Captain James A. Lovell Federal Health Care Center

BACKGROUND: Obstructive sleep apnea (OSA) is associated with coronary artery disease (CAD). Intermittent hypoxia associated with OSA increases sympathetic activity and may cause systemic inflammation, which may contribute to CAD in patients with OSA. Treatment with continuous positive airway pressure (CPAP) has been shown to change levels of inflammatory markers. We analyzed data from published studies by a systematic meta-analysis. OBJECTIVE: To asses if treatment for sleep apnea by CPAP will affect levels of inflammatory markers. DATA RESOURCES: PubMed, Embase and Cochrane library. METHODS: Study eligibility criteria full text English studies of adult, human subjects, addressing values of at least one of the inflammatory markers before and after CPAP treatment. We used the definition of OSA as an apnea-hypopnea index (AHI) of ≥ 5/h, reported values in mean and standard deviation or median with range. PARTICIPANTS: Adult, human. INTERVENTIONS: CPAP treatment for OSA. STUDY APPRAISAL AND SYNTHESIS METHOD: A total of 3835 studies were reviewed for inclusion, while 23 studies pooled for analysis. A total of 14 studies with 771 patients were pooled for C-reactive protein (CRP); 9 studies with 209 patients were pooled for tumor necrosis factor-alpha (TNF-α); and 8 studies with 165 patients were pooled for interleukin-6 (IL-6). ENDPOINT DEFINITIONS: THE FOLLOWING INFLAMMATORY MARKERS WERE CHOSEN: CRP, TNF-α, and IL-6. RESULTS: C-reactive protein: Study level means ranged from 0.18 to 0.85 mg/dl before CPAP treatment and 0.10 to 0.72 mg/dl after CPAP treatment. Mean differences, at a study level, ranged from -0.05 to 0.50. The pooled mean difference was 0.14 [95% confidence interval 0.08 to 0.20, p < 0.00001]. There was heterogeneity in this endpoint (df = 13, p < 0.00001, I(2) = 95%). Tumor necrosis factor-α: Study level means ranged from 1.40 to 50.24 pg/ml before CPAP treatment and 1.80 to 28.63 pg/ml after CPAP treatment. Mean differences, at a study level, ranged from -1.23 to 21.61. The pooled mean difference was 1.14 [95% confidence interval 0.12 to 2.15, p = 0.03]. There was heterogeneity in this endpoint (df = 8, p < 0.00001, I2 = 89%). Interleukin-6: Study level means ranged from 1.2 to 131.66 pg/ml before CPAP treatment and 0.45 to 66.04 pg/ml after CPAP treatment. Mean differences, at a study level, ranged from -0.40 to 65.62. The pooled mean difference was 1.01 [95% confidence interval -0.00 to 2.03, p = 0.05]. There was heterogeneity in this endpoint (df = 7, p < 0.00001, I(2) = 95%). LIMITATIONS: Only published data. Studies pooled were mainly small, non-randomized trials. CONCLUSION: Sleep apnea treatment with CPAP improves levels of inflammatory markers.

There are a handful of studies that have been done investigating the effect of music on various vital signs, namely systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Many studies have also assessed effects of music on self-reported anxiety level, attributing some degree of music-induced anxiety relief to the beneficial impacts of music on vital signs. Several randomised studies have shown varying effects of music on these vital parameters and so a meta-analysis was done to compare the effect of music on them. The fixed effects model was used as studies were homogenous. A two-sided alpha error < 0.05 was considered to be statistically significant. Compared to those who did not receive music therapy, those who did receive music therapy had a significantly greater decrease in SBP before and after (difference in means, -2.629, confidence interval (CI), -3.914 to -1.344, P < 0.001), a significantly greater decrease in DBP (difference in means, -1.112, CI, -1.692 to -0.532, P < 0.001), and a significantly greater decrease in HR (difference in means, -3.422, CI, -5.032 to -1.812, P < 0.001).

