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Introduction Exercise is one of several factors known to lower the risk of developing cancer, as well as improve outcomes in patients already diagnosed. People who exercise after cancer have lower rates of cancer complications, treatment toxicities, relapse and improved survival. This review highlights the supportive data and biochemical processes, which explain these potential benefits. Sources of data PubMed, Embase, Medline and Cochrane libraries were searched for papers which addressed the effects of exercise and physical activity on cancer for this review. The search terms used were physical activity, exercise and cancer up to February 2021. We also referred to the background research required for international exercise intervention study involving men with prostate cancer (INTERVAL-GAP4) and scrutinized references within the robust papers published on this subject to ensure we did not miss any clinically studies. One hundred and eighty eight papers were included. Areas of agreement Exercise programmes mitigate many of the complications and risks associated with cancer, particularly thromboembolism, fatigue, weight gain, arthralgia, cognitive impairment and depression. Areas of controversy Molecular and biomarker changes, resulting from exercise, suggest that exercise elicits beneficial changes in insulin-related pathways, down-regulates inflammation and serum oestrogen levels, and enhances oxidative, immune and cellular repair pathways. Nonetheless, the evidence remains preliminary. Growing points The timing, intensity and challenges of prehabilitation, adjunct and rehabilitation exercise programmes are being increasingly understood but their implementation remains sporadic. Areas for developing research More robust clinical trial data are needed to substantiate a causal effect of exercise on overall and cancer-specific survival. These studies are ongoing. Research evaluating the most cost-efficient ways of incorporating prehabilitation, adjunct and rehabilitation programmes into routine practice would be helpful to funding bodies and health care strategists.

Background Assess if changes in sleep quality (Sleep Quality Index, SQI) based on cardiopulmonary coupling-analysis (CPC) impacts serum adiponectin-levels in patients with cardiovascular disease (CVD). Methods Secondary analysis of electrocardiogram (ECG) data from the Heart Biomarker Evaluation in Apnea Treatment study (HeartBEAT), a multicenter, controlled trial in patients with CVD and moderate-severe sleep apnea, randomly assigned to intervention of Continuous Positive Airway Pressure (CPAP), Nocturnal Supplemental Oxygen (NSO) or Healthy Lifestyle and Sleep Hygiene Education (HLSE; control group). Participants with good-quality ECG-signal (n = 241) were included. Results Improving CPC-sleep quality was associated with net average improvements in serum adiponectin-levels 2.69 μg/ml (p = 0.005) irrespective of therapy initiated. After controlling for confounders, a unit increase in SQI was associated with increase in serum adiponectin-levels 0.071 μg/ml (p = 0.012) and decrease in insulin-levels 0.197 μIU/ml (p = 0.0018). Similarly, a percentage point increase in sleep apnea indicator (SAI) was associated with decrease in serum adiponectin-levels of 0.071 μg/ml (p = 0.017) and increase in insulin-levels of 0.218 μIU/ml (p = 0.020). A percentage point increase in CPC-sleep fragmentation (eLFCBB) had a predicted increase in glucose-levels 0.371 mg/dl (p = 0.009) and insulin-levels 0.284 μIU/ml (p = 0.010). In patients receiving CPAP-therapy, a difference in serum adiponictin levels of 3.82 μg/ml (p = 0.025) is observed comparing patients in which SQI-improved to patients that SQI-declined during the study period. The difference is mostly due to a decrease in serum adiponectin levels in patients that decline in SQI (−3.20 μg/ml). Conclusion Improvements in sleep quality were associated with higher serum adiponectin-levels, and improved measures of glycemic metabolism which may have beneficial effects on metabolic syndrome and cardiovascular health. Clinical trial registration name and number The Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT) study is registered at https://clinicaltrials.gov/ct2/show/NCT01086800 .

STUDY OBJECTIVES: The recognition of specific endotypes as drivers of sleep apnea suggests the need of therapies targeting individual mechanisms. Acetazolamide is known to stabilize respiration at high altitude but benefits at sea level are less well understood. METHODS: All controlled studies of acetazolamide in obstructive sleep apnea and/or central sleep apnea (CSA) were evaluated. The primary outcome was the apnea-hypopnea index. RESULTS: Fifteen trials with a total of 256 patients were pooled in our systematic review. Acetazolamide reduced the overall apnea-hypopnea index (mean difference [MD] −15.82, 95% CI: −21.91 to −9.74, P < .00001) in central sleep apnea (MD −22.60, 95% CI: −29.11 to −16.09, P < .00001), but not in obstructive sleep apnea (MD −10.29, 95% CI: −33.34 to 12.77, P = .38). Acetazolamide reduced the respiratory related arousal index (MD −0.82, 95% CI: −1.56 to −0.08, P = .03), improved partial arterial of oxygen (MD 11.62, 95% CI: 9.13–14.11, P < .00001), mean oxygen saturation (MD 1.78, 95% CI: 0.53–3.04, P = .005), total sleep time (MD 25.74, 95% CI: 4.10–47.38, P = .02), N2 sleep (MD 3.34, 95% CI: 0.12–6.56, P = .04) and sleep efficiency (MD 4.83, 95% CI: 0.53–9.13, P = .03). CONCLUSIONS: Acetazolamide improves the apnea-hypopnea index and several sleep metrics in central sleep apnea. The drug may be of clinical benefit in patients with high loop gain apnea of various etiologies and patterns. The existence of high heterogeneity is an important limitation in applicability of our analysis. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; Name: The effect of acetazolamide in patients with sleep apnea at sea level: a systematic review and meta analysis; URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020163316; Identifier: CRD42020163316. CITATION: Ni Y-N, Yang H, Thomas RJ. The role of acetazolamide in sleep apnea at sea level: a systematic review and meta-analysis. J Clin Sleep Med. 2021;17(6):1295–1304.

Background While obesity is linked with brain atrophy and dementia incidence, associations with regional adiposity are uncertain. Our goal was to determine whether cerebral gray matter volume is related to neck circumference (NC), a measure of regional adiposity having unique relationships with metabolic disorders and cardiovascular disease. Methods Magnetic resonance imaging and NC were cross-sectionally assessed from 2011 to 2014 in a population-based sample of 2916 men and women in the Korean Genome and Epidemiology Study. Results For men, NC was inversely associated with total and regional gray matter in the frontal, temporal, and occipital lobes after adjusting for age and intracranial brain volume. Associations were especially strong in the presence of diabetes. With further adjustment for indices of body composition and other characteristics, total and frontal gray matter in diabetic men were lowered by 6.1 mL (95% confidence interval: 2.5-9.7, P=0.004) and 2.9 mL (95% confidence interval: 1.0-4.9, P=0.017), respectively, per SD increase in NC (2.3 cm). For men without diabetes, and in all women, associations were less apparent. Conclusions In men with diabetes, NC was inversely associated with cerebral gray matter volume. The link between neck anthropometry and brain aging in diabetic men warrants further consideration.

