Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives.

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40-19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.

Novel temperature-controlled sleep system to improve sleep: a proof-of-concept study.

The sleep-wake cycle is regulated by circadian Process C and homeostatic Process S. Selective thermal stimulation (STS) of the cervical spine region enhances glabrous skin blood flow (GSBF) and augments body heat dissipation to increase distal-to-proximal skin gradient (DPG) causing decrease of core body temperature (CBT), which can shorten sleep onset latency (SOL) and improve sleep quality. A total of 11 young healthy/normal sleeper males challenged to go to bed (lights-off) 2 h earlier than usual were subjected in a randomised order to non-consecutive treatment and control night-time sleep sessions. The treatment night entailed activation of a dual-temperature zone mattress with a cooler centre and warmer periphery plus STS pillow that applied mild heating to the cervical spinal skin for 30 min after lights-off for sleep. During the first 30 min after lights-off, GSBF (mean [standard error (SE)] Δ = 49.77 [19.13] perfusion units, p = 0.013) and DPG (mean [SE] Δ = 2.05 [0.62] °C, p = 0.005) were significantly higher and CBT (mean [SE] Δ = -0.15 [0.07] °C, p = 0.029) was significantly lower in the treatment than control night, while there was no significant difference in these variables during the 45 min prior to lights-off (baseline). Moreover, SOL was significantly reduced (mean [SE] Δ = -48.6 [23.4] min, p = 0.032) and subjective sleep quality significantly better (p < 0.001) in the treatment than control night. In conclusion, the novel sleep facilitating system comprised of the STS pillow plus dual-temperature zone mattress induced earlier increase in GSBF and DPG and earlier decline in CBT. This resulted in statistically significant shortened SOL and improved overall sleep quality, thereby reducing sleep pressure of Process S, even under the challenging investigative protocol requiring participants to go to sleep 2 h earlier than customary.

Does Timing of Antihypertensive Medication Dosing Matter?

PURPOSE OF REVIEW: Current hypertension guidelines do not provide recommendation on when-to-treat. Herein, we review the current evidence on ingestion-time differences of hypertension medications in blood pressure (BP)-lowering effects and prevention of cardiovascular disease (CVD) events. RECENT FINDINGS: The vast (81.6%) majority of the 136 published short-term treatment-time trials document benefits, including enhanced reduction of asleep BP and increased sleep-time relative BP decline (dipping), when hypertension medications and their combinations are ingested before sleep rather than upon waking. Long-term outcome trials further document bedtime hypertension therapy markedly reduces risk of major CVD events. The inability of the very small 18.4% of the published trials to substantiate treatment-time difference in effects is mostly explained by deficiencies of study design and conduct. Our comprehensive review of the published literature reveals no single study has reported better benefits of the still conventional, yet scientifically unjustified, morning than bedtime hypertension treatment scheme.

Deep Neural Network Sleep Scoring Using Combined Motion and Heart Rate Variability Data.

Background: Performance of wrist actigraphy in assessing sleep not only depends on the sensor technology of the actigraph hardware but also on the attributes of the interpretative algorithm (IA). The objective of our research was to improve assessment of sleep quality, relative to existing IAs, through development of a novel IA using deep learning methods, utilizing as input activity count and heart rate variability (HRV) metrics of different window length (number of epochs of data). Methods: Simultaneously recorded polysomnography (PSG) and wrist actigraphy data of 222 participants were utilized. Classic deep learning models were applied to: (a) activity count alone (without HRV), (b) activity count + HRV (30-s window), (c) activity count + HRV (3-min window), and (d) activity count + HRV (5-min window) to ascertain the best set of inputs. A novel deep learning model (Haghayegh Algorithm, HA), founded on best set of inputs, was developed, and its sleep scoring performance was then compared with the most popular University of California San Diego (UCSD) and Actiwatch proprietary IAs. Results: Activity count combined with HRV metrics calculated per 5-min window produced highest agreement with PSG. HA showed 84.5% accuracy (5.3-6.2% higher than comparator IAs), 89.5% sensitivity (6.2% higher than UCSD IA and 6% lower than Actiwatch proprietary IA), 70.0% specificity (8.2-34.3% higher than comparator IAs), and 58.7% Kappa agreement (16-23% higher than comparator IAs) in detecting sleep epochs. HA did not differ significantly from PSG in deriving sleep parameters-sleep efficiency, total sleep time, sleep onset latency, and wake after sleep onset; moreover, bias and mean absolute error of the HA model in estimating them was less than the comparator IAs. HA showed, respectively, 40.9% and 54.0% Kappa agreement with PSG in detecting rapid and non-rapid eye movement (REM and NREM) epochs. Conclusions: The HA model simultaneously incorporating activity count and HRV metrics calculated per 5-min window demonstrates significantly better sleep scoring performance than existing popular IAs.