Background: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is more sensitive than echocardiography for the detection of intracardiac thrombus because of its unique ability to identify thrombus based on tissue characteristics related to avascularity. The long-term prognostic significance of left ventricular (LV) thrombus detected by LGE CMR is unknown. Methods: We performed a matched cohort study of consecutive adult patients with LV thrombus detected by LGE CMR who were matched on the date of CMR, age, and LV ejection fraction to up to 3 patients without LV thrombus. We investigated the long-term incidence of a composite of embolic events: stroke, transient ischemic attack, or extracranial systemic arterial embolism. We also compared outcomes among patients with LV thrombus detected by LGE CMR stratified by whether the LV thrombus was also detected by echocardiography or not. Results: Of 157 LV thrombus patients, 155 were matched to 400 non-LV thrombus patients. During a median follow-up of 3.3 years, the cumulative incidence of embolism was significantly higher in LV thrombus patients compared with the matched non-LV thrombus patients ( P &lt;0.001), with annualized rates of 3.7% and 0.8% for LV thrombus and matched non-LV thrombus patients, respectively. LV thrombus was the only independent predictor of the composite embolic end point (hazard ratio, 3.99 [95% CI, 1.54–10.35]; P =0.004). The cumulative incidence of embolism was not different in patients with LV thrombus that was also detected by echocardiography versus patients with LV thrombus not detected by echocardiography ( P =0.25). Conclusions: Despite contemporary antithrombotic treatment, LV thrombus detected by LGE CMR is associated with a 4-fold higher long-term incidence of embolism compared with matched non-LV thrombus patients. LV thrombus detected by LGE CMR but not by echocardiography is associated with a similar risk of embolism as that detected by both LGE CMR and echocardiography.

BACKGROUND: Diabetes is known to affect visual function before onset of retinopathy (diabetic retinopathy (DR)). Protection of visual function may signal disruption of mechanisms underlying DR. METHODS: This was a 6-month randomised, controlled clinical trial of patients with type 1 and type 2 diabetes with no retinopathy or mild to moderate non-proliferative retinopathy assigned to twice daily consumption of placebo or a novel, multi-component formula containing xanthophyll pigments, antioxidants and selected botanical extracts. Measurement of contrast sensitivity, macular pigment optical density, colour discrimination, 5-2 macular threshold perimetry, Diabetic Peripheral Neuropathy Symptoms, foveal and retinal nerve fibre layer thickness, glycohaemoglobin (HbA1c), serum lipids, 25-OH-vitamin D, tumour necrosis factor α (TNF-a) and high-sensitivity C reactive protein (hsCRP) were taken at baseline and 6 months. Outcomes were assessed by differences between and within groups at baseline and at study conclusion using meand ± SDs and t tests (p<0.05) for continuous variables. RESULTS: There were no significant intergroup differences at baseline. At 6 months, subjects on active supplement compared with placebo had significantly better visual function on all measures (p values ranging from 0.008 to <0.0001), significant improvements in most serum lipids (p values ranging from 0.01 to 0.0004), hsCRP (p=0.01) and diabetic peripheral neuropathy (Fisher's exact test, p=0.0024) No significant changes in retinal thickness, HbA1c, total cholesterol or TNF-α were found between the groups. CONCLUSIONS: This study provides strong evidence of clinically meaningful improvements in visual function, hsCRP and peripheral neuropathy in patients with diabetes, both with and without retinopathy, and without affecting glycaemic control. TRIAL REGISTRATION NUMBER: www.ClinicalTrials.gov Identifier: NCT01646047.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

BACKGROUND: Many patients fulfill criteria for both posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Electroconvulsive therapy (ECT) is generally acknowledged to be the most-effective treatment for refractory MDD. This study investigated the efficacy of ECT on long-term clinical outcome of comorbid PTSD and MDD. METHODS: This retrospective nested matched case-control study is inclusive of 22,164 subjects [3,485 with comorbid MDD and PTSD (92 with ECT and 3,393 without ECT) and 18,679 without MDD and PTSD]. RESULTS: Using the clinical global impression scale (CGI) to assess efficacy, more-robust improvement of PTSD and MDD symptoms was observed with ECT (90%), compared to antidepressant-treatment alone(50%) (P = 0.001). During the median of 8 years of follow-up, the death-rate was 8% in subjects without PTSD and MDD, 9.7% in PTSD and MDD treated with ECT and 18% in PTSD and MDD without ECT (P < 0.05). The suicide-rate was 2.2 and 5.9% in PTSD and MDD with and without ECT-treatment, respectively (P < 0.05). Survival-analyses revealed that the relative-risk of cardiovascular and all-cause mortality is not significantly different in patients with comorbid MDD and PTSD treated with ECT, compared to a matched-cohort without PTSD and MDD (P > 0.05). The relative risk of suicidality, all-cause, and cardiovascular mortality was reduced 64, 65, and 46% in MDD and PTSD patients treated with ECT, compared to those without ECT (P < 0.05). CONCLUSION: ECT is associated with a significant reduction of symptoms of PTSD and MDD, as well as reduction in risk of suicidality, cardiovascular, and all-cause mortality in MDD and PTSD, an effect more robust than antidepressant-therapy alone.