Background Complete heart block (CHB) is a frequent cause for acute admission in older patients with significant cardiac conduction disease. Common presenting symptoms are syncope and dyspnoea. Some patients may exhibit clinical and radiological signs of left ventricular (LV) decompensation, despite preserved LV ejection fraction on transthoracic echocardiography (TTE) and absent pre-existing LV dysfunction. Case summary In this clinical report, we present a case of CHB associated with transient but severe elevation in pulmonary artery systolic pressure, measured as the equivalent right ventricular systolic pressure (RVSP = 99 mmHg) by TTE in the absence of right ventricular outflow tract obstruction, that subsequently ‘normalized’ after implantation of a permanent pacemaker. After searching our echocardiogram database, we did find other cases with similar findings. Discussion There is limited literature describing transient acute elevation in estimated pulmonary pressures in the setting of new CHB that is subsequently reversed by permanent pacing. The true prevalence and mechanism of transient estimated pulmonary pressure as a result of CHB remains unknown. Based on our limited assessment, we postulate that the acute elevation in estimated pulmonary pressures is predominantly related to a compensatory augmentation of RV stroke volume and is caused by the underlying bradycardia and need to maintain forward cardiac output. This phenomenon may require further investigation and validation in future studies.

Tea contains polyphenols such as flavonoids, anthocyanidins, flavanols and phenolic acids which in laboratory studies have reported to promote antioxidant enzyme formation, reduces excess inflammation, slow cancer cell proliferation and promote apoptosis. Evidence from epidemiological studies on the effect of tea consumption on prostate cancer (CaP) incidence has been conflicting. We analysed data from 25 097 men within the intervention arm of the 155 000 participant Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Histologically confirmed cases of prostate cancer were reported in 3088 men (12·3 %) during the median 11·5 year follow-up. Tea consumption was assessed with a FFQ. Baseline characteristics were compared between groups using χ2 and Kruskal–Wallis tests. Cox regression models were used to assess associations between tea intake and CaP incidence. There was no statistical difference between the risk of CaP between men who never drank tea to those who drank tea at any quantity. Amongst tea drinkers, those in the highest third of consumption group had a small but significantly lower risk compared with those in the lowest third (11·2 % v. 13·2 % hazard ratio 1·16; (95 % CI 1·05, 1·29), P = 0·004). This pattern persisted with adjustments for demographics and lifestyle. In conclusion, among tea drinkers, there was a small positive association between drinking tea and a reduced risk of prostate cancer. It does not support starting to drink tea, if men previously did not, to reduce the risk. Further research is needed to establish whether tea is justified for future prospective nutritional intervention studies investigating CaP prevention.

International audience; High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX. We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100 mg/m(2), instead of the usual dose of 3500 mg/m(2), and daily hemodialysis started 24 h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment. We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100 mg/m(2) as a viable therapeutic modality in ESRD patients. (C) 2021 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.

Background and Purpose— Commonly used tools to determine functional outcome after aneurysmal subarachnoid hemorrhage (aSAH) have limitations. Time spent at the patient’s home has previously been proposed as a robust outcome measure after ischemic stroke. Here, we set out to validate home-time as an outcome measure after aSAH. Methods— We examined prospectively collected data from a nationwide multicenter registry of aSAH patients admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009–2015). We calculated mean home-time (defined as days spent at home for the first 90 days after aSAH) and 95% CIs for each category of modified Rankin Scale at discharge and 1-year follow-up, using linear regression models to analyze home-time differences per modified Rankin Scale category. Results— We had home-time data from 1076 of 1866 patients (57.7%), and multiple imputation was used to fill-in missing data from the remaining 790 patients. Increasing home-time was associated with improved modified Rankin Scale scores at time of hospital discharge ( P P Conclusions— Home-time for the first 90 days after aSAH offers a robust and easily ascertainable outcome measure, discriminating particularly well across better recovery levels at time of hospital discharge and at 1-year follow-up. This measure complies with the modern trend of patient-centered healthcare and research, representing an outcome that is particularly relevant to the patient. Clinical Trial Registration— URL: https://clinicaltrials.gov . Unique identifier: NCT03245866.

Background Excessive daytime sleepiness (EDS), a primary symptom of obstructive sleep apnea (OSA), negatively affects functioning and quality of life (QoL). EDS can persist despite primary airway therapy, and often remains unmanaged, potentially due to inadequate provider-patient communication. Ethnographic research was conducted to assess provider-patient communication about EDS. Methods Participating physicians (primary care n = 5; pulmonologists n = 5; sleep specialists n = 3) identified adult patients (n = 33) diagnosed with OSA who were prescribed positive airway pressure (PAP) therapy ≥6 months prior and previously reported EDS. Visits and post-visit interviews were video-recorded and analyzed using standardized, validated sociolinguistic techniques. Results Despite 55% of patients (18/33) reporting QoL impacts post-visit, this was discussed during 28% (5/18) of visits. Epworth Sleepiness Scale was administered during 27% (9/33) of visits. Many patients (58% [19/33]) attributed EDS to factors other than OSA. Physicians provided EDS education during 24% of visits (8/33). Prior to the visit, 30% (10/33) of patients were prescribed EDS medication, of which 70% (7/10) reported currently experiencing EDS symptoms. Conclusions EDS was minimally discussed and rarely reassessed or treated after PAP therapy initiation in this study. Patients often attributed EDS to factors other than OSA. The findings suggest physicians and patients may benefit from dialogue tools, routine use of screening tools, and patient education.