Accuracy of Wristband Fitbit Models in Assessing Sleep: Systematic Review and Meta-Analysis.

BACKGROUND: Wearable sleep monitors are of high interest to consumers and researchers because of their ability to provide estimation of sleep patterns in free-living conditions in a cost-efficient way. OBJECTIVE: We conducted a systematic review of publications reporting on the performance of wristband Fitbit models in assessing sleep parameters and stages. METHODS: In adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we comprehensively searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, Embase, MEDLINE, PubMed, PsycINFO, and Web of Science databases using the keyword Fitbit to identify relevant publications meeting predefined inclusion and exclusion criteria. RESULTS: The search yielded 3085 candidate articles. After eliminating duplicates and in compliance with inclusion and exclusion criteria, 22 articles qualified for systematic review, with 8 providing quantitative data for meta-analysis. In reference to polysomnography (PSG), nonsleep-staging Fitbit models tended to overestimate total sleep time (TST; range from approximately 7 to 67 mins; effect size=-0.51, P<.001; heterogenicity: I2=8.8%, P=.36) and sleep efficiency (SE; range from approximately 2% to 15%; effect size=-0.74, P<.001; heterogenicity: I2=24.0%, P=.25), and underestimate wake after sleep onset (WASO; range from approximately 6 to 44 mins; effect size=0.60, P<.001; heterogenicity: I2=0%, P=.92) and there was no significant difference in sleep onset latency (SOL; P=.37; heterogenicity: I2=0%, P=.92). In reference to PSG, nonsleep-staging Fitbit models correctly identified sleep epochs with accuracy values between 0.81 and 0.91, sensitivity values between 0.87 and 0.99, and specificity values between 0.10 and 0.52. Recent-generation Fitbit models that collectively utilize heart rate variability and body movement to assess sleep stages performed better than early-generation nonsleep-staging ones that utilize only body movement. Sleep-staging Fitbit models, in comparison to PSG, showed no significant difference in measured values of WASO (P=.25; heterogenicity: I2=0%, P=.92), TST (P=.29; heterogenicity: I2=0%, P=.98), and SE (P=.19) but they underestimated SOL (P=.03; heterogenicity: I2=0%, P=.66). Sleep-staging Fitbit models showed higher sensitivity (0.95-0.96) and specificity (0.58-0.69) values in detecting sleep epochs than nonsleep-staging models and those reported in the literature for regular wrist actigraphy. CONCLUSIONS: Sleep-staging Fitbit models showed promising performance, especially in differentiating wake from sleep. However, although these models are a convenient and economical means for consumers to obtain gross estimates of sleep parameters and time spent in sleep stages, they are of limited specificity and are not a substitute for PSG.

Gender, socioeconomic, medical, and environmental factors related to domestic accidents of the elderly in Spain. Findings of a national survey.

Domestic accidents pose serious threats to the independence of the elderly. We explored associations between domestic accidents and gender, socioeconomic, medical, and environmental factors using data from the European Health Survey 2014 for elderly Spanish female and male nationals. Records of 5960 participants (mean age ± SD: 75.9 ± 7.6 years), 59.8% of whom were women, were examined. Domestic accidents occurred in 460 (7.1%) seniors, predominately in women (78.5%). Age (adjusted odds ratio [aOR]: 1.02 [95% confidence interval [CI]: 1.00-1.03, p = .003], female gender (aOR 2.04 [95% CI 1.60-2.60, p < .001]), difficulty managing 12 stairs (reference: none) (some: aOR 2.03 [95% CI 1.53-2.68, p < .001]; much: aOR 2.88 [95% CI 2.15-3.87, p < .001]; inability: aOR 3.09 [95% CI 2.14-4.45, p < .001]), and depressive symptoms severity (reference: absent) (mild: aOR 1.44 [95% CI 1.10-1.89, p = .008]; moderate: aOR 1.91 [95% CI 1.35-2.71, p < .001];. Very severe: aOR 2.53 [95% CI 1.72-3.71, p < .001]; extremely severe: aOR 2.38 [95% CI 1.45-3.93, p = .001]) were independently associated with domestic accidents. Severity of depressive symptoms was the most prominent feature for women, while inability to manage 12 stairs was the most prominent for men. Our results suggest important gender differences in factors associated with domestic accidents that are relevant to intervention and preventive programs.