BACKGROUND: Longevinex® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D3 and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. METHODS: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). RESULTS: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient's pathophysiology. No side effects were observed. CONCLUSIONS: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.

PURPOSE: Rare spontaneous remissions from age-related macular degeneration (AMD) suggest the human retina has large regenerative capacity, even in advanced age. We present examples of robust improvement of retinal structure and function using an OTC oral resveratrol (RV) based nutritional supplement called Longevinex® or L/RV (circa 2004, Resveratrol Partners, LLC, Las Vegas, NV, USA). RV, a polyphenolic phytoalexin caloric-restriction mimic, induces hormesis at low doses with widespread beneficial effects on systemic health. RV alone inhibits neovascularization in the murine retina. Thus far, published evidence includes L/RV mitigation of experimentally induced murine cardiovascular reperfusion injury, amelioration of human atherosclerosis serum biomarkers in a human Japanese randomized placebo controlled trial, modulation of micro RNA 20b and 539 that control hypoxia-inducing-factor (HIF-1) and vascular endothelial growth factor (VEGF) genes in the murine heart (RV inhibited micro RNA20b 189-fold, L/RV 1366-fold). Little is known about the effects of L/RV on human ocular pathology. METHODS: Absent FDA IRB approval, but with permission from our Chief of Staff and medical center IRB, L/RV is reserved for AMD patients, on a case-by-case compassionate care basis. Patients include those who progress on AREDS II type supplements, refuse intra-vitreal anti-VEGF injections or fail to respond to Lucentis®, Avastin® or Eylea®. Patients are clinically followed traditionally as well as with multi-spectral retinal imaging, visual acuity, contrast sensitivity, cone glare recovery and macular visual fields. Three cases are presented. RESULTS: Observed dramatic short-term anti-VEGF type effect including anatomic restoration of retinal structure with a suggestion of improvement in choroidal blood flow by near IR multispectral imaging. The visual function improvement mirrors the effect seen anatomically. The effect is bilateral with the added benefit of better RPE function. Effects have lasted for one year or longer when taken daily, at which point one patient required initiation of anti-VEGF agents. Unanticipated systemic benefits were observed. CONCLUSIONS: Preliminary observations support previous publications in animals and humans. Restoration of structure and visual function in octogenarians with daily oral consumption of L/RV is documented. Applications include failure on AREDS II supplements, refusing or failing conventional anti-VEGF therapy, adjunct therapy to improve RPE function, and compassionate use in medically underserved or economically depressed third-world countries.

Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to support the notion that prazosin is effective for PTSD nightmares. However, PTSD-related nightmares often do not resolve completely on a low dose of prazosin. The capacity of prazosin to treat daytime symptoms of PTSD which are distressing to patients has not been well studied. Clinicians are reluctant to increase the dose of prazosin due to side effect concerns. To date, the highest reported dose of prazosin used for PTSD is 16 mg daily. We illustrate two case reports using high-dose (up to 30 and 45 mg) prazosin for PTSD with comorbid treatment-resistant mood disorders. We report that high-dose prazosin was safe, tolerable and effective for PTSD in adults. To our knowledge, this is the first case series to highlight the importance of using high-dose prazosin for the treatment of PTSD. In patients with partial response to currently available medications for PTSD, greater utilization of high-dose prazosin for the management of PTSD may lead to better outcomes.

Background: Myocardial fibrosis is a well-described histopathologic feature in heart transplant recipients. Whether myocardial fibrosis in heart transplant recipients is independently associated with clinical outcomes is unclear. We sought to determine whether myocardial fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging in heart transplant recipients was independently associated with all-cause death or major adverse cardiac outcomes in the long-term. Methods: Using a cohort of consecutive heart transplant recipients that had cardiovascular magnetic resonance imaging, we determined the prevalence and the patterns of myocardial fibrosis and analyzed associations between myocardial fibrosis and a composite end point of all-cause death or major adverse cardiac events: retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. Results: One hundred and fifty-two heart transplant recipients (age, 54±15 years; 29% women; 5.0±5.4 years after heart transplantation) were included. Myocardial fibrosis was present in 18% (37% infarct pattern, 41% noninfarct pattern, and 22% both). Its prevalence was positively associated with cardiac allograft vasculopathy grade. With a median follow-up of 2.6 years, myocardial fibrosis was independently associated with all-cause death or major adverse cardiac events (hazard ratio, 2.88; 95% CI, 1.59–5.23; P &lt;0.001) after adjustment for cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume. Every 1% increase in myocardial fibrosis was independently associated with a 6% higher hazard for all-cause death or major adverse cardiac events (hazard ratio, 1.06; 95% CI, 1.03–1.09; P &lt;0.001). The addition of myocardial fibrosis variables to models with cardiac allograft vasculopathy, history of rejection, time since transplantation, left ventricular ejection fraction, and indexed right ventricular end-diastolic volume resulted in significant improvements in model fit, suggesting incremental prognostic value. Conclusions: In heart transplant recipients, myocardial fibrosis is seen on late gadolinium enhancement cardiovascular magnetic resonance imaging in 18%. Both the presence and the extent of myocardial fibrosis are independently associated with the long-term risk of all-cause death or major adverse cardiac events.