Study Objectives Age-related comorbidities and immune activation raise concern for advanced brain aging in people living with HIV (PLWH). The brain age index (BAI) is a machine learning model that quantifies deviations in brain activity during sleep relative to healthy individuals of the same age. High BAI was previously found to be associated with neurological, psychiatric, cardiometabolic diseases, and reduced life expectancy among people without HIV. Here, we estimated the effect of HIV infection on BAI by comparing PLWH and HIV− controls. Methods Clinical data and sleep EEGs from 43 PLWH on antiretroviral therapy (HIV+) and 3,155 controls (HIV−) were collected from Massachusetts General Hospital. The effect of HIV infection on BAI, and on individual EEG features, was estimated using causal inference. Results The average effect of HIV on BAI was estimated to be +3.35 years (p < 0.01, 95% CI = [0.67, 5.92]) using doubly robust estimation. Compared to HIV− controls, HIV+ participants exhibited a reduction in delta band power during deep sleep and rapid eye movement sleep. Conclusion We provide causal evidence that HIV contributes to advanced brain aging reflected in sleep EEG. A better understanding is greatly needed of potential therapeutic targets to mitigate the effect of HIV on brain health, potentially including sleep disorders and cardiovascular disease

Context The majority of people in need of palliative care (PC) in low- and middle-income countries lack access to it and suffer unnecessarily as a consequence. This unmet need is due, in part, to the lack of trained PC providers. Objectives This study aims to assess the effects of regional training in PC for doctors, nurses, and pharmacists in the Caribbean through assessment of participant satisfaction, anticipated course impact on participants’ clinical practice, barriers to changing practice, and perceived course impact on achievement of key PC milestones. Methods We created and taught a course in basic PC for clinicians from the Caribbean region and collected and analyzed postcourse quantitative and qualitative data on satisfaction and expected impact. Results Eighty-three clinicians from five Caribbean countries participated in this workshop. Thirty participants completed the post-course survey. One hundred percent of these participants ranked the quality of the course as “very high quality” or “high quality.” The majority of participants anticipated changing their practice as a result of this course. Several barriers were reported, including lack of formal PC training in participants’ home countries. Results of participants’ retrospective pre- and postcourse self-assessment for achievement of key PC milestones showed a statistically significant mean increase of at least one point on the seven-point Likert scale for each milestone. Conclusion Overall satisfaction with the course was high, and self-assessed competency in PC improved. These data suggest that an intensive training over several days is an effective format for increasing providers’ perceived efficacy in delivering PC.

Decellularized porcine corneal scaffolds are a potential alternative to human cornea for keratoplasty. Although clinical trials have reported promising results, there can be corneal haze or scar tissue. Here, we examined if recellularizing the scaffolds with human keratocytes would result in a better outcome. Scaffolds were prepared that retained little DNA (14.89 ± 5.56 ng/mg) and demonstrated a lack of cytotoxicity by in vitro. The scaffolds were recellularized using human corneal stromal cells and cultured for between 14 in serum-supplemented media followed by a further 14 days in either serum free or serum-supplemented media. All groups showed full-depth cell penetration after 14 days. When serum was present, staining for ALDH3A1 remained weak but after serum-free culture, staining was brighter and the keratocytes adopted a native dendritic morphology with an increase (p < 0.05) of keratocan, decorin, lumican and CD34 gene expression. A rabbit anterior lamellar keratoplasty model was used to compare implanting a 250 μm thick decellularized lenticule against one that had been recellularized with human stromal cells after serum-free culture. In both groups, host rabbit epithelium covered the implants, but transparency was not restored after 3 months. Post-mortem histology showed under the epithelium, a less-compact collagen layer, which appeared to be a regenerating zone with some α-SMA staining, indicating fibrotic cells. In the posterior scaffold, ALDH1A1 staining was present in all the acellular scaffold, but in only one of the recellularized lenticules. Since there was little difference between acellular and cell-seeded scaffolds in our in vivo study, future scaffold development should use acellular controls to determine if cells are necessary.

A new concept of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep is proposed, that of multi-component integrative states that define stable and unstable sleep, respectively, NREMS, NREMUS REMS, and REMUS. Three complementary data sets are used: obstructive sleep apnea (20), healthy subjects (11), and high loop gain sleep apnea (50). We use polysomnography (PSG) with beat-to-beat blood pressure monitoring, and electrocardiogram (ECG)-derived cardiopulmonary coupling (CPC) analysis to demonstrate a bimodal, rather than graded, characteristic of NREM sleep. Stable NREM (NREMS) is characterized by high probability of occurrence of the US) has the opposite features: a fragmented and discontinuous integrated multicomponent network model of NREM sleep which captures sleep onset (e.g., ventrolateral preoptic area-based sleep switch) processes, synaptic homeostatic delta power kinetics, and the interaction of global and local sleep processes as reflected in the spatiotemporal evolution of cortical “UP” and “DOWN” states, while incorporating the complex dynamics of autonomic-respiratory-hemodynamic systems during sleep. Bimodality of REM sleep is harder to discern in health. However, individuals with combined obstructive and central sleep apnea allows ready recognition of REMS and REMUS (stable and unstable REM sleep, respectively), especially when there is a discordance of respiratory patterns in relation to conventional stage of sleep.

Background After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. Methods The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. Discussion The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. Trial registration EudraCT Number: 2018–000987-27 Clinical trial registry & ID: ClinicalTrials.gov: NCT03682276.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

STUDY OBJECTIVES: To describe sex, age, and body mass index (BMI) differences in comorbidities and polysomnography measures, categorized using 3 different apnea-hypopnea index (AHI) criteria in sleep clinic patients with mild obstructive sleep-disordered breathing. METHODS: A retrospective cohort of 305 (64% female) adult sleep clinic patients who underwent full-night in-laboratory polysomnography having been diagnosed with mild sleep-disordered breathing and prescribed positive airway pressure. Effects of sex, age, and BMI on comorbidities and polysomnography measures, including rates of AHI defined by ≥ 3% desaturations (AHI(3%)), with arousals (AHI(3%A)), by ≥ 4% desaturations (AHI(4%)), and by respiratory disturbance index, were evaluated. RESULTS: Sixty-nine (23%), 116 (38%), 258 (85%), and 267 (88%) patients had AHI(4%), AHI(3%), AHI(3%A), and respiratory disturbance index ≥ 5 events/h, respectively. Ninety-day positive airway pressure adherence rates were 45.9% overall and higher in women > 50-years-old (51.2%, P = 0.013) and men (54.5%, P = 0.024) with no difference whether AHI(4%) or AHI(3%A) was < 5 or ≥ 5 events/h. Men and women had similar rates of daytime sleepiness (43.3%), anxiety (44.9%), and hypertension (44.9%). Women were more likely to have obesity, anemia, asthma, depression, diabetes, fibromyalgia, hypothyroidism, migraine, and lower rates of coronary artery disease. More patients with AHI(4%) < 5 events/h had depression, migraines, and anemia, and more patients with AHI(4%) ≥ 5 events/h had congestive heart failure. Women were more likely to have higher sleep maintenance and efficiency, shorter average obstructive apnea and hypopnea durations, and less supine-dominant pattern. Average obstructive apnea and hypopnea duration decreased with increasing BMI, and average hypopnea duration increased with age. Obstructive apnea duration and obstructive hypopnea with arousal duration decreased with increasing BMI. More women had AHI(4%) < 5 (81.5% vs 69.1%), AHI(3%) < 5 (68.7% vs 49.1%), and AHI(3%A) < 5 events/h (18.5% vs 10.0%). Greater age and higher BMI were associated with higher AHI. CONCLUSIONS: Current AHI criteria do not predict comorbidities or adherence in mild sleep-disordered breathing patients. In this hypothesis-generating descriptive analysis, sex, BMI, and age may all be factors that should be accounted for in future research of mild sleep-disordered breathing patients. Different sleep study measures may weigh differently in calculations of risk for cardiovascular versus somatic comorbidities. CITATION: Johnson KG, Johnson DC, Thomas RJ, Rastegar V, Visintainer P. Cardiovascular and somatic comorbidities and sleep measures using three hypopnea criteria in mild obstructive sleep-disordered breathing: sex, age, and body mass index differences in a retrospective sleep clinic cohort. J Clin Sleep Med. 2020;16(10):1683–1691.

