Triple-fusion protein (TriFu): A potent, targeted, enzyme-like inhibitor of all three complement activation pathways.

The introduction of a therapeutic anti-C5 antibody into clinical practice in 2007 inspired a surge into the development of complement-targeted therapies. This has led to the recent approval of a C3 inhibitory peptide, an antibody directed against C1s and a full pipeline of several complement inhibitors in preclinical and clinical development. However, no inhibitor is available that efficiently inhibits all three complement initiation pathways and targets host cell surface markers as well as complement opsonins. To overcome this, we engineered a novel fusion protein combining selected domains of the three natural complement regulatory proteins decay accelerating factor, factor H and complement receptor 1. Such a triple fusion complement inhibitor (TriFu) was recombinantly expressed and purified alongside multiple variants and its building blocks. We analyzed these proteins for ligand binding affinity and decay acceleration activity by surface plasmon resonance. Additionally, we tested complement inhibition in several in vitro/ex vivo assays using standard classical and alternative pathway restricted hemolysis assays next to hemolysis assays with paroxysmal nocturnal hemoglobinuria erythrocytes. A novel in vitro model of the alternative pathway disease C3 glomerulopathy was established to evaluate the potential of the inhibitors to stop C3 deposition on endothelial cells. Next to the novel engineered triple fusion variants which inactivate complement convertases in an enzyme-like fashion, stoichiometric complement inhibitors targeting C3, C5, factor B, and factor D were tested as comparators. The triple fusion approach yielded a potent complement inhibitor that efficiently inhibits all three complement initiation pathways while targeting to surface markers.

The complement model disease paroxysmal nocturnal hemoglobinuria.

We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.

Artificial light at night suppresses the day-night cardiovascular variability: evidence from humans and rats.

Artificial light at night (ALAN) affects most of the population. Through the retinohypothalamic tract, ALAN modulates the activity of the central circadian oscillator and, consequently, various physiological systems, including the cardiovascular one. We summarised the current knowledge about the effects of ALAN on the cardiovascular system in diurnal and nocturnal animals. Based on published data, ALAN reduces the day-night variability of the blood pressure and heart rate in diurnal and nocturnal animals by increasing the nocturnal values of cardiovascular variables in diurnal animals and decreasing them in nocturnal animals. The effects of ALAN on the cardiovascular system are mainly transmitted through the autonomic nervous system. ALAN is also considered a stress-inducing factor, as glucocorticoid and glucose level changes indicate. Moreover, in nocturnal rats, ALAN increases the pressure response to load. In addition, ALAN induces molecular changes in the heart and blood vessels. Changes in the cardiovascular system significantly depend on the duration of ALAN exposure. To some extent, alterations in physical activity can explain the changes observed in the cardiovascular system after ALAN exposure. Although ALAN acts differently on nocturnal and diurnal animals, we can conclude that both exhibit a weakened circadian coordination among physiological systems, which increases the risk of future cardiovascular complications and reduces the ability to anticipate stress.

The metabolic fuel of paroxysmal nocturnal haemoglobinuria.

Metabolic reprogramming has been investigated in haematological malignancies. To date, a few studies have analysed the metabolic profile of paroxysmal nocturnal haemoglobinuria (PNH). The study by Chen and colleagues sheds light on the involvement of metabolic changes in the proliferation of PNH clones. Commentary on: Chen et al. The histone demethylase JMJD1C regulates CPS1 expression and promotes the proliferation of PNH clones through cell metabolic reprogramming. Br J Haematol 2024;204:2468-2479.

The histone demethylase JMJD1C regulates CPS1 expression and promotes the proliferation of paroxysmal nocturnal haemoglobinuria clones through cell metabolic reprogramming.

Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to address the underlying cause of the disease-the pathogenic PNH clones. In this study, we found that the expression of carbamoyl phosphate synthetase 1 (CPS1) was downregulated in PNH clones, and the level of CPS1 was negatively correlated with the proportion of PNH clones. Using PIG-A knockout K562 (K562 KO) cells, we demonstrated that CPS1 knockdown increased cell proliferation and altered cell metabolism, suggesting that CPS1 participates in PNH clonal proliferation through metabolic reprogramming. Furthermore, we observed an increase in the expression levels of the histone demethylase JMJD1C in PNH clones, and JMJD1C expression was negatively correlated with CPS1 expression. Knocking down JMJD1C in K562 KO cells upregulated CPS1 and H3K36me3 expression, decreased cell proliferation and increased cell apoptosis. Chromatin immunoprecipitation analysis further demonstrated that H3K36me3 regulated CPS1 expression. Finally, we demonstrated that histone demethylase inhibitor JIB-04 can suppressed K562 KO cell proliferation and reduced the proportion of PNH clones in PNH mice. In conclusion, aberrant regulation of the JMJD1C-H3K36me3-CPS1 axis contributes to PNH clonal proliferation. Targeting JMJD1C with a specific inhibitor unveils a potential strategy for treating PNH patients.

Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is associated with the progression of cardiovascular diseases, arrhythmias, and sudden cardiac death (SCD). However, the acute impacts of OSA and its consequences on heart function are not yet fully elucidated. We hypothesized that desaturation events acutely destabilize ventricular repolarization, and the presence of accompanying arousals magnifies this destabilization. Ventricular repolarization lability measures, comprising heart rate corrected QT (QTc), short-time-variability of QT (STVQT), and QT variability index (QTVI), were calculated before, during, and after 20,955 desaturations from lead II electrocardiography signals of 492 patients with suspected OSA (52% men). Variations in repolarization parameters were assessed during and after desaturations, both with and without accompanying arousals, and groupwise comparisons were performed based on desaturation duration and depth. Regression analyses were used to investigate the influence of confounding factors, comorbidities, and medications. The standard deviation (SD) of QT, mean QTc, SDQTc, and STVQT increased significantly (P < 0.01), whereas QTVI decreased (P < 0.01) during and after desaturations. The changes in SDQT, mean QTc, SDQTc, and QTVI were significantly amplified (P < 0.01) in the presence of accompanying arousals. Desaturation depth was an independent predictor of increased SDQTc (ß = 0.405, P < 0.01), STVQT (ß = 0.151, P < 0.01), and QTVI (ß = 0.009, P < 0.01) during desaturation. Desaturations cause acute changes in ventricular repolarization, with deeper desaturations and accompanying arousals independently contributing to increased ventricular repolarization lability. This may partially explain the increased risk of arrhythmias and SCD in patients with OSA, especially when the OSA phenotype includes high hypoxic load and fragmented sleep.NEW & NOTEWORTHY Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.

Contrasting seasonal responses to wind in migrating songbirds on a globally important flyway.

During spring migration, nocturnal migrants attempt to minimize their travel time to reach their breeding grounds early. However, how they behave and respond to unfavourable conditions during their springtime travels is much less understood. In this study, we reveal the effects of atmospheric factors on nocturnal bird migration under adverse conditions during spring and autumn, based on one of the most detailed bird migration studies globally, using radar data from 13 deployments over a period of seven years (2014-2020) in the Levant region. Using ERA5 reanalysis data, we found that migratory birds maintain similar ground speeds in both autumn and spring migrations, but during spring, when encountering unfavourable winds, they put more effort into maintaining their travel speed by increasing self-powered airspeed by 18%. Moreover, we report for the first time that spring migrants showed less selectivity to wind conditions and migrated even under unfavourable headwind and crosswind conditions. Interestingly, we discovered that temperature was the most important weather parameter, such that warm weather substantially increased migration intensities in both seasons. Our results enhance our understanding of bird migration over the Levant region, one of the world's largest and most important migration flyways, and the factors controlling it. This information is essential for predicting bird migration, which-especially under the ongoing anthropogenic changes-is of high importance.