OBJECTIVES/HYPOTHESIS: To determine if tympanic membrane perforation offers any protection from inner ear damage and determine the incidence and pattern of otologic blast injury in military personnel returning from deployment. STUDY DESIGN: Retrospective analysis of US service members injured in Operation Iraqi Freedom and Operation Enduring Freedom from October 2006 to October 2007. METHODS: One-hundred ten blast-injured patients were compared to 54 nonblast-injured patients returning from deployment. Data captured included audiogram results, presence of tympanic membrane perforation, demographic data, location and nature of injury, loss of consciousness, sleep disturbance, confusion, and symptoms of headache, dizziness, memory loss, and tinnitus. RESULTS: Of 110 blast-injured patients, 18 patients suffered tympanic membrane perforation (16%), of which nine patients suffered bilateral tympanic membrane perforation (8%). Blast patients suffered more hearing loss than controls as measured by pure-tone averages of varying speech reception frequencies and at 6,000 Hz. Of the blast patients who recorded an audiogram, nearly 24% suffered moderate to profound hearing loss. There was no statistically significant difference in hearing outcomes between blast-injured patients with tympanic membrane perforations and those without; however, when comparing patients with unilateral perforations with their contralateral ear, there was a difference in hearing thresholds at 6,000 Hz. There was a significantly increased risk of tinnitus, memory loss, headache, and dizziness between blast-injured patients compared to controls. CONCLUSIONS: Due to its violent nature, blast exposure causes greater neuro-otological manifestations and deserves prompt otologic evaluation.

Background. Obstructive sleep apnea (OSA) is associated with coronary artery disease. Intermittent hypoxia associated with OSA increases sympathetic activity and may cause systemic inflammation, which may contribute to atherosclerosis leading to an increase in the size of carotid intima media thickness (CIMT). Methods. PubMed and Cochrane library were reviewed by utilizing different combinations of key words: sleep apnea, carotid disease, intima media thickness, and carotid atherosclerosis. Inclusion criteria were English articles; studies with adult population with OSA and without OSA; CIMT recorded by ultrasound in mean and standard deviation or median with 95% confidence interval; and OSA defined as apnea hypopnea index of ≥5/h. A total of 95 studies were reviewed for inclusion, with 16 studies being pooled for analysis. Results. Ninety-five studies were reviewed, while 16 studies were pooled for analysis; since some studies have more than one data set, there were 25 data sets with 1415 patients being pooled for meta-analysis. All studies used ultrasound to measure CIMT. CIMT standardized difference in means ranged from -0.883 to 8.01. The pooled standardized difference in means was 1.40 (lower limit 0.996 to upper limit 1.803, (P < 0.0001). Conclusion. Patients with OSA appear to have increased CIMT suggestive of an atherosclerotic process.

Skin barrier defects play an important role in atopic dermatitis (AD) pathogenesis. Loricrin, an important barrier protein suppressed in human AD, is down-regulated by IL-4 in keratinocytes. However, the molecular mechanism is unknown. Since loricrin transcription requires p300/CBP, and Stat6 also recruits this common coactivator for its stimulated factors, we hypothesize that IL-4-activated Stat6 competes for the available endogenous p300/CBP, leading to loricrin transcription inhibition. First, we showed that loricrin is suppressed in the skin of IL-4 transgenic mice, an AD mouse model. In human keratinocytes, IL-4 down-regulation of loricrin is abrogated by a pan-Jak inhibitor, suggesting that the Jak-Stat pathway is involved. To further investigate the downstream molecular mechanism, we transfected HaCat cells with a loricrin promoter and then treated them with either IL-4 or vehicle. Not surprisingly, IL-4 greatly suppressed the promoter activity. Interestingly, this suppression was prevented when we knocked down Stat6, indicating that Stat6 participates in IL-4 regulation of loricrin. A Stat6-specific inhibitor confirmed the knockdown study. Finally, IL-4 suppression of loricrin was reversed with transfection of a CBP expression vector in a dose-dependent manner. Taken together, for the first time, we delineate a molecular mechanism for IL-4 down-regulation of loricin expression in human keratinocytes, which may play an important role in AD pathogenesis.