Louis-Ferdinand, Robert Thomas, Ph.D. , University of Rhode Island August, 1969. The Modification of Hepatic Microsomal Drug Metabolism by Phenobarbital and Amphetamine. Major Professor: Dr. George C. Fuller. This investigation was carried out to provide a mechanistic explanation for the modification of hepatic microsomal drug metabolism produced by amphetamine· and phenobarbital. The influence of phenobarbital administration on the activity of microsomal ribonuclease during induction of drug-metabolizing enzymes, was determined. Administration of phenobarbital (100 mg/kg) for six days resulted in a significant (P .£0. 05) increase in hepatic microsomal oxidative demethylation. Conversely, hepatic microsomal ribonuclease activity of phenobarbital-treated rats was significantly reduced to less than 5% of control values. When phenobarbital (50 mg/kg) was administered for 5 days ribonuclease activity was inhibited to about one-half of control values. Phenolpthalein {3-glucuronidase activity of hepatic microsomal fractions obtained from phenobarbital treated animals was not significantly (P) O. 05) different from controls. Phenobarbital(lxlo-\1olar) did not inhibit ribonuclease activity following in vitro additions to the assay system. Time-response studies were. conducted following the administration of a single dose of phenobarbital (100 mg/kg). Results of these studies indicated that microsomal p-chloro-N-methylaniline (PCMA) demethylase stimulation and ribonuclease inhibition were temporaily related, except for a 24 hour lag in the PCMA demethylase response. Administration of phenobarbital (50 mg/kg twice-daily) produced significant inhibition of ribonuclease and stimulaticn of drug metabolism in liver microsomes of intact, adrenalectomized or hypophysectomized rats. Administration of 3-methylcholanthrene (40 mg/kg) to male rats resulted in a non-significant inhibition of ribonuclease activity while p-nitroanisole demethylation was stimulated three-fold. In vitro recombination experiments in which 105, 000 x g rat liver supernatants from control and treated animals were combined ·with rnicrosomes

Objectives This study sought to evaluate the proportion of patients with atrial fibrillation (AF) who also have undiagnosed sleep apnea and examine the impact of its diagnosis on adherence to sleep apnea therapies. Background Sleep apnea is a modifiable risk factor for AF. However, the proportion of patients with AF who also have undiagnosed sleep apnea and the impact of its diagnosis on therapy have not been well studied. Methods This prospective study included 188 consecutive patients with AF without a prior diagnosis of sleep apnea who were scheduled to undergo AF ablation. Participants underwent home sleep apnea testing, completed a sleep apnea screening questionnaire (STOP-BANG [Snoring; Tiredness, Fatigue, or Sleepiness During the Daytime; Observation of Apnea and/or Choking During Sleep; Hypertension; Body Mass Index >35 kg/m2; Age >50 Years; Neck Circumference >40 cm; and Male Sex]) and were followed for ≥2 years to evaluate the impact of diagnosis on therapy. Results Home sleep apnea testing was positive in 155 of 188 patients (82.4%); among those 155, 127 (82%) had a predominant obstructive component and 28 (18%) had mixed sleep apnea with a 15.2 ± 7.4% central component. Sleep apnea severity was mild in 43.8%, moderate in 32.9%, and severe in 23.2%. The sensitivity and specificity of a STOP-BANG questionnaire were 81.2% and 42.4%, respectively. In a multivariate analysis, STOP-BANG was not predictive for sleep apnea (odds ratio: 0.54; 95% confidence interval: 0.17 to 1.76; p = 0.31). Therapy with continuous positive airway pressure ventilators was initiated in 73 of 85 patients (85.9%) with moderate or severe sleep apnea, and 68 of the 73 patients (93.1%) remained complaint after a mean follow-up period of 21 ± 6.2 months. Conclusions Sleep apnea is exceedingly prevalent in patients with AF who are referred for ablation, with a large proportion being undiagnosed due the limited predictive value of sleep apnea symptoms in this AF population. Screening for sleep apnea resulted in high rate of long-term continuous positive airway pressure adherence.

Objective Brain Age Index (BAI), calculated from sleep electroencephalography (EEG), has been proposed as a biomarker of brain health. This study quantifies night-to-night variability of BAI and establishes probability thresholds for inferring underlying brain pathology based on a patient's BAI. Methods 86 patients with multiple nights of consecutive EEG recordings were selected from Epilepsy Monitoring Unit patients whose EEGs reported as being within normal limits. BAI was calculated for each 12-hour segment of patient data using a previously described algorithm, and night-to-night variability in BAI was measured. Results The within-patient night-to-night standard deviation in BAI was 7.5 years. Estimates of BAI derived by averaging over 2, 3, and 4 nights had standard deviations of 4.7, 3.7, and 3.0 years, respectively. Conclusions Averaging BAI over n nights reduces night-to-night variability of BAI by a factor of the square root of n, rendering BAI more suitable as a biomarker of brain health at the individual level. Significance With increasing ease of EEG acquisition including wearable technology, BAI has the potential to track brain health and detect deviations from normal physiologic function. In a clinical setting, BAI could be used to identify patients who should undergo further investigation or monitoring., 18 pages, 6 figures, 2 tables

