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Sleep apnea (SA) is recognized as a predictor of incident atrial fibrillation (AF) and AF recurrence after treatment. However, data on the prevalence of SA phenotypes in patients with AF and the effect of widespread SA screening on AF outcomes are scarce. We conducted a retrospective study of patients with AF referred for SA testing between March 2018 and April 2020. The screening was performed using home sleep testing or polysomnography. AF outcomes were examined by assessment of AF progression as defined by a change from paroxysmal AF to persistent AF, change in antiarrhythmic drug, having an ablation or cardioversion. Of 321 patients evaluated for AF, 251 patients (78%) completed SA testing. A total of 185 patients with complete follow-up data and SA testing were included in our analysis: 172 patients (93%) had SA; 90 of those (49%) had primarily obstructive sleep apnea, 77 patients (42%) had mixed apnea, and 5 patients (3%) had pure central apnea. Time from AF diagnosis to SA testing was associated with AF progression; after 2 years, the risk of AF progression increased (plt;0.008). Continuous positive airway pressure treatment did not affect AF progression (p = 0.99). In conclusion, SA is highly prevalent in an unselected population of patients with AF, with mixed apnea being present in over 40% of the population. Early SA testing was associated with decreased rates of AF progression, likely because of earlier and potentially more aggressive pursuit of rhythm control.

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.

International audience

Standardization is crucial when culturing cells including human embryonic stem cells (hESCs) which are valuable for therapy development and disease modeling. Inherent issues regarding reproducibility of protocols are problematic as they hinder translation to good manufacturing practice (GMP), thus reducing clinical efficacy and uptake. Pluripotent cultures require standardization to ensure that input material is consistent prior to differentiation, as inconsistency of input cells creates end-product variation. To improve protocols, developers first must understand the cells they are working with and their related culture dynamics. This innovative work highlights key conditions required for optimized and cost-effective bioprocesses compared to generic protocols typically implemented. This entailed investigating conditions affecting growth, metabolism, and phenotype dynamics to ensure cell quality is appropriate for use. Results revealed critical process parameters (CPPs) including feeding regime and seeding density impact critical quality attributes (CQAs) including specific metabolic rate (SMR) and specific growth rate (SGR). This implied that process understanding, and control is essential to maintain key cell characteristics, reduce process variation and retain CQAs. Examination of cell dynamics and CPPs permitted the formation of a defined protocol for culturing H9 hESCs. The authors recommend that H9 seeding densities of 20,000 cells/cm2, four-day cultures or three-day cultures following a recovery passage from cryopreservation and 100% medium exchange after 48 hours are optimal. These parameters gave ~SGR of 0.018 hour−1 ± 1.5x10−3 over three days and cell viabilities ≥95%±0.4, while producing cells which highly expressed pluripotent and proliferation markers, Oct3/4 (>99% positive) and Ki-67 (>99% positive)., Graphical abstract

Work undertaken using the embryonic carcinoma 2102Ep line, highlighted the requirement for robust, well-characterized and standardized protocols. A systematic approach utilizing ‘quick hit’ experiments demonstrated variability introduced into culture systems resulting from slight changes to culture conditions (route A). This formed the basis for longitudinal experiments investigating long-term effects of culture parameters including seeding density and feeding regime (route B).Results demonstrated that specific growth rates (SGR) of passage 59 (P59) cells seeded at 20,000 cells/cm2 and subjected to medium exchange after 48h prior to reseeding at 72h (route B2) on average was marginally higher than, P55 cells cultured under equivalent conditions (route A1); whereby SGR values were (0.021±0.004) and (0.019±0.004). Viability was higher in route B2 over 10 passages with average viability reported as (86.3%±8.1) compared to route A1 (83.3±8.8). The metabolite data demonstrated both culture route B1 (P57 cells seeded at 66,667 cells/cm2) and B2 had consistent-specific metabolite rates (SMR) for glucose, but SMR values of route B1 was consistently lower than route B2 (0.00001 mmol, cell-1.d-1 and 0.000025).Results revealed interactions between phenotype, SMR and feeding regime that may not be accurately reflected by growth rate or observed morphology. This implies that current schemes of protocol control do not adequately account for variability, since key cell characteristics, including phenotype and SMR, change regardless of standardized seeding densities. This highlights the need to control culture parameters through defined protocols, for processes that involve culture for therapeutic use, biologics production, and reference lines., GRAPHICAL ABSTARCT