BACKGROUND: Transformative learning (TL) is an educational theory focused on deep fundamental shifts in an individual's worldview. Such shifts are well known to occur within graduate medical education (GME). However, TL in GME has yet to be formally explored. OBJECTIVE: We performed a scoping review of the literature on TL within GME to identify areas where trainees currently experience or have potential to experience TL, and to explore areas where fostering TL has been used as a pedagogical tool. METHODS: . RESULTS: A total of 956 articles were identified through database search with 3 unique articles found via hand-searching. Abstracts and manuscripts were screened by 2 authors and disagreements arbitrated by a third, yielding 28 articles for our analysis. The main components of TL (disorienting dilemma, reflection, discourse, action) took various forms. TL was closely linked with professionalism training and professional identity formation. Training programs in primary care fields were most frequently referenced. Often, trainees were experiencing TL without recognition of the theory by their educators. Gaps in the graduate medical education literature exist pertaining to TL in venues such as diversity, equity, and inclusion. CONCLUSIONS: Our scoping review uncovered the following themes: TL and professionalism, TL and primary care, and TL by other names. TL is likely occurring but going unrecognized in some settings.

Studies have documented an association between influenza vaccination and risk reduction in myocardial infarction, all-cause mortality, and major adverse cardiac events. This meta-analysis pooled data from 5 trials with a total of 292 383 patients. Influenza vaccination was found to be associated with significant reductions in myocardial infarction, all-cause mortality, and major adverse cardiac events. The risk reduction afforded by vaccination and the lack of major adverse events related to the influenza vaccination makes it particularly important to vaccinate those with a known cardiovascular disease or those at high risk of developing cardiovascular disease.

OBJECTIVE: Infraspinatus syndrome (IS) results from injury to the suprascapular nerve. For reasons that are poorly understood, volleyball players are at greater risk of developing IS than are athletes who compete in other overhead sports. Differences between the shoulder kinematics of volleyball-related overhead skills and those skills demanded by other overhead sports might explain the pronounced prevalence of IS among volleyball athletes. DESIGN: Observational, laboratory-based, cross-sectional study. SETTING: The American Sports Medicine Institute. PARTICIPANTS: Fourteen healthy female Division 1 collegiate volleyball athletes. METHODS: Upper limb biomechanics of 14 healthy female Division 1 collegiate volleyball athletes while spiking and serving were quantified, then compared to the results from data previously obtained from female baseball pitchers and tennis players. RESULTS: Although the general movement pattern at the shoulder girdle is qualitatively similar for the upper limb skills required by a variety of overhead sports, volleyball spiking and serving result in greater shoulder abduction and horizontal adduction at the moment of ball contact/release than do baseball pitching or tennis serving. CONCLUSION: The authors suggest that the unique scapular mechanics which permit the extreme shoulder abduction and horizontal adduction that characterise volleyball spiking and serving place anatomically predisposed volleyball athletes at increased risk for developing cumulative traction-related injury to the suprascapular nerve at the level of the spinoglenoid notch.

In patients with sleep-disordered breathing and heart failure, continuous positive airway pressure has been found to be associated with an improvement in cardiovascular end points. We conducted a systematic review of the current literature and a meta-analysis to pool data from 15 published randomized controlled trials. End points analyzed were left ventricular ejection fraction, diastolic blood pressure, systolic blood pressure, heart rate, and mortality. A fixed effects model was used for end points demonstrating homogeneity among included studies, whereas a random effects model was used for end points demonstrating heterogeneity among included studies. A significant improvement in left ventricular ejection fraction was noted with continuous positive airway pressure (mean difference, 5.05%; 95% confidence interval [CI]: 3.72 to 6.38), diastolic blood pressure (mean difference, −1.67; 95% CI: −3.09 to −0.25), and heart rate (mean difference, −5.92; 95% CI: −10.12 to−1.72). No significant changes in mortality (odds ratio, 0.63; 95% CI: 0.40 to 1.00) and systolic blood pressure were noted (mean difference, −6.35; 95% CI: −16.11 to 2.41). The analysis also revealed the need for additional studies to clarify the associations noted and the presence of publication bias with small studies with a paucity of small studies with negative results. In this meta-analysis, treatment with continuous positive airways pressure was associated with improvements in ejection fraction, diastolic blood pressure, and heart rate in patients with sleep-disordered breathing and congestive heart failure.