Development of a Novel Prediction Tool for Response to First-Line Treatments of Monosymptomatic Nocturnal Enuresis: A Randomized, Controlled, International, Multicenter Study (DRYCHILD).

PURPOSE: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE. MATERIALS AND METHODS: A randomized, controlled, international, multicenter study was conducted in 324 treatment-naïve children (6-14 years old) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment, and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated. RESULTS: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (risk ratio = 1.21 [1.02-1.45], P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (risk ratio = 1.46 [1.14-1.87], P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (receiver operating characteristic curve 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improves response to first-line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response. CLINICAL TRIAL REGISTRATION NO.: NCT03389412.

Reclassification of Adolescent Ambulatory Prehypertension and Unclassified Blood Pressures by 2022 American Heart Association Pediatric Ambulatory Blood Pressure Monitoring Guidelines.

OBJECTIVE: To describe the epidemiology of reclassification of prehypertensive and unclassified adolescents by 2022 American Heart Association pediatric ambulatory blood pressure monitoring (ABPM) guidelines, and to evaluate the association of the new diagnostic categories with left ventricular hypertrophy (LVH). STUDY DESIGN: A single-center, retrospective review of ABPM reports from adolescents 13-21 years old, from 2015 through 2022, was performed. Adolescents with prehypertension or unclassified by 2014 guidelines were reclassified by 2022 definitions. Logistic regression models evaluated the association of reclassification phenotypes with LVH. RESULTS: A majority of prehypertensive adolescents reclassified to hypertension (70%, n = 49/70). More than one-half (57%, n = 28/49) of the hypertension was isolated nocturnal hypertension, and 80% was systolic hypertension. Reclassification to hypertension was more common in males. The majority (55.6%) of unclassified adolescents were reclassified to normotension. No demographic or clinical variables were associated with reclassification categories. LVH was not associated with hypertension in the reclassified prehypertensive or unclassified groups. CONCLUSIONS: The 2022 ABPM guidelines clearly define blood pressure phenotypes. However, reclassification to hypertension was not associated with an increased odds of LVH. Because most prehypertensive adolescents reclassified as hypertensive by nighttime BPs alone, this study highlights the lowered threshold for nocturnal hypertension. Prospective studies in larger, well-defined cohorts are needed to describe better the predictive value of 2022 BP phenotypes for target organ damage.

Instantaneous Q10 of night-time leaf respiratory CO2 efflux - measurement and analytical protocol considerations.

The temperature sensitivity (e.g. Q10) of night-time leaf respiratory CO2 efflux (RCO2) is a fundamental aspect of leaf physiology. The Q10 typically exhibits a dependence on measurement temperature, and it is speculated that this is due to temperature-dependent shifts in the relative control of leaf RCO2. Two decades ago, a review hypothesized that this mechanistically caused change in values of Q10 is predictable across plant taxa and biomes. Here, we discuss the most appropriate measuring protocol among existing data and for future data collection, to form the foundation of a future mechanistic understanding of Q10 of leaf RCO2 at different temperature ranges. We do this primarily via a review of existing literature on Q10 of night-time RCO2 and only supplement this to a lesser degree with our own original data. Based on mechanistic considerations, we encourage that instantaneous Q10 of leaf RCO2 to represent night-time should be measured: only at night-time; only in response to short-term narrow temperature variation (e.g. max. 10°C) to represent a given midpoint temperature at a time; in response to as many temperatures as possible within the chosen temperature range; and on still attached leaves.

Effect of binocular visual cue availability on fruit and insect grasping performance in two cheirogaleids: Implications for primate origins hypotheses.