BACKGROUND: General Aviation (GA) pilots who encounter hazardous weather inflight have a high probability of incurring fatal accidents. To mitigate this problem, previous research investigated pilot decision making and the effects of new technology. Limited investigations have examined usability and interpretability of observation and forecast weather products available to pilots. Therefore, this study examined the interpretability of weather observation and forecast reports that GA pilots use for preflight weather planning and the impact of pilot certification level on the interpretability of these displays.METHOD: There were 204 GA pilots (Mean age = 22.50 yr; Median flight hours = 131.0) who completed a 90-item multiple choice Aviation Weather Product Test. The questions portrayed static weather displays available on the NOAA/National Weather Service Aviation Weather Center website. The questions were designed to have high cognitive fidelity in comparison with preflight weather planning tasks.RESULTS: The results revealed overall low mean interpretability scores (Mean percent correct= 59.29%, SD = 16.01%). The scores for observation products and product attributes were lower for student pilots than experienced pilots. Forecast product scores for student and private pilots did not differ, however, student pilot scores were significantly lower than instrument rated private and commercial pilots.DISCUSSION: The low interpretability scores indicate that GA pilots misinterpret weather information provided by most weather observation and forecast products. Possible contributing factors to the low product interpretation scores include poor usability and a lack of training. Future research should measure the usability of weather displays designed for pilots.Blickensderfer BL, Guinn TA, Lanicci JM, Ortiz Y, King JM, Thomas RL, DeFilippis N. Interpretability of aviation weather information displays for general aviation. Aerosp Med Hum Perform. 2020; 91(4):318–325.

Background: Previous studies of nurses' critical thinking skills that included demographic characteristics as determinants have been inconclusive. This study explored demographic determinants of critical thinking skills among nurses from public hospitals in Peninsular Malaysia. Method: This cross-sectional study included 549 nurses recruited via multistage cluster sampling. Nurses completed the demographic questionnaire and Health Sciences Reasoning Test (HSRT). Results: The majority of respondents failed to demonstrate critical thinking skills with a mean overall HSRT score of 13.8 ( SD = 3.4). Educational qualifications ( p = .003) and clinical specialties ( p = .022) were significantly related to nurses' critical thinking skills. Years of clinical experience, age, and job ranking were not significant Conclusion: The findings indicate a need to address the present curriculum in nursing education and to reinforce critical thinking skills in the nursing workforce. Future research on how nurses in Malaysia acquire critical thinking skills is needed. [ J Contin Educ Nurs . 2020;51(3):109–117.]

Children requiring long-term ventilation (LTV) via tracheostomy often require enteral tube feeding. We sought to investigate what proportion of these children underwent gastrostomy insertion to inform decision making at time of tracheostomy formation.A retrospective review of all children commenced on LTV via a tracheostomy at Royal Manchester Children's Hospital over a 9-year period (2012-2020). Data are presented as median [IQR].Forty-one LTV patients had tracheostomy insertion with an average age of 167 days [101-604]. Reasons for tracheostomy insertion were upper airway obstruction (18), central neurological condition (7), neuromuscular condition (12) and lower respiratory tract disease (4). Twenty-two patients were born preterm and chronic lung disease of prematurity was a contributory factor in their requirement for LTV. Eight children had gastrostomies inserted prior to tracheostomy formation. A further 22 children had a gastrostomy inserted at an average of 139 days [99-227] following tracheostomy. Four children remained on nasogastric feed and the rest were fed orally. Seventy-three percentage of LTV children with tracheostomy were gastrostomy fed. Neither indication for LTV nor prematurity predicted whether a child was gastrostomy fed.The large majority of children requiring LTV are tube fed and gastrostomy insertion should be considered at time of formation of tracheostomy.