Hypertension: New perspective on its definition and clinical management by bedtime therapy substantially reduces cardiovascular disease risk.

Diagnosis of hypertension-elevated blood pressure (BP) associated with increased cardiovascular disease (CVD) risk-and its management for decades have been based primarily on single time-of-day office BP measurements (OBPM) assumed representative of systolic (SBP) and diastolic BP (DBP) during the entire 24-hours span. Around-the-clock ambulatory blood pressure monitoring (ABPM), however, reveals BP undergoes 24-hours patterning characterized in normotensives and uncomplicated hypertensives by striking morning-time rise, 2 daytime peaks-one ~2-3 hours after awakening and the other early evening, small midafternoon nadir and 10-20% decline (BP dipping) in the asleep BP mean relative to the wake-time BP mean. A growing number of outcome trials substantiate correlation between BP and target organ damage, vascular and other risks is greater for the ABPM-derived asleep BP mean, independent and stronger predictor of CVD risk, than daytime OBPM or ABPM-derived awake BP. Additionally, bedtime hypertension chronotherapy, that is, ingestion of ≥1 conventional hypertension medications at bedtime to achieve efficient attenuation of asleep BP, better reduces total CVD events by 61% and major events (CVD death, myocardial infarction, ischaemic and haemorrhagic stroke) by 67%-even in more vulnerable chronic kidney disease, diabetes and resistant hypertension patients-than customary on-awaking therapy that targets wake-time BP. Such findings of around-the-clock ABPM and bedtime hypertension outcome trials, consistently indicating greater importance of asleep BP than daytime OBPM or ambulatory awake BP, call for a new definition of true arterial hypertension plus modern approaches for its diagnosis and management.

Bedtime Chronotherapy with Conventional Hypertension Medications to Target Increased Asleep Blood Pressure Results in Markedly Better Chronoprevention of Cardiovascular and Other Risks than Customary On-awakening Therapy.

The bases for bedtime hypertension chronotherapy (BHCT) as superior chronoprevention against cardiovascular disease (CVD) are: (1) correlation between blood pressure (BP) and various risks is greater for ambulatory BP monitoring (ABPM) than office BP measurements (OBPM); (2) asleep BP mean is a better predictor of CVD risk than ABPM awake and 24-hour means and OBPM; and (3) targeting of asleep BP by BHCT with one or more conventional medications versus usual on-awakening therapy better reduces major and total CVD events. BHCT offers the most cost-effective chronoprevention against adverse CVD outcomes in regular and vulnerable renal, diabetic, and resistant hypertensive patients.

Bedtime Blood Pressure Chronotherapy Significantly Improves Hypertension Management.

Consistent evidence of numerous studies substantiates the asleep blood pressure (BP) mean derived from ambulatory BP monitoring (ABPM) is both an independent and a stronger predictor of cardiovascular disease (CVD) risk than are daytime clinic BP measurements or the ABPM-determined awake or 24-hour BP means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of 6 different classes and their combinations significantly improves BP control, particularly sleep-time BP, and reduces adverse effects.

Temporal Patterns of In-Hospital Falls of Elderly Patients.

