 expression, which results in low membrane-associated PTEN expression. This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation.

Sleep Disorders in Human Immunodeficiency Virus: A Substudy of the Pharmacokinetics and Clinical Observations in People Over Fifty (POPPY) Study.

BACKGROUND: Self-reported sleep quality is poor in persons with human immunodeficiency virus (PWH), but prior studies commonly used nonspecific questionnaires, investigated only single sleep disorders, or lacked human immunodeficiency virus (HIV)-negative controls. We addressed these limitations in the Pharmacokinetics and Clinical Observations in People Over Fifty (POPPY) Sleep Substudy by assessing PWH and HIV-negative controls for insomnia, restless legs syndrome (RLS), and sleep apnea (SA). METHODS: Previously enrolled POPPY participants coenrolled in this substudy without regard to sleep symptoms. Participants completed validated sleep assessments including the Insomnia Severity Index questionnaire, International Restless Legs Syndrome Study Group questionnaire, and in-home, wrist-worn overnight oximetry. They also completed health-related quality of life questionnaires including 36-item Short Form (SF-36) and Patient-Reported Outcomes Measurement Information System (PROMIS) sleep questionnaires. RESULTS: We enrolled 357 PWH (246 >50 years of age; 111 between 18 and 50 years) and 126 HIV-negative controls >50 years of age. Among PWH, criteria were met by 21% for insomnia, 13% for RLS, and 6% for SA. Compared with HIV-negative controls, PWH had a higher risk of insomnia (adjusted odds ratio, 5.3; 95% confidence interval, 2.2-12.9) but not RLS or SA. Compared with PWH without insomnia, those with insomnia reported significantly worse scores on all SF-36 and PROMIS components; fewer than 30% reported previous diagnosis or treatment for insomnia. CONCLUSIONS: Insomnia was more common in PWH, associated with worse health-related quality of life, and frequently undiagnosed. Further research should focus on the pathogenesis of insomnia in PWH and the development of effective screening and intervention strategies for this unique population.

Sleep Apnea Symptoms as a Predictor of Fatigue in an Urban HIV Clinic.

Fatigue is common among persons living with HIV (PLWH), and risk factors for obstructive sleep apnea (OSA) such as older age and obesity are increasingly prevalent. Studies of OSA among PLWH are lacking, so we aimed to characterize OSA symptoms and associated clinical consequences (e.g., fatigue) among a contemporary population of PLWH. Self-administered surveys containing 23 items that included self-reported snoring, witnessed apneas, estimated sleep duration, the Epworth Sleepiness Score (ESS), and the FACIT-Fatigue score were mailed to PLWH receiving care at an urban HIV clinic. Clinical/demographic data were collected from the medical record. Multivariable linear regression models were created to study relationships between fatigue, clinical variables, and OSA symptoms. Of 535 surveys, 203 (38%) responded. Eight patients (3.9%) had known OSA. Among those without known OSA, mean respondent characteristics included: age 47 years; 80% male, 41% African American, 48% Caucasian, BMI 26.4 kg/m(2), duration of HIV diagnosis 12 years, 93% on antiretroviral therapy, and 81% with <50 HIV RNA copies/mL. 27% reported snoring, 24% reported witnessed apneas, and 38% had excessive daytime sleepiness. Witnessed apnea was the strongest independent predictor of fatigue (lower FACIT-Fatigue score; ß = -6.49; p < 0.001); this difference of 6.49 points exceeds the accepted minimal clinically important difference of 3.0 points. Other predictors included opioid use (ß = -5.53; p < 0.001), depression (ß = -4.18; p = 0.02), antidepressant use (ß = -4.25; p = 0.02), and sleep duration < 6 h (ß = -3.42; p = 0.02). Our data strongly support the need for increased efforts directed at OSA screening and treatment in PLWH.