Congenital oesophageal stenosis (COS) is characterised by an intrinsic oesophageal narrowing that is present, but not necessarily symptomatic at birth. Small studies report an association of COS with oesophageal atresia (OA) in up to 14% of OA cases. Although OA is usually appreciated shortly after birth, the diagnosis of a concomitant COS is frequently delayed. This risk may be increased with the current movement away from routine postoperative upper gastrointestinal (GI) contrast study following OA repair. We performed a systematic review of the literature to assess the timing of diagnosis of COS in patients with COS and OA and how this impacted on patient outcomes.A systematic review in accordance with PRISMA guidelines was undertaken. Only patients with OA associated with COS were included. Delayed diagnosis was defined as presentation 1 month of age.14 full-text studies with a total of 131 patients were included. Diagnosis of COS was delayed in 62/131 (47%) patients. These children presented with symptoms of dysphagia and aspiration at a median age of 13.5 months (IQR 7-30 months). In total, 18/131 patients were identified at the initial operation, due to difficulty passing a tube distally into the stomach. The data on timing of contrast studies were provided in 60/131 (46%) patients. A routine postoperative contrast study was performed in 39/60 (65%) of these, of which COS was identified immediately in 28/39 (72%). A diagnosis of COS could also be made on retrospective review of the early contrast study in a further 6/39 patients, giving an overall sensitivity of 87%.The association of COS and OA may be underrecognised and diagnosis delayed if routine contrast study is not performed. Contrast studies, performed in the neonatal period are effective at detecting a concomitant COS (sensitivity 87%). This review supports routine early contrast study after OA repair with specific consideration of the presence of COS.

We conducted a systematic review of the literature on the effects of cordycepin on cell survival and proliferation, inflammation, signal transduction and animal models. A total of 1204 publications on cordycepin were found by the cut-off date of 1 February 2021. After application of the exclusion criteria, 791 papers remained. These were read and data on the chosen subjects were extracted. We found 192 papers on the effects of cordycepin on cell survival and proliferation and calculated a median inhibitory concentration (IC50) of 135 µM. Cordycepin consistently repressed cell migration (26 papers) and cellular inflammation (53 papers). Evaluation of 76 papers on signal transduction indicated consistently reduced PI3K/mTOR/AKT and ERK signalling and activation of AMPK. In contrast, the effects of cordycepin on the p38 and Jun kinases were variable, as were the effects on cell cycle arrest (53 papers), suggesting these are cell-specific responses. The examination of 150 animal studies indicated that purified cordycepin has many potential therapeutic effects, including the reduction of tumour growth (37 papers), repression of pain and inflammation (9 papers), protecting brain function (11 papers), improvement of respiratory and cardiac conditions (8 and 19 papers) and amelioration of metabolic disorders (8 papers). Nearly all these data are consistent with cordycepin mediating its therapeutic effects through activating AMPK, inhibiting PI3K/mTOR/AKT and repressing the inflammatory response. We conclude that cordycepin has excellent potential as a lead for drug development, especially for age-related diseases. In addition, we discuss the remaining issues around the mechanism of action, toxicity and biodistribution of cordycepin.

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Manufacturing of cell therapy products requires sufficient understanding of the cell culture variables and associated mechanisms for adequate control and risk analysis. The aim of this study was to apply an unstructured ordinary differential equation-based model for prediction of T-cell bioprocess outcomes as a function of process input parameters. A series of models were developed to represent the growth of T-cells as a function of time, culture volumes, cell densities, and glucose concentration using data from the Ambr®15 stirred bioreactor system. The models were sufficiently representative of the process to predict the glucose and volume provision required to maintain cell growth rate and quantitatively defined the relationship between glucose concentration, cell growth rate, and glucose utilization rate. The models demonstrated that although glucose is a limiting factor in batch supplied medium, a delivery rate of glucose at significantly less than the maximal specific consumption rate (0.05 mg 1 × 106 cell h-1 ) will adequately sustain cell growth due to a lower glucose Monod constant determining glucose consumption rate relative to the glucose Monod constant determining cell growth rate. The resultant volume and exchange requirements were used as inputs to an operational BioSolve cost model to suggest a cost-effective T-cell manufacturing process with minimum cost of goods per million cells produced and optimal volumetric productivity in a manufacturing settings. These findings highlight the potential of a simple unstructured model of T-cell growth in a stirred tank system to provide a framework for control and optimization of bioprocesses for manufacture.