We investigated both independent and interconnected effects of 3 lifestyle factors on brain volume, measuring yearly changes using large-scale longitudinal magnetic resonance imaging, in middle-aged to older adults. We measured brain volumes in a cohort (n = 984, 49-79 years) from the Korean Genome and Epidemiology Study group, using baseline and follow-up estimates after 4 years. In our analysis, the accelerated brain atrophy in normal aging was observed across regions (e.g., brain tissue: -0.098 ± 0.01 mL/y, p0.001). An independent lifestyle-specific trend of brain atrophy across time was also evident in men, where smoking (p = 0.012) and physical activity (p = 0.014) showed the strongest association with the atrophy rate. Linear regression analysis of the interconnected effect revealed that brain atrophy is mitigated by intense physical activity in smoking males. Lifestyle factors did not show any significant effect on brain volume in women. These results provide important information regarding lifestyle factors that affect brain aging in mid-to-late adulthood. Our findings may aid in the identification of preventive measures against dementia.

Study Objective: Sleep is reflected not only in the electroencephalogram but also in heart rhythms and breathing patterns. Therefore, we hypothesize that it is possible to accurately stage sleep based on the electrocardiogram (ECG) and respiratory signals. Methods: Using a dataset including 8,682 polysomnographs, we develop deep neural networks to stage sleep from ECG and respiratory signals. Five deep neural networks consisting of convolutional networks and long short-term memory networks are trained to stage sleep using heart and breathing, including the timing of R peaks from ECG, abdominal and chest respiratory effort, and the combinations of these signals. Results: ECG in combination with the abdominal respiratory effort achieve the best performance for staging all five sleep stages with a Cohen's kappa of 0.600 (95% confidence interval 0.599 -- 0.602); and 0.762 (0.760 -- 0.763) for discriminating awake vs. rapid eye movement vs. non-rapid eye movement sleep. The performance is better for young participants and for those with a low apnea-hypopnea index, while it is robust for commonly used outpatient medications. Conclusions: Our results validate that ECG and respiratory effort provide substantial information about sleep stages in a large population. It opens new possibilities in sleep research and applications where electroencephalography is not readily available or may be infeasible, such as in critically ill patients., Contains supplementary material at the end. Sleep 2019

Study Objectives Sleep behaviors are related to brain structure and function, but the impact of long-term changes in sleep timing on brain health has not been clearly addressed. The purpose of this study was to examine the association of longitudinal changes in sleep timing from middle to late-life with gray matter volume (GMV), an important marker of brain aging. Methods We enrolled 1798 adults (aged 49–82 years, men 54.6%) who underwent magnetic resonance imaging (MRI) between 2011 and 2014. Midsleep time (MST) on free days corrected for sleep debt on workdays was adopted as a marker of sleep timing. Data on MST were available at the time of MRI assessment and at examinations that were given 9 years earlier (2003–2004). Longitudinal changes in MST over the 9-year period were derived and categorized into quartiles. Subjects in quartile 1 were defined as “advancers” (MST advanced ≥ 1 h) while those in quartile 4 were defined as “delayers” (MST delayed ≥ 0.2 h). Quartiles 2–3 defined a reference group (MST change was considered modest). The relationship of GMV with MST changes over 9 years was investigated. Results Nine-year change in MST were significantly associated with GMV. Compared to the reference group, advancers had smaller GMVs in the frontal and temporal regions. A delay in MST was also associated with smaller cerebellar GMV. Conclusions In middle-to-late adulthood, the direction of change in MST is associated with GMV. While advancers and delayers in MST tend to present lower GMV, associations appear to differ across brain regions.

BACKGROUND There are limited data on the association between obstructive sleep apnea (OSA), which is characterized by intermittent hypoxia, and male-pattern baldness (MPB). Low blood iron levels are reportedly associated with hypoxia and hair loss. This study explored a possible link among OSA, iron status, and MPB. METHODS Polysomnography (PSG) and hair assessments were conducted in a cross-sectional study including 932 men aged 46-76 years. OSA was defined as an apnea-hypopnea index ≥5 by PSG evaluation and MPB as scales from IV to VII according to the Norwood-Hamilton scale classification. Serum transferrin saturation (TSA) levels were assessed. RESULTS A total of 224 men (24%) were identified as MPB cases and 495 men (53%) as having OSA. After considering potential risk factors, OSA and other sleep-related variables were not associated with MPB. In joint analysis of OSA and family history of hair loss, men with these two factors showed a sevenfold higher multivariate odds ratio (95% confidence interval: 3.70, 12.56) for MPB than those without both of them (P

Sleep, a vital process of human being, is carefully orchestrated by the brain and consists of cyclic transitions between rapid eye movement (REM) and non-REM (NREM) sleep. Autonomic tranquility during NREM sleep is characterized by vagal dominance and stable breathing, providing an opportunity for the cardiovascular-neural axis to restore homeostasis, in response to use, distress or fatigue inflicted during wakefulness. Abrupt irregular swings in sympathovagal balance during REM sleep act as phasic loads on the resting cardiovascular system. Any causes of sleep curtailment or fragmentation such as sleep restriction, sleep apnea, insomnia, periodic limb movements during sleep, and shift work, not only impair cardiovascular restoration but also impose a stress on the cardiovascular system. Sleep disturbances have been reported to play a role in the development of stroke and other cardiovascular disorders. This review aims to provide updated information on the role of abnormal sleep in the development of stroke, to discuss the implications of recent research findings, and to help both stroke clinicians and researchers understand the importance of identification and management of sleep pathology for stroke prevention and care.

The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.

Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase, nitric oxide (NO) generation, and decreased activity of the mitogen-activated protein kinase (MAPK) JNK (c-Jun NH2-terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity, which, in turn, activates protein kinase G (PKG) by increasing cGMP levels. In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGMP-PKG pathway. Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels. Furthermore, zaprinast, a phosphodiesterase inhibitor, enhanced cGMP and MKP-5 and prolonged the action of BK. These data indicate that BK enhances insulin action by inhibition of negative feedback by JNK and ERK via upregulation of MKP-5, mediated by the sGC-cGMP-PKG signaling pathway.