Forward-facing eyes with parallel optic axes, which provide a wide field of binocular vision and precise depth perception, are among the diagnostic features of crown primates; however, the adaptive significance of this feature remains contentious. Two of the most prominent primate-origins hypotheses propose that either foraging for fruit or nocturnal predation on insects created selective pressures that led to the evolution of diagnostic primate traits, including a wide binocular field. To determine whether either of these hypotheses provides a viable explanation for the evolution of primates' derived eye orientation, the importance of binocular depth cues for the two tasks invoked by these hypotheses was evaluated experimentally in Microcebus murinus and Cheirogaleus medius, cheirogaleids' considered reasonable living analogs of the earliest euprimates. Performance in grasping insects and fruit was evaluated when the animals made use of their full binocular visual field and when their binocular visual field was restricted using a helmet-mounted blinder. Restriction of the binocular field had no effect on fruit grasping performance; however, restriction of the binocular field resulted in a significant deficit in insect predation performance. Differences in behavioral variables also suggest that insect predation is a more visually demanding task than fruit foraging. These results support the role of insect predation, but not fruit foraging, in contributing to the selective pressures that led to the evolution of parallel optic axes and a wide binocular field in crown primates.

Development of a target concentration intervention to individualize paroxysmal nocturnal hemoglobinuria treatment with pegcetacoplan.

Pegcetacoplan (Aspaveli®/Empaveli™) is a factor C3 inhibitor that is approved for the treatment of paroxysmal nocturnal hemoglobinuria. An individualized dosing strategy might be useful to improve patient-friendliness and cost-effectiveness of this very expensive drug. Therefore, the aim of this study was to develop an individualized treatment regimen for pegcetacoplan based on the pharmacokinetic-pharmacodynamic data of the manufacturer. We conducted a clinical trial simulation with the approved dosing regimen of 1080 mg twice-weekly and a target concentration intervention-based dosing regimen in patients with and without prior eculizumab use. For eculizumab-naïve patients, the target concentration intervention-based dosing regimen resulted in a comparable fraction of patients with LDH normalization (LDH < 226 U/L) and hemoglobulin normalization (> 12 g/dL) compared to the approved regimen (LDH 50.2% and 50.0% respectively and hemoglobulin 45.6% and 44.4%). A modest dose reduction of ~ 5% was possible with target concentration intervention-based dosing. An intensified dosing interval was necessary in 2.3% of the patients however an interval prolongation was possible in 28.2% of the patients. Similar results were obtained for patients prior treated with eculizumab. In this study we show the potential of an individualized dosing regimen of pegcetacoplan with can improve patient friendliness in approximately 30% of the patients and improve therapy in approximately 2% of the patients at slightly reduced costs.

Comparison of human leukocyte antigen in patients with paroxysmal nocturnal hemoglobinuria of different clone sizes.

Glycosylphosphatidylinositol-anchored protein-deficient hematopoietic stem and progenitor cell development caused by PIGA mutations cannot fully explain the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH). Herein, patients newly diagnosed with PNH at our hospital between April 2019 and April 2021 were recruited. The human leukocyte antigen (HLA) class I and II loci were analyzed, and patients were stratified by PNH clone sizes: small (< 50%) and large (≥ 50%). In 40 patients (29 males; 72.5%), the median PNH clone size was 72%. Thirteen (32.5%) and twenty-seven (67.5%) patients harbored small and large PNH clones, respectively. DRB1*15:01 and DQB1*06:02 had higher frequencies in patients with PNH than in healthy controls (adjusted P-value = 4.10 × 10-4 and 4.10 × 10-4, respectively). Whole HLA class I and II allele contributions differed (P = 0.046 and 0.065, not significant difference) when comparing patients with small and large PNH clones. B*13:01 and C*04:01 allelic frequencies were significantly higher in patients with small clones (P = 0.032 and P = 0.032, respectively). Patients with small clones had higher class II HLA evolutionary divergence (HED) (P = 0.041) and global class I and II HED (P = 0.019). In the entire cohort, 17 HLA aberrations were found in 11 (27.5%) patients. No significant differences in HLA aberrations were found between patients with small or large clones. In conclusion, patients with small clones tended to have a higher frequency of immune attack-associated alleles. A higher HED in patients with small clones may reflect a propensity for T cell-mediated autoimmunity. HLA aberrations were similar between patients with small and large clones.