The complex interplay of the sleep and circadian systems, which are substantially differentially regulated, provides for plasticity that is expressed in health and disease. The classic circadian rhythm disorders are readily recognizable, but atypical forms can be identified by actigraphy and melatonin profilometry. Although the dim-light melatonin onset test maps the start of the biological night, 24-hour mapping can define the limits of the biological night, whereas other forms of strategic testing can identify conditions such as iatrogenic hypermelatoninemia. Routine testing in clinical practice can expand the range of identifiable circadian rhythm disorders.

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.

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

Objective: Sleep related respiratory abnormalities are typically detected using polysomnography. There is a need in general medicine and critical care for a more convenient method to automatically detect sleep apnea from a simple, easy-to-wear device. The objective is to automatically detect abnormal respiration and estimate the Apnea-Hypopnea-Index (AHI) with a wearable respiratory device, compared to an SpO2 signal or polysomnography using a large (n = 412) dataset serving as ground truth. Methods: Simultaneously recorded polysomnographic (PSG) and wearable respiratory effort data were used to train and evaluate models in a cross-validation fashion. Time domain and complexity features were extracted, important features were identified, and a random forest model employed to detect events and predict AHI. Four models were trained: one each using the respiratory features only, a feature from the SpO2 (%)-signal only, and two additional models that use the respiratory features and the SpO2 (%)-feature, one allowing a time lag of 30 seconds between the two signals. Results: Event-based classification resulted in areas under the receiver operating characteristic curves of 0.94, 0.86, 0.82, and areas under the precision-recall curves of 0.48, 0.32, 0.51 for the models using respiration and SpO2, respiration-only, and SpO2-only respectively. Correlation between expert-labelled and predicted AHI was 0.96, 0.78, and 0.93, respectively. Conclusions: A wearable respiratory effort signal with or without SpO2 predicted AHI accurately. Given the large dataset and rigorous testing design, we expect our models are generalizable to evaluating respiration in a variety of environments, such as at home and in critical care., Co-First Authors: Wolfgang Ganglberger, Abigail A. Bucklin Co-Senior Authors: Robert J. Thomas, M. Brandon Westover

Yak dung is used as fuel in Tibetan homes; however, this use is hazardous to health. An alternative use of the dung that would be profitable and offset the loss as a fuel would be very beneficial. Sweet sorghum silage with yak dung biochar as an additive was compared with a control silage with no additives and three silages with different commercial additives, namely Lactobacillus buchneri, Lactobacillus plantarum and Acremonium cellulase. Biochar-treated silage had a significantly greater concentration of water-soluble carbohydrates than the other silages (76 vs 12.4-45.8 g/kg DM) and a greater crude protein content (75.5 vs 61.4 g/kg DM), lactic acid concentration (40.7 vs 27.7 g/kg DM) and gross energy yield (17.8 vs 17.4 MJ/kg) than the control silage. Biochar-treated and control silages did not differ in in vitro digestibility and in total gas (507 vs 511 L/kg DM) and methane production (57.9 vs 57.1 L/kg DM). Biochar inhibited degradation of protein and water-soluble carbohydrates and enhanced lactic acid production, which improved storability of feed. It was concluded that yak dung biochar is an efficient, cost-effective ensiling additive. The profit could offset the loss of dung as fuel and improve the health of Tibetan people.

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.

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.