New trials, PARTNER 3 and Evolut Low Risk, showed promising results for transcatheter aortic valve replacement for low-risk surgical patients with severe aortic stenosis. However, there remain caveats to its use in this population in clinical practice. Aortic stenosis (AS) is the most common valve disease in developed countries.1 In the absence of valve replacement, severe AS has a 2-year mortality rate of more than 50%.2 Historically, surgery was the predominant treatment option for severe AS. However, two recent randomised controlled trials have further examined the use of a minimally invasive approach: transcatheter aortic valve replacement (TAVR). PARTNER 33 and Evolut Low Risk4 examined the safety and efficacy of TAVR in patients with severe AS at low risk for surgical AVR (SAVR). Patients having open operations can be categorised into low, intermediate and high risk for perioperative mortality using a validated risk-prediction model called the Society of Thoracic Surgery (STS) score.5 PARTNER 3 randomised …

Each night millions of patients use continuous positive airway pressure (CPAP) to treat obstructive sleep apnea (OSA). To facilitate monitoring of treatment success, modern CPAP machines routinely record and analyze the respiratory signal in near real-time and submit some of these data to the manufacturer's centralized cloud server. Some of the conditions frequently associated with OSA such as heart failure or chronic obstructive pulmonary disease result in characteristic changes of the respiratory signal (“signatures”), especially during exacerbations. Thus, this infrastructure could be leveraged to detect changes in patients' health status facilitating early interventions. To illustrate this concept, we present and discuss the case of a patient with OSA who showed abrupt changes in his breathing pattern (increase in periodic breathing and machine-detected obstructive apneas) from 10 days prior until 8 days after a hospitalization for acute heart failure exacerbation. CITATION: Schmickl CN, Heckman E, Owens RL, Thomas RJ. The respiratory signature: a novel concept to leverage continuous positive airway pressure therapy as an early warning system for exacerbations of common diseases such as heart failure. J Clin Sleep Med. 2019;15(6):923–927.

Introduction Boerhaave syndrome is associated with high morbidity and mortality rates. Outcomes are dependent on early recognition and intervention. Until recently, surgery has been the mainstay of management. However, with recent advances in therapeutic endoscopy, there has been increasing interest in endoscopic options, including endoluminal vacuum therapy (EVT). EVT is a minimally invasive technique, allowing wound debridement and drainage; promoting granulation tissue formation to enable wound healing. EVT has been associated with excellent clinical outcomes, including lower mortality rates when compared to both surgery and oesophageal stenting. EVT has been adopted into practice across Europe for the management of oesophageal perforations. However, in the UK there have only been two cases reported. We report a case of a 66 year old female with Boerhaave syndrome, successfully managed with EVT. Methods EVT for oesophageal perforation involves the placement of a polyurethane sponge into the wound cavity. The cavity is initially assessed with an endoscope before an overtube is introduced under visual control. The sponge is pushed into the cavity through the overtube. Once the sponge is in place, the overtube is removed; allowing the sponge to unfold. Sponge position is confirmed endoscopically and adjusted if necessary. The sponge is connected via a trans-nasal drain to continuous negative pressure. Sponge exchange is performed every 3–5 days. Results Having been deemed unfit for surgical intervention, due to difficulties with ventilation and haemodynamic instability, our patient was initially stabilised on the Intensive Care Unit (ICU) with the aid of radiologically placed chest drains and intravenous antibiotics. She was subsequently referred for EVT, using the EsoSPONGE ® (B.Braun, Medical Ltd, Sheffield, UK). Her first therapeutic endoscopy took place on Day 10 of admission; revealing a 5 cm defect in the oesophageal wall and an adjacent cavity; major vessels and the chest drains could be visualised endoscopically. The EsoSPONGE was placed into the cavity and connected to suction. She remained on ICU for 3 months and during this period her EsoSPONGE was exchanged 16 times; resulting in resolution of sepsis and healing of the defect. She was successfully stepped down from ICU and has now been discharged. Conclusions EVT was an effective management strategy for our patient with Boerhaave syndrome. Use of the EsoSPONGE aided drainage of the septic focus and closure of the defect; with this our patient made an excellent recovery. Mortality for this case would otherwise have been extremely high as she was too unstable for surgery. This case supports the evidence that EVT provides a promising approach for the management of Boerhaave syndrome.

The human electroencephalogram (EEG) of sleep undergoes profound changes with age. These changes can be conceptualized as “brain age”, which can be compared to chronological age to reflect the degree of deviation from normal aging. Here, we develop an interpretable machine learning model to predict brain age based on two large sleep EEG datasets: the Massachusetts General Hospital sleep lab dataset (MGH, N = 2,532; ages 18 to 80); and the Sleep Hearth Health Study (SHHS, N = 1,974; ages 40 to 80). The model obtains a mean absolute deviation of 7.6 years between brain age (BA) and chronological age (CA) in healthy participants in the MGH dataset. As validation, a subset of SHHS containing longitudinal EEGs 5.2 years apart shows an average of 5.4 years increase in BA. Participants with significant neurological or psychiatric disease exhibit a mean excess brain age, or “brain age index” (BAI = BA - CA) of 4 years relative to healthy controls. Participants with hypertension and diabetes have a mean excess brain age of 3.5 years. The findings raise the prospect of using the sleep EEG as a potential biomarker for healthy brain aging.

Large data sharing projects amongst the pharmaceutical industry have the potential to generate new insights using data on a scale that has not been previously available. A retrospective analysis of the preclinical toxicology data collected as part of the eTOX project was conducted with the aim to provide background rates and treatment-related value analysis on both clinical pathology and histopathology datasets. Incorporated into this analysis was an extensive data consolidation task to standardise all data. Reference intervals for common clinical pathology parameters in rat and dog were generated, alongside background histopathology incidence rates in the liver, heart and kidney. Systematically applied decision thresholds allowed consistent relabelling of data points considered anomalous, and maximum fold change estimates. Relabelling of anomalous data points was conducted for the histopathology data using a Bayesian model to identify dose-dependent increases in pathologies. The results of this study allow: newly generated data to be analysed using the same methodology, rates and distributions to be used when building predictive dose-response models, and the possibility to correlate clinical pathology findings with concurrent histopathology findings. In the first half of this paper we discuss data curation, in the second half we report on the analytical methods and results.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P