BACKGROUND: A potentially important factor yet to receive adequate study is the time when hospital falls occur. A prior study conducted before the system-wide introduction of preventive measures revealed a biphasic 24-hour pattern of hospital falls with major peak in the morning. OBJECTIVES: The purpose was to identify the temporal patterning of falls among elderly patients in hospitals with comprehensive fall prevention programs in place. METHODS: A 4-year observational study was conducted by the local health authority in the five nonteaching public hospitals located in the province of Ferrara, Italy. Fall records involving patients of ages ≥65 years hospitalized in the general medical departments were used. Single- and multiple-component cosinor (time series) analyses were used to explore 24-hour, weekly, and annual patterns of falls. RESULTS: A total of 763 falls were experienced by 709 different elderly hospitalized patients. Falls typically took place in the patient's hospital room (72%) and bathroom (23%). Major causes were patient instability (32%) and accident (13%), and most occurred when not wearing footwear (45%) or wearing inappropriate sling-back open-toe shoes (39%). Falls happened while standing (39%), while seated (21%), and while getting into, out of, or laying in bed (32%)-either with the bed rails raised or lowered. Fall outcome usually involved no injury (58%) or slight injury (35%), but some (7%) were disabling. Fall occurrence was higher during the night (46%) compared to either the morning (30%) or afternoon (24%) shift. Patterns across 24 hours were characterized by a single major and one or more minor peaks that seemed to be associated with a variety of scheduled patient, hospital, and nursing activities. Multiple-component cosinor analysis identified significant (p < .05) prominent day-night patterns according to fall location, patient position, cause, injury severity, and type of footwear. Falls were more frequent, but not significantly so, on Fridays, Sundays, and Mondays compared with Tuesdays, and were more frequent in winter and spring (p = .003). DISCUSSION: Documentation by cause and circumstance of these moderate- to high-amplitude temporal patterns in hospital falls of elderly patients advances the knowledge of fall epidemiology by identifying the times of day, week, and year and nursing shifts of elevated risk that is of critical importance to improving hospital patient safety programs.

Abnormalities in chronic kidney disease of ambulatory blood pressure 24 h patterning and normalization by bedtime hypertension chronotherapy.

In chronic kidney disease (CKD), the prevalence of hypertension is very high, escalating with diminishing renal function. Typically, the diagnosis of hypertension and the clinical decisions regarding its treatment are based on daytime clinic blood pressure (BP) measurements. However, the correlation between BP level and target organ damage, cardiovascular risk and long-term prognosis is greater for ambulatory than clinic measurements. Moreover, evidence is consistent among numerous studies that the elevated risk and incidence of end-organ injury and fatal and non-fatal cardiovascular events are significantly associated with blunted night-time BP decline, and that the asleep BP better predicts cardiovascular events than either the awake or 24-h BP mean. The prevalence of abnormally high asleep BP is extensive in CKD, significantly increasing with its severity. In CKD, the diagnoses of hypertension and its therapeutic control are often inaccurate in the absence of complete and careful assessment of the entire 24 h, i.e. daytime and night-time, BP pattern. Accordingly, ambulatory BP monitoring should be the preferred method to comprehensively assess and decide the optimal clinical management of patients with CKD. Recent findings indicate therapeutic restoration of normal physiologic BP reduction during night-time sleep is the most significant independent predictor of decreased cardiovascular and cerebrovascular risk, both in patients with and without CKD, and is best achieved when antihypertensive medications, mainly those blocking the renin-angiotensin-aldosterone system, are routinely taken at bedtime.

Around-the-clock ambulatory blood pressure monitoring is required to properly diagnose resistant hypertension and assess associated vascular risk.

Diagnosis of resistant hypertension (RH) is currently based upon awake-time office blood pressure (BP). An increasing number of studies have documented abnormally elevated sleep-time BP in most RH patients, indicating that diagnosis of true RH cannot be determined solely by comparison of office BP with either patient awake-time BP self-measurements or awake-BP mean from ambulatory monitoring (ABPM), as is customary in the published literature. Moreover, the ABPM-determined sleep-time BP mean is an independent and stronger predictor of cardiovascular and cerebrovascular disease (CVD) risk than either daytime office/ABPM-derived awake or 24-hour means. Results of the recently completed MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares) prospective outcomes study, which included a large cohort of RH patients, established that time of treatment relative to circadian rhythms constituted a critically important yet often neglected variable with respect to BP control. The study found that bedtime versus morning ingestion of the full dose of ≥1 BP-lowering medications resulted in both better therapeutic normalization of sleep-time BP and reduced CVD morbidity and mortality, including in RH patients. Accordingly, ABPM is highly recommended to properly diagnose and manage true RH, with a bedtime hypertension medication regimen as the therapeutic scheme of choice.