Tissue-engineered corneal constructs offer the potential of readily available corneal substitutes for transplantation. As with all medical devices and implants, these constructs require rigorous safety assessments, combined with well-described analyses of the implant's physical and biological characteristics. Although the constructs are developed in vitro, such studies are currently unable to fully emulate the complex biomechanical and biochemical conditions within living tissue, as well as the interplay between this environment and immunological factors. For these reasons, animal models remain essential to characterize such interactions. They form a stage where corneal implants can be tested for utility and survival in a living location to assess their ability to provide vision and avoid adverse event. Here, we examine the surgical considerations of animal models and we describe how the rabbit can be used for this purpose. This animal has been the routine model for ophthalmological studies and we set out methods to implant corneal constructs with this species.

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

Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are of in high demand to accommodate complex therapeutic regimens. A novel design approach was employed to fabricate highly modular 3D printed ‘polypill’ capsules with bespoke release patterns for multiple drugs. Complex structures were devised using combined fused deposition modelling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with 4 separate compartments were devised: i) concentric format: two external compartments for early release whilst two inner compartments for delayed release, or ii) parallel format: where non-dissolving capsule shells with free-pass corridors and dissolution rate-limiting pores were used to achieve immediate and extended drug releases, respectively. Controlling drug release was achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles were achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules revealed how the developed approach could be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.

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 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

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.

Background:While normative data on neuropsychological performance provide baseline metrics for the assessment and diagnosis of mild cognitive impairment and dementia, a lack of comparative normative data in non-Caucasian populations makes it difficult to conduct similar evaluations and studies in individuals from diverse backgrounds. The current paper aims to provide normative data on a range of cognitive measures in a Korean general population sample and investigate various demographic and health variables associated with cognitive performance in this representative population.Method(s):The study population was 1,528 stroke and dementia-free individuals who participated in the Korean Genome and Epidemiology study (KoGES) (mean age 60.43 ± 7.30, 52.42% female). All participants underwent a comprehensive neuropsychological test battery that included verbal and visual memory, language, attention, and executive function measures. A health examination and a questionnaire-based interview were also administered.Results:The majority of cognitive test results were associated with age, education, and gender. In general, higher education and younger age was associated with better cognitive performance. Explained variance increased modestly in models that included measures of general health and depressive symptoms.Conclusion:Normative data of cognitive performance in a community based Korean population are presented. These norms provide reference values in a non-Caucasian middle to older aged sample.

Current cell therapy product limitations include the need for in-depth product understanding to ensure product potency, safety and purity. New technologies require development and validation to address issues of production scale-up to meet clinical need; assays are required for process control, validation and release. Prior to clinical realization, an understanding of production processes is required to implement process changes that are essential for process control. Identification of key parameters forms the basis of process tolerances, allowing for validated, adaptive manufacturing processes. This enables greater process control and yield while withstanding regulatory scrutiny. This report summaries key milestones in specifically for ventral midbrain dopaminergic neuroprogenitor differentiation and key translational considerations and recommendations to enable successful, robust and reproducible current cell therapy product-manufacturing.

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 …

Manufacturing processes for autologous cell therapy need to reproducibly generate in specification (quality and quantity) clinical product. However, patient variability prevents the level of control of cell input material that could be achieved in a cell line or allogeneic-based process. We have applied literature data on bone marrow-derived mesenchymal stromal cells variability to estimate probability distributions for stem cell yields given underlying truncated normal distributions in total nucleated cell concentration, stem cell percentage and plausible aspirate volumes. Monte Carlo simulation identified potential variability in harvested stem cell number in excess of an order of magnitude. The source material variability was used to identify the proportion of donor manufacturing runs that would achieve a target yield specification of 2E7 cells in a fixed time window with given proliferative rates and different aspirate volumes. A rapid, screening, development approach was undertaken to assess culture materials and process parameters (T-flask surface, medium, feed schedule) to specify a protocol with identified proliferative rate and a consequent model-based target aspirate volume. Finally, four engineering runs of the candidate process were conducted and a range of relevant quality parameters measured including expression of markers CD105, CD73, CD44, CD45, CD34, CD11b, CD19, HLA-DR, CD146 (melanoma cell adhesion molecule), CD106 (vascular cell adhesion molecule) and SSEA-4, specific metabolic activity and vascular endothelial growth factor secretion, and osteogenic differentiation potential. Our approach of using estimated distributions from publicly available information provides a route for data-poor earl- stage developers to plan manufacture with defined risk based on rational assumptions; furthermore, the models produced by such assumptions can be used to evaluate candidate processes, and can be incrementally improved with accumulating distribution understanding or subdivision by new process variables.