Study objectives Age-related brain white matter changes (WMC) have been associated separately with obstructive sleep apnea (OSA) and short telomere length (TL). No studies have examined their interaction effect on WMC. Methods This is a cross-sectional study with a community-based sample of 420 participants (mean age, 61.3 ± 7.2) from the Korean Genome and Epidemiology Study during 2011-2012. An overnight fasted blood sample was taken to determine glucose and blood lipid levels at the sleep laboratory of Korea University Ansan Hospital. The status of brain WMC was determined using structural magnetic resonance imaging at 1.5 Tesla. Overnight polysomnography was performed, and leukocyte TL was measured. OSA was determined based on apnea-hypopnea index, and short TL was defined as the lowest quartile of the study participants. Results Adjusting for age, sex, BMI, smoking, drinking, snoring, and hypertension, odds ratio (OR) of brain WMC was estimated using multivariate logistic regression. The odds ratio was significant for cardiovascular disease (OR, 4.5; 95% CI, 1.2-16.3) and OSA (OR, 4.0; 95% CI, 1.0-15.2) among those with short TL; and for diabetes (OR, 3.0; 95% CI, 1.3-13.0) and age (OR, 1.1; 95% CI, 1.0-1.1) among those with longer TL. Interaction effect of OSA and short TL (OR, 4.3; 95% CI, 1.4-13.8) was significant, compared to those with neither OSA nor short TL. Conclusions This study provides a first evidence of mediated interaction of short TL with OSA on brain WMC in a community-based sample. The results generate new hypotheses regarding mechanisms of impaired brain health in sleep apnea.

Key Points Question Can an electroencephalography-based brain age index, calculated as the difference between chronological and estimated brain age through sleep electroencephalography, serve as a potential biomarker associated with dementia? Findings This cross-sectional study of 9834 polysomnograms using machine learning found that brain age index increased monotonically from nondementia to dementia subpopulations. Meaning These findings suggest that brain age index may be a useful biomarker associated with dementia and could have utility as a screening tool for the presence of underlying neurodegenerative disease and monitoring of disease progression., This cross-sectional study examines a sleep electroencephalography-based brain age index as a potential biomarker associated with dementia., Importance Dementia is an increasing cause of disability and loss of independence in the elderly population yet remains largely underdiagnosed. A biomarker for dementia that can identify individuals with or at risk for developing dementia may help close this diagnostic gap. Objective To investigate the association between a sleep electroencephalography-based brain age index (BAI), the difference between chronological age and brain age estimated using the sleep electroencephalogram, and dementia. Design, Setting, and Participants In this retrospective cross-sectional study of 9834 polysomnograms, BAI was computed among individuals with previously determined dementia, mild cognitive impairment (MCI), or cognitive symptoms but no diagnosis of MCI or dementia, and among healthy individuals without dementia from August 22, 2008, to June 4, 2018. Data were analyzed from November 15, 2018, to June 24, 2020. Exposure Dementia, MCI, and dementia-related symptoms, such as cognitive change and memory impairment. Main Outcomes and Measures The outcome measures were the trend in BAI when moving from groups ranging from healthy, to symptomatic, to MCI, to dementia and pairwise comparisons of BAI among these groups. Findings A total of 5144 sleep studies were included in BAI examinations. Patients in these studies had a median (interquartile range) age of 54 (43-65) years, and 3026 (59%) were men. The patients included 88 with dementia, 44 with MCI, 1075 who were symptomatic, and 2336 without dementia. There was a monotonic increase in mean (SE) BAI from the nondementia group to the dementia group (nondementia: 0.20 [0.42]; symptomatic: 0.58 [0.41]; MCI: 1.65 [1.20]; dementia: 4.18 [1.02]; P

Introduction Sleep EEG is a promising tool to measure brain aging in vulnerable populations such as people with HIV, who are high risk of brain aging due to co-morbidities, increased inflammation, and antiretroviral neurotoxicity. Our lab previously developed a machine learning model that estimates age from sleep EEG (brain age, BA), which reliably predicts chronological age (CA) in healthy adults. The difference between BA and CA, the brain age index (BAI), independently predicts mortality, and is increased by cardiovascular co-morbidities. Here, we assessed BAI in HIV+ compared to matched HIV- adults. Methods Sleep EEGs from 43 treated HIV+ adults were gathered and matched to controls (HIV-, n=284) by age, gender, race, alcoholism, smoking and substance use history. We compared BAI between groups and used additional causal interference methods to ensure robustness. Individual EEG features that underlie BA prediction were also compared. We performed a sub-analysis of BAI between HIV+ with or without a history of AIDS. Results After matching, mean CA of HIV+ vs HIV- adults were 49 and 48 years, respectively (n.s.). The mean HIV+ BAI was 3.04 years higher than HIV- (4.4 vs 1.4 yr; p=0.048). We found consistent and significant results with alternative causal inference methods. Several EEG features predictive of BA were different in the HIV+ and HIV- cohorts. Most notably, non-REM stage 2 sleep (N2) delta power (1-4Hz) was decreased in HIV+ vs. HIV- adults, while theta (4-8Hz) and alpha (8-12Hz) power were increased. Those with AIDS (n=19, BAI=4.40) did not have significantly different BAI than HIV+ without AIDS (n=23, BAI=5.22). HIV+ subjects had higher rates of insomnia (56% vs 29%, p Conclusion HIV+ individuals on ART have excess sleep-EEG based brain age compared to matched controls. This excess brain age is partially due to reduction in delta power during N2, suggesting decreased sleep depth. These results suggest sleep EEG could be a valuable brain aging biomarker for the HIV population. Support This research is supported by the Harvard Center for AIDS Research HU CFAR NIH/NIAID 5P30AI060354-16.

Study Objectives To assess, using fractional anisotropy (FA) analysis, alterations of brain network connectivity in adults with obstructive sleep apnea (OSA). Abnormal networks could mediate clinical functional deficits and reflect brain tissue injury. Methods Structural brain networks were constructed using diffusion tensor imaging (DTI) from 165 healthy (age 57.99 ± 6.02 years, male 27.9%) and 135 OSA participants (age 59.01 ± 5.91 years, male 28.9%) and global network properties (strength, global efficiency, and local efficiency) and regional efficiency were compared between groups. We examined MRI biomarkers of brain tissue injury using FA analysis and its effect on the network properties. Results Differences between groups of interest were noted in global network properties (p-value < 0.05, corrected), and regional efficiency (p-value < 0.05, corrected) in the left middle cingulate and paracingulate gyri, right posterior cingulate gyrus, and amygdala. In FA analysis, OSA participants showed lower FA values in white matter (WM) of the right transverse temporal, anterior cingulate and paracingulate gyri, and left postcentral, middle frontal and medial frontal gyri, and the putamen. After culling fiber tracts through WM which showed significant differences in FA, we observed no group difference in network properties. Conclusions Changes in WM integrity and structural connectivity are present in OSA participants. We found that the integrity of WM affected brain network properties. Brain network analysis may improve understanding of neurocognitive deficits in OSA, enable longitudinal tracking, and provides explanations for specific symptoms and recovery kinetics.