Nocturnal paroxysmal dystonia to sleep-related hypermotor epilepsy: A critical review.

Sleep-related paroxysmal motor episodes (SPMEs) have been described by various names, including nocturnal paroxysmal dystonia, nocturnal frontal lobe epilepsy (NFLE), and sleep-related hypermotor epilepsy. The underlying pathophysiology has been debated over the years, with these episodes assumed to be a form of paroxysmal dystonia or parasomnia versus a form of epilepsy. In most studies published on SPMEs and their variants (paroxysmal arousals, nocturnal paroxysmal dystonia, and episodic nocturnal wanderings) in the early 1990s, the authors speculated on the pathophysiology but did not commit to one idea. It was not until the mid-1990s that epilepsy became the leading prospect. We performed a narrative review of the major articles that have described this syndrome in a chronological fashion. We identified three eras, 1972-1993, 1994-1998, and 1999 to the present, each era marked by a landmark study. Our critical review of these early studies shows that the neurophysiological data supporting epilepsy as the sole basis for all SPME cases is very weak. In 1994-1995, a familial pattern of this syndrome was described and the term autosomal dominant NFLE was coined, with the authors claiming that all their patients had a form of frontal lobe epilepsy. With the exception of a few reference cases, the neurophysiological evidence that all patients had frontal lobe epilepsy was very weak. Compared to articles published on surgical series of frontal lobe epilepsy, the percentage of SPME cases with positive interictal/ictal electroencephalograms remained very low, seriously questioning the epileptic basis of the syndrome. Our critical review and analysis of the published literature shows that the evidence presented in favor of SPMEs being a homogenous focal epilepsy syndrome is very weak. Neurologists must recognize that SPMEs could be a form of movement disorder, parasomnia, or epilepsy. We recommend a pragmatic semiology-based classification of these episodes using the four-dimensional classification system.

Polarisation vision in the dark: green-sensitive photoreceptors in the nocturnal ball-rolling dung beetle Escarabaeus satyrus.

Many insects utilise the polarisation pattern of the sky to adjust their travelling directions. The extraction of directional information from this sky-wide cue is mediated by specialised photoreceptors located in the dorsal rim area (DRA). While this part of the eye is known to be sensitive to the ultraviolet, blue or green component of skylight, the latter has only been observed in insects active in dim light. To address the functional significance of green polarisation sensitivity, we define the spectral and morphological adaptations of the DRA in a nocturnal ball-rolling dung beetle-the only family of insects demonstrated to orient to the dim polarisation pattern in the night sky. Intracellular recordings revealed polarisation-sensitive green photoreceptors in the DRA of Escarabaeus satyrus. Behavioural experiments verified the navigational relevance of this finding. To quantify the adaptive value of green sensitivity for celestial orientation at night, we also obtained the polarisation properties of the night sky in the natural habitat of the beetle. Calculations of relative photon catch revealed that under a moonlit sky the green-sensitive DRA photoreceptors can be expected to catch an order of magnitude more photons compared with the UV-sensitive photoreceptors in the main retina. The green-sensitive photoreceptors - which also show a range of morphological adaptations for enhanced sensitivity - provide E. satyrus with a highly sensitive system for the extraction of directional information from the night sky.

Wake up to gastro-oesophageal reflux disease: The interplay between arousal and night-time reflux.