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.

Background The apnea-hypopnea index (AHI) (or one of its derivatives) is the primary clinical metric for characterizing sleep disordered breathing—the value of which with respect to a threshold determines severity of diagnosis and eligibility for treatment reimbursement. The index value, however, is taken as a perfect point estimate, with no measure of statistical uncertainty. Thus, current practice does not robustly account for variability in diagnosis/eligibility due to chance. In this paper, we quantify the statistical uncertainty associated with respiratory event indices for sleep disordered breathing and the effect of uncertainty on treatment eligibility. Methods We develop an empirical estimate of uncertainty using a non-parametric bootstrap on the interevent times, as well as a theoretical Poisson estimate reflecting the current formulation of the AHI. We then apply these methods to estimate AHI uncertainty for 2049 subjects (954/1095 M/F, age: mean 69 ± 9.1) from the Multi-Ethnic Study of Atherosclerosis (MESA). Results and Conclusions The mean 95% empirical confidence interval width was 11.500 ± 6.208 events per hour and the mean 95% theoretical Poisson confidence interval width was 5.998 ± 2.897 events per hour, suggesting that uncertainty is likely a major confounding factor within the current diagnostic framework. Of the 278 subjects in the symptomatic population (ESS>10), 27% (76/278) had uncertain diagnoses given the 95% empirical confidence interval. Of the 2049 subjects in the full population, 43% (880/2049) had uncertain diagnoses given the 95% empirical confidence interval. The inclusion of subjects with uncertain diagnoses increases the number of eligible patients by 21.3% for the symptomatic population and by 84.8% for the full population. The exclusion of subjects with uncertain diagnoses given the 95% empirical confidence interval decreases the number of eligible patients by 12.4% for the symptomatic population and by 34.8% for full population. Additional analyses suggest that it is practically infeasible to gain diagnostic statistical significance through additional testing for a broad range of borderline cases. Overall, these results suggest that AHI uncertainty is a vital additional piece of information that would greatly benefit clinical practice, and that the inclusion of uncertainty in epidemiological analysis might help improve the ability for researchers to robustly link AHI with co-morbidities and long-term outcomes.

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.

Hypertension and dyslipidaemia are modifiable risk factors associated with cardiovascular diseases (CVDs) and often require a complex therapeutic regimen. The administration of several medicines is commonly associated with poor levels of adherence among patients, to which World Health Organisation (WHO) proposed a fixed-dose combination unit (polypill) as a strategy to improve adherence. In this work, we demonstrate the fabrication of patient-specific polypills for the treatment of CVDs by fused deposition modelling (FDM) 3D printing and introduce a novel solution to meet critical quality attributes. The construction of poly(vinyl alcohol) (PVA)-based polypills containing four model drugs (lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine besylate) was revealed for the first time. The impact of tablet architecture was explored using multi-layered and unimatrix structures. The novel approach of using distilled water as a ‘temporary co-plasticiser’ is reported and was found to significantly lower the extruding (90 °C) and 3D printing (150 °C) temperatures from 170 °C and 210 °C respectively, with consequent reduction in thermal stress to the chemicals. XRD indicated that lisinopril dihydrate and amlodipine besylate maintained their crystalline form while indapamide and rosuvastatin calcium were essentially in amorphous form in the PVA tablets. From the multilayer polypills, the release profile of each drug was dependent on its position in the multilayer. In addition to the multilayer architecture offering a higher flexibility in dose titration and a more adaptive solution to meet the expectations of patient-centred therapy, we identify that it also allows orchestrating the release of drugs of different physicochemical characteristics. Adopting such an approach opens up a pathway towards low-cost multidrug delivery systems such as tablets, stents or implants for wider range of globally approved actives.

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

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.