Chronotherapeutics of conventional blood pressure-lowering medications: simple, low-cost means of improving management and treatment outcomes of hypertensive-related disorders.

Correlation between blood pressure (BP) target organ damage, cardiovascular risk, and long-term prognosis is greater for ambulatory monitored (ABPM) than daytime in-clinic measurements. Additionally, consistent evidence of numerous studies substantiates the ABPM-determined asleep BP mean is an independent and stronger predictor of risk and incidence of end-organ injury and cardiovascular events than the awake or 24-h means. Hence, cost-effective control of sleep-time BP is of great clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly impacts beneficial and/or adverse effects. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers better controls the asleep than awake BP means, with additional benefit independent of terminal half-life of converting the 24-h BP profile into more normal dipper patterning. Recent findings authenticate therapeutic reduction of sleep-time BP, best achieved when the full daily dose of ≥1 hypertension medications is routinely ingested at bedtime, is the most significant independent predictor of lowered cardiovascular and cerebrovascular risk.

Twenty-four-hour pattern in French firemen of lag time response to out-of-hospital cardiac arrest and work-related injury.

Circadian cognitive and physical rhythms plus 24 h patterns of accidents and work-related injuries (WRI) have been verified in numerous studies. However, rarely, if ever, have 24 h temporal differences in both work performance and risk of WRI been assessed in the same group of workers. We explored in a homogenous group of French firemen (FM) 24 h patterns of both lag time (LT) response duration to emergency calls for medical help (ECFM) for life-threatening out-of-hospital cardiac arrests (OHCA), used as a non-specific index of work performance, and WRI. Our studies demonstrate rather high amplitude statistically significant 24 h patterns of the two variables. The LT response duration was twice as long -0500 h (slowest response) than -1600 h (fastest response). In the same group of FM, the actual number WRI/h was greatest -1600 h and lowest in the early morning hours. However, the 24 h pattern of the relative risk (RR) of WRIs, i.e., per clock hour number of WRI/(total number of responses to emergency calls x number of FM at risk per response), was very different, the RR being greatest -0200 h and lowest in the afternoon. The 24 h pattern in LT response duration to ECMH for OHCA and RR of WRI was strongly correlated (r = +0.85, P < 0.01), with the nocturnal trough (slowest response) in LT response duration coinciding with the nocturnal peak RR of WRI. These findings indicate the requirement for circadian rhythm-based interventions to improve the nocturnal compromised work performance and elevated risk of WRI of shift-working FM.

Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Pioneering new frontiers in circadian medicine chronotherapies for cardiovascular health.

Cardiovascular disease (CVD) is a global health concern. Circadian medicine improves cardiovascular care by aligning treatments with our body's daily rhythms and their underlying cellular circadian mechanisms. Time-based therapies, or chronotherapies, show special promise in clinical cardiology. They optimize treatment schedules for better outcomes with fewer side effects by recognizing the profound influence of rhythmic body cycles. In this review, we focus on three chronotherapy areas (medication, light, and meal timing) with potential to enhance cardiovascular care. We also highlight pioneering research in the new field of rest, the gut microbiome, novel chronotherapies for hypertension, pain management, and small molecules that targeting the circadian mechanism.

Critical appraisal of recent translational chronopharmacology and chronotherapeutic reviews, meta-analyses, and pragmatic patient trials discloses significant deficiencies of design and conduct and suspect findings.