Apnea/hypopnea index (AHI), especially without arousal criteria, does not adequately risk stratify patients with mild obstructive sleep apnea (OSA). We describe and test scoring reliability of an event, Flow Limitation/Obstruction With recovery breath (FLOW), representing obstructive airflow disruptions using only pressure transducer and snore signals available without electroencephalography.The following process was used (i) Development of FLOW event definition, (ii) Training period and definition refinement, and (iii) Reliability testing on 10 100-epoch polysomnography (PSG) samples and two 100-sample tests. Twenty full-night in-laboratory baseline PSGs in OSA patients with AHI with ≥4% desaturations15 were rescored for FLOW events, traditional hypopneas with desaturations, respiratory-related arousal (RRA) events (hypopneas with arousals and respiratory-effort related arousals) and non-respiratory arousals (NRA).Scoring of FLOW events in 100-epoch samples had good reliability with intraclass correlation (ICC) of 0.91. The overall kappa for presence of events on two sets of 100 sample events was 0.84 and 0.87 demonstrating good agreement. Moreover, 80% of RRA and 8% of NRA were concurrent with FLOW events. Furthermore, 56% of FLOW events were independent of RRA events. FLOW stratifies patients in traditional AHI categories with 50%/8% of AHI with ≥3% desaturations (AHI3)5 and 12%/63% of AHI35 in lowest/highest tertiles of AHI3 plus FLOW index.Scoring of FLOW after training is reliable. FLOW scores a high proportion of RRA and many currently unrepresented obstructive airflow disruptions. FLOW allows for stratification within the current normal-mild OSA category, which may better identify patients who will benefit from treatment.

Background Asymptomatic bacteriuria is frequent in kidney transplant recipients (KTRs). However, there is no consensus on diagnosis or management. We conducted a European survey to explore current practice related to the diagnosis and management of asymptomatic bacteriuria in adult KTRs. Methods A panel of experts from the European Renal Association-European Dialysis Transplant Association/Developing Education Science and Care for Renal Transplantation in European States working group and the European Study Group for Infections in Compromised Hosts of the European Society of Clinical Microbiology and Infectious Diseases designed this cross-sectional, questionnaire-based, self-administered survey. Invitations to participate were e-mailed to European physicians involved in the care of KTRs. Results Two hundred and forty-four participants from 138 institutions in 25 countries answered the survey (response rate 30%). Most participants [72% (176/244)] said they always screen for asymptomatic bacteriuria in KTRs. Six per cent (15/240) reported never treating asymptomatic bacteriuria with antibiotics. When antimicrobial treatment was used, 24% of the participants (53/224) said they would start with empirical antibiotics. For an episode of asymptomatic bacteriuria caused by a fully susceptible microorganism and despite no contraindications, a majority of participants (121/223) said they would use a fluoroquinolone (n = 56), amoxicillin/clavulanic acid (n = 38) or oral cephalosporins (n = 27). Conclusions Screening for and treating asymptomatic bacteriuria are common in KTRs despite uncertainties around the benefits and harms. In an era of antimicrobial resistance, further studies are needed to address the diagnosis and management of asymptomatic bacteriuria in these patients.

Primary endocrine therapy (PET) is a treatment option for elderly patients with ER-positive breast cancer enabling frail patients to avoid surgery. As a long-term treatment option, it has been shown to be inferior to surgery in controlling local disease. Decision-making in these patients is crucial in avoiding treatment failure. We examined the influence of decision-making on outcomes of PET failure as a secondary analysis as part of a large observational study. Consecutive patients treated with PET between 2005 and 2015 for operable breast cancers were included in a retrospective observational study in 3 breast centres in the North-East. Treatment decision processes were examined by case note review and outcomes of treatment success or failure recorded. 488 patients were included with mean follow-up of 31 months. Overall 63 (12%) experienced treatment failure. 227 (46.6%) were given a choice between surgery and PET at diagnosis. Logistic regression identified older age [OR 0.94 (0.91–0.96) p

Key Clinical Message Aorto‐esophageal fistula is often a terminal event in many patients. The commonest causes are thoracic aortic aneurysm and esophageal malignancy. To achieve a good outcome in this condition, a MDT approach is required that combines the expertize of vascular surgeons, radiologists, and emergency physicians.

Background: Restless legs syndrome (RLS) is a common sleep disorder, although it has a low prevalence in Asian populations. However, the reported RLS prevalence in ­Korean adults is mostly 4.5–12.1%, which is higher than that reported in other Asian populations. This study aimed to diagnose RLS and exclude mimicking conditions in 2 independent samples of Korean adults, and to compare its prevalence to that from previous studies performed in Asian countries. Methods: Study populations included a (1) nationwide stratified random sample (n = 2,824; age 19–79 years) and (2) community-based cohort (n = 2,685; age 47–79 years). We applied the Cambridge-Hopkins diagnostic questionnaire to diagnose RLS and differentiate it from RLS mimics. Sleep-related symptoms, mood, and medical conditions were compared between the RLS and non-RLS groups. Prior studies of the RLS prevalence in Asia were systematically reviewed and compared to our findings. Results: The adjusted RLS prevalence was 0.4 and 1.3% in populations 1 and 2, respectively. In both populations, subjects with RLS had more depression. The prevalence of RLS mimics was 5.1 and 2.6%, in populations 1 and 2, respectively. The RLS prevalence in Asia was higher when RLS was defined by the presence of essential clinical features and lower when a differential diagnosis was additionally implemented. Conclusions: The RLS prevalence in Korean adults considering RLS mimics is comparable to that in adults from other Asian countries (< 2%). The reported RLS prevalence varies depending on the diagnostic method employed.

Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by a variety of uncomfortable sensations associated with an urge to move the legs, relief with movement, strong circadian modulation, and often occurring at sleep onset, impairing sleep quality and inducing insomnia and reduced quality of life. RLS often responds to dopaminergic treatment, but over time, augmentation develops. Some additional key features of the disorder include greater somatotrophic spread when severe or with augmentation, painful sensations, and an association with brain iron deficiency. These features across neurophysiologic subsystems suggest a neural network disorder.