This review examines the temporal association between nocturnal gastro-oesophageal reflux and sleep-arousal cycles. Most nocturnal gastro-oesophageal reflux events occur during the awake cycle, and arousals precede most nocturnal gastro-oesophageal reflux events, indicating that arousal from sleep predisposes to nocturnal gastro-oesophageal reflux. This sheds light on the complex relationship between nocturnal gastro-oesophageal reflux and sleep, and has implications for managing nocturnal gastro-oesophageal reflux symptoms. The appearance of symptoms and the pathophysiology of nocturnal gastro-oesophageal reflux are influenced by sleep hygiene, sleep disturbances and the misalignment of circadian rhythms. Nocturnal gastro-oesophageal reflux and its related sleep disorders are prevalent and negatively impact the quality of life. There is conflicting evidence on whether nocturnal gastro-oesophageal reflux and sleep disturbances are causally linked, and whether sleep disturbances drive nocturnal gastro-oesophageal reflux. Poor sleep quality increases oesophageal hypersensitivity and overall acid exposure. The nocturnal gastro-oesophageal reflux is linked to the more severe forms of gastro-oesophageal reflux disease, especially with atypical/extra-oesophageal manifestations and complications of mucosal damage such as oesophagitis and stricture, Barret's oesophagus, and oesophageal adenocarcinoma. This review highlights the role of sleep problems in presenting nocturnal gastro-oesophageal reflux, and the potential benefits of treating sleep disturbances in enhancing patient care and quality of life.

Identifying time-resolved features of nocturnal sleep characteristics of narcolepsy using machine learning.

The differential diagnosis of narcolepsy type 1, a rare, chronic, central disorder of hypersomnolence, is challenging due to overlapping symptoms with other hypersomnolence disorders. While recent years have seen significant growth in our understanding of nocturnal polysomnography narcolepsy type 1 features, there remains a need for improving methods to differentiate narcolepsy type 1 nighttime sleep features from those of individuals without narcolepsy type 1. We aimed to develop a machine learning framework for identifying sleep features to discriminate narcolepsy type 1 from clinical controls, narcolepsy type 2 and idiopathic hypersomnia. The population included polysomnography data from 350 drug-free individuals (114 narcolepsy type 1, 90 narcolepsy type 2, 105 idiopathic hypersomnia, and 41 clinical controls) collected at the National Reference Centers for Narcolepsy in Montpelier, France. Several sets of nocturnal sleep features were explored, as well as the value of time-resolving sleep architecture by analysing sleep per quarter-night. Several patterns of nighttime sleep evolution emerged that differed between narcolepsy type 1, clinical controls, narcolepsy type 2 and idiopathic hypersomnia, with increased nighttime instability observed in patients with narcolepsy type 1. Using machine learning models, we identified rapid eye movement sleep onset as the best single polysomnography feature to distinguish narcolepsy type 1 from controls, narcolepsy type 2 and idiopathic hypersomnia. By combining multiple feature sets capturing different aspects of sleep across quarter-night periods, we were able to further improve between-group discrimination and could identify the most discriminative sleep features. Our results highlight salient polysomnography features and the relevance of assessing their time-dependent changes during sleep that could aid diagnosis and measure the impact of novel therapeutics in future clinical trials.

The role of physical activity on obstructive sleep apnea severity and hypoxic load, and the mismatch between subjective and objective physical activity assessments.

Obesity is the primary risk factor for the development of obstructive sleep apnea, and physical inactivity plays an important role. However, most studies have either only evaluated physical activity subjectively or objectively in obstructive sleep apnea. The objectives of this study were: (i) to assess the relationship between obstructive sleep apnea severity (both apnea-hypopnea index and desaturation parameters) and both objectively and subjectively measured physical activity after adjustment for anthropometry and body composition parameters; and (ii) to assess the relationship between objective and subjective physical activity parameters and whether obstructive sleep apnea severity has a modulatory effect on this relationship. Fifty-four subjects (age 47.7 ± 15.0 years, 46% males) were categorized into groups according to obstructive sleep apnea severity: no obstructive sleep apnea; mild obstructive sleep apnea; and moderate-to-severe obstructive sleep apnea. All subjects were evaluated with subjective and objective physical activity, anthropometric and body composition measurements, and 3-night self-applied polysomnography. A one-way ANOVA was used to evaluate the differences between the three obstructive sleep apnea severity groups and multiple linear regression to predict obstructive sleep apnea severity. Differences in subjectively reported sitting time (p ≤ 0.004) were found between participants with moderate-to-severe obstructive sleep apnea, and those with either mild or no obstructive sleep apnea (p = 0.004). Age, body mass index and neck circumference explained 63.3% of the variance in the apnea-hypopnea index, and age, body mass index and visceral adiposity explained 67.8% of the variance in desaturation parameters. The results showed that the person's physical activity does not affect obstructive sleep apnea severity. A weak correlation was found between objective and subjective physical activity measures, which could be relevant for healthcare staff encouraging patients with obstructive sleep apnea to increase their physical activity.