Obstructive sleep apnea (OSA) is associated with diabetes, hypertension, stroke, coronary artery disease, and premature death. Positive airway pressure (PAP) is the mainstay of therapy. Despite its effective treatment with PAP therapy, noncompliance remains high. Many factors determine compliance. The role of severity of OSA measured by the apnea-hypopnea index (AHI) remains controversial. Meta-analysis of studies examining this role of AHI was performed. A systematic review of the medical literature was conducted using PubMed and Cochrane library by utilizing different combinations of key words: sleep apnea, AHI, compliance, and nonadherence. Inclusion criteria were English articles; Studies with adult population; with 2 groups of patients (compliant and noncompliant); Studies utilizing objective definition of compliance (PAP usage of >4 hours per night for 70% of days or usage >5 d/wk and for >4 hours per night). Studies were analyzed by standard methods of meta-analysis. The studies were heterogeneous for AHI; therefore, the random effect model was used. Six hundred forty-one manuscripts were found. Of these, 230 were found to be appropriate for full text evaluation. Thirty-one met inclusion criteria. Twelve of these studies used objective criteria for PAP compliance and were hence included in meta-analysis. All the subjects had OSA determined by polysomnography, for whom PAP was employed. Compliance to PAP therapy was evaluated after a period of time ranging from 4 weeks to 8 years. There were 1438 subjects included in the meta-analysis; 886 subjects were PAP compliant, whereas 552 subjects were noncompliant. A greater AHI was found in PAP compliant patients. The mean difference between compliant and noncompliant groups was 5.9 (95% confidence interval: 0.19-11.67, P < 0.05). Patients with mild OSA are less likely to be compliant with PAP therapy. These patients should receive aggressive management particularly at the start of therapy with close follow-up to increase compliance.

A few trials have investigated the efficacy of colesevelam in the reduction of glycemic and lipid outcomes. These meta-analysis pooled data from 8 such trials and found that colesevelam is associated with significant reductions in plasma fasting glucose, hemoglobin A1c, and low-density lipoprotein. Insignificant reductions in high-density lipoprotein and total cholesterol were also noted along with significant increase in triglycerides. This analysis concludes that colesevelam may be of particular benefit in managing type 2 diabetic patients with hyperlipidemia in whom low-density lipoprotein levels are of particular concern. Caution should be taken in patients who have hypertriglyceridemia or low high-density lipoprotein levels before starting therapy.

Cyclophilin-D (Cyp-D) is a mitochondrial matrix peptidyl-prolyl isomerase. Because cyclophilins can regulate nuclear gene expression, we examined whether Cyp-D could regulate mitochondrial gene expression. We demonstrated in HEK 293T cells that transfected Cyp-D interacts with mitochondrial transcription factors B1 and B2 (TFB2M) but not with mitochondrial transcription factor A. We also demonstrated that Cyp-D interacts in vivo with TFB2M. Genetic silencing of Cyp-D and pharmacologic inhibition of Cyp-D markedly reduced mitochondrial transcription to 18 ± 5% (P < 0.05) and 24 ± 3% (P < 0.05) of respective controls. The level of interaction between Cyp-D and TFB2M correlated with the level of nascent mitochondrial RNA intensity (r = 0.896; P = 0.0156). Cyp-D silencing down-regulated mitochondrial transcripts initiated from the heavy strand promoter 2 [i.e., NADH dehydrogenase 1 (ND1) by 11-fold, P < 0.005; cytochrome oxidase 1 (COX1) by 4-fold, P < 0.001; and ATP synthase subunit 6 (ATP6) by 6.5-fold, P < 0.005); but not NADH dehydrogenase 6 (ND6)], which is initiated from the light strand promoter. Cyp-D silencing reduced mitochondrial membrane potential and cellular oxygen consumption (from 59 ± 5 to 34 ± 1 µmol oxygen/min/10(6) cells, P < 0.001); the latter without a statistically significant reversal after uncoupling electron transport from ATP synthesis, consistent with down-regulation of electron transport complexes. Accordingly, these studies provide novel evidence that Cyp-D could play a key role in regulating mitochondrial gene expression.