The conduct of molecular and laboratory animal circadian rhythm research has increased exponentially in the past few decades, such that today investigations are being performed by scientists of many diverse disciplines. Knowledge gained from past works is now being explored for translational applications to clinical medicine, often termed "circadian medicine," through the implementation of patient trials. However, these trials are being led, more often than not, by investigators who have little or no formal training and in-depth expertise in the methods of human circadian rhythm research, causing them to be deficient in design and produce dubious findings that have already led to unnecessary medical controversy at the expense of advances in patient care. Evidence of the very significant shortcomings of today's translational circadian medicine research is exemplified in two recent publications in well-read reputable medical journals concerning the chronotherapy of blood pressure (BP) medications: one a review and meta-analysis by Maqsood et al. published in the journal Hypertension in 2023 that pertains to ingestion-time differences in the extent of BP reduction exerted by hypertensive medications and the other a report by Mackenzie et al. in the journal Lancet in 2022 that details the results of the pragmatic TIME study that assessed ingestion-time differences in cardiovascular disease outcomes. Herein, we appraise the inaccurate trial selection, lack of quality assessment, and the numerous other shortcomings that culminated in suspect findings and faulty conclusions of the former, as well as the deficiencies in design and conduct of the latter using as reference the eight items identified in 2021 by a working committee of the International Society for Chronobiology and American Association for Medical Chronobiology and Chronotherapeutics as being necessary for high-quality research of circadian rhythm-dependencies of the therapeutic effects of BP-lowering medications. The TIME study when rated for its quality according to the extent to which its investigational methods satisfy all of the eight recommended items attains a very low overall score of + 1 out of a possible range of -1 to + 7. Moreover, our review of the methods of the currently ongoing pragmatic BedMed trial discloses major deficiencies of the same sort rending a poor quality score of + 0.5. Although the focus of this article is the appraisal of the quality of contemporary circadian medicine hypertension chronotherapy research, it additionally exposes the inadequacies and dubious quality of the critique of such manuscripts submitted for publication to influential journals, in that some peer reviewers might also be deficient in the knowledge required to properly rate their merit.

Circadian rhythms of risk factors and management in atherosclerotic and hypertensive vascular disease: Modern chronobiological perspectives of an ancient disease.

Atherosclerosis, a chronic inflammatory disease of the arteries that appears to have been as prevalent in ancient as in modern civilizations, is predisposing to life-threatening and life-ending cardiac and vascular complications, such as myocardial and cerebral infarctions. The pathogenesis of atherosclerosis involves intima plaque buildup caused by vascular endothelial dysfunction, cholesterol deposition, smooth muscle proliferation, inflammatory cell infiltration and connective tissue accumulation. Hypertension is an independent and controllable risk factor for atherosclerotic cardiovascular disease (CVD). Conversely, atherosclerosis hardens the arterial wall and raises arterial blood pressure. Many CVD patients experience both atherosclerosis and hypertension and are prescribed medications to concurrently mitigate the two disease conditions. A substantial number of publications document that many pathophysiological changes caused by atherosclerosis and hypertension occur in a manner dependent upon circadian clocks or clock gene products. This article reviews progress in the research of circadian regulation of vascular cell function, inflammation, hemostasis and atherothrombosis. In particular, it delineates the relationship of circadian organization with signal transduction and activation of the renin-angiotensin-aldosterone system as well as disturbance of the sleep/wake circadian rhythm, as exemplified by shift work, metabolic syndromes and obstructive sleep apnea (OSA), as promoters and mechanisms of atherogenesis and risk for non-fatal and fatal CVD outcomes. This article additionally updates advances in the clinical management of key biological processes of atherosclerosis to optimally achieve suppression of atherogenesis through chronotherapeutic control of atherogenic/hypertensive pathological sequelae.

Recommended timing of medications that impact sleep and wakefulness: A review of the American Prescribers' Digital Reference.

An appreciable number of medicines have a recommended unique single time-of-day or asymmetrical or unequal-interval multiple-daily administration schedule. Many prescription and over-the-counter (OTC) products, according to administration time, can exert positive or negative impact on nighttime sleep and daytime wakefulness. Intuitively, medicines used to manage nighttime sleep and daytime wake disorders should be taken, respectively, at night before bedtime and morning after arising. However, some utilized for other medical conditions, if improperly timed, may compromise nocturnal sleep and diurnal attentiveness. We conducted a comprehensive review of the American Prescribers' Digital Reference, internet version of the Physician's Desk Reference, for the recommended scheduling of medications and OTC remedies that can impact sleep and wakefulness. The search revealed several hundred therapies of various classes -- α2-receptor agonists, antidepressants, barbiturates, central nervous system stimulants, benzodiazepines, dopamine agonists, dopamine norepinephrine reuptake inhibitors, selective norepinephrine reuptake inhibitors, eugeroics, γ-aminobutyric acid modulators, H1 and H3-receptor antagonists, melatonin analogues, OTC melatonin-containing products, non-benzodiazepine benzodiazepine-receptor agonists, dual orexin-receptor antagonists, and serotonin modulators -- that have a recommended unique dosing schedule. The tables and text of this article are intended to guide the proper scheduling of these medicines to optimize desired and/or minimize undesired effects.