A model-based hypothesis framework to define and estimate the diel niche via the 'Diel.Niche' R package.

How animals use the diel period (24-h light-dark cycle) is of fundamental importance to understand their niche. While ecological and evolutionary literature abound with discussion of diel phenotypes (e.g. diurnal, nocturnal, crepuscular, cathemeral), they lack clear and explicit quantitative definitions. As such, inference can be confounded when evaluating hypotheses of animal diel niche switching or plasticity across studies because researchers may be operating under different definitions of diel phenotypes. We propose quantitative definitions of diel phenotypes using four alternative hypothesis sets (maximizing, traditional, general and selection) aimed at achieving different objectives. Each hypothesis set is composed of mutually exclusive hypotheses defined based on the activity probabilities in the three fundamental periods of light availability (twilight, daytime and night-time). We develop a Bayesian modelling framework that compares diel phenotype hypotheses using Bayes factors and estimates model parameters using a multinomial model with linear inequality constraints. Model comparison, parameter estimation and visualizing results can be done in the Diel.Niche R package. A simplified R Shiny web application is also available. We provide extensive simulation results to guide researchers on the power to discriminate among hypotheses for a range of sample sizes (10-1280). We also work through several examples of using data to make inferences on diel activity, and include online vignettes on how to use the Diel.Niche package. We demonstrate how our modelling framework complements other analyses, such as circular kernel density estimators and animal movement modelling. Our aim is to encourage standardization of the language of diel activity and bridge conceptual frameworks and hypotheses in diel research with data and models. Lastly, we hope more research focuses on the ecological and conservation importance of understanding how animals use diel time.

NITES, a nocturnal bladder score to aid diagnosis during the transition to older age care.

BACKGROUND: As adults transition to older age, bothersome nocturnal lower urinary tract symptoms (LUTS) become common. There is need for a reliable assessment metric to detect and measure specific symptoms. OBJECTIVE: To subject the nocturnal LUTS score for older individuals, Nocturia, Incontinence, Toileting and Enuresis Symptom Score (NITES), to psychometric analysis. MATERIAL AND METHODS: Factor analysis of the metric was conducted with completed questionnaires from 151 older individuals who were either admitted to a tertiary hospital or attending an outpatient continence clinic. Test re-test reliability involved 18 older community dwelling individuals attending a Geriatrician clinic completing the metric at two timepoints separated by at least 1 week. Intra-class correlation coefficients were determined for reliability of each factor and item. RESULTS: The NITES metric was completed by 98 hospitalized older individuals and 53 attending a continence clinic (mean age 83.2 years [SD 7.0]). Factor analysis demonstrated that one item had a floor effect and two items had poor endorsement. After test re-test reliability analysis, a further three items were removed: one due to poor correlation between timepoints and two demonstrating inadequate internal consistency. The final NITES metric is comprised of three factors: Sleep 4-items, Incontinence 4-items, and Personal Bother 2-items. A 4-item short form for symptom screening was extracted from the longer measure. CONCLUSION: The final NITES metric is a 10-item questionnaire with an embedded 4-item short symptom screen. It has utility utilized to detect nocturnal bladder symptoms in both community dwelling and hospitalized older adults.