Measuring and recording outcome.

Achieving good health outcomes for patients is the fundamental purpose of healthcare. What really matters to patients is the outcome of an intervention and the effect it will have on their wellbeing and life expectancy. After media coverage, and public enquiry into high mortality rates for paediatric cardiac surgery at the Bristol Royal Infirmary during the early 1990s, mortality rates for paediatric cardiac surgical procedures decreased dramatically both in Bristol and nationally. There can be little doubt that one of the prime 'drivers for change' was the placement of outcome data into the public domain. After events in Bristol, the Society for Cardiothoracic Surgery in Britain and Ireland (SCTS) has taken the lead in measuring and publishing clinical outcome data. It has also discussed how outcome data could be used to assess an individual's clinical performance and how, in the future, this might be linked to continuing professional development, appraisal, and revalidation. Measuring quality and outcome in healthcare is complex. Ideal outcome measures should be specific, sensitive, reliable, responsive, validated, timely, and easy to measure. Monitoring of outcomes can be 'process' orientated or 'clinically' orientated. The 2010 National Health Service (NHS) White Paper aimed for an NHS which 'moves away from centrally driven process targets and focuses on delivering outcomes which matter to people'. Measuring outcome in anaesthesia is problematic. There are issues around clinical coding, risk adjustment, the influence of clinical teamworking, and environmental factors. The National Institute of Academic Anaesthesia (NIAA) has identified that the description of clinical practice in anaesthesia and perioperative medicine is currently limited by a lack of valid, reliable quality measures. The NIAA suggests that there is a requirement for further research into identifying the anaesthetic outcome indicators which are most relevant to patients, and then benchmarking the performance of anaesthetic departments and anaesthetists.

Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans.

Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.

Current management of adults receiving oral anti-cancer medications: A scoping review.

PURPOSE: Oral anti-cancer medication (OAM) has revolutionised oncology care. Due to their potential toxicities and associated safety challenges ongoing assessment and monitoring is essential; currently generally performed in acute care settings. Internationally there exists a transformative vision to shift patient care from acute to primary care. A nurse-led integrated model of care could be developed for OAM patient management in primary care. The aim of this study was to examine international literature regarding current clinical management practices for assessment and monitoring of patients receiving OAM. METHODS: Following PRISMA-ScR guidelines, databases MEDLINE, CINAHL and Web of Science were searched for English studies published between 2010 and 2020 using keywords: assessment, cancer, care, management, oral anticancer medications. Articles were screened and assessed for eligibility. From eligible studies, data were extracted to summarize, collate and make a narrative account of the findings. RESULTS: 2261 papers were reviewed, 14 met inclusion criteria. Three phases of management are reported: 1. Patient treatment plan development; 2. Patient education; 3. Patient monitoring. Within these phases seven specific stages of care were identified broadly representing the patient's journey: (1) treatment decision, (2) prescribing of OAM, (3) OAM dispensing and administration, (4) maximising patient safety (5) ongoing patient assessment (6) patient support (7) communication with other health-care professionals. CONCLUSIONS: Despite a paucity of international literature, a dedicated OAM clinic was endorsed as a means to achieve improved care. Nurses and pharmacists were identified as being of particular importance especially in education and ongoing management of patients receiving OAMs.

Extraocular circadian phototransduction in humans.

Physiological and behavioral rhythms are governed by an endogenous circadian clock. The response of the human circadian clock to extraocular light exposure was monitored by measurement of body temperature and melatonin concentrations throughout the circadian cycle before and after light pulses presented to the popliteal region (behind the knee). A systematic relation was found between the timing of the light pulse and the magnitude and direction of phase shifts, resulting in the generation of a phase response curve. These findings challenge the belief that mammals are incapable of extraretinal circadian phototransduction and have implications for the development of more effective treatments for sleep and circadian rhythm disorders.

Effects of prolonged use of azithromycin in patients with cystic fibrosis: a meta-analysis.

Azithromycin has been studied as potential therapeutic anti-inflammatory agent for cystic fibrosis (CF) patients. Azithromycin (AZM) has been used as an immunomodulating agent, based on few small studies. Considering the cost and potential side effects of long-term azithromycin therapy, it is important to identify the group of patients that would benefit the most. Weighted mean difference was used for pulmonary function tests, and risk ratios for all other variables. The random-effects model was applied for all reports. Combining four studies (N=368), azithromycin showed increase in FEV(1) (3.53%, 95% CI 0.00, 7.07, p=0.05; I(2)=38%) and FVC (4.24%, 95% CI 2.02, 6.45, p=0.0002; I(2)=0%). When trials were analyzed by baseline Pseudomonas sputum colonization, the heterogeneity decreased (I(2)=0%), FEV(1) significantly increased to 4.66% (95% CI 1.18, 8.15, p=0.009), and FVC increased to 4.64% (95% CI 2.11, 7.17, p=0.0003). The GI side effects were 72% higher with azithromycin use (RR 1.72, 95% CI 1.33, 2.21, p=0.00003), the main side effects being nausea (RR 2.04, 95% CI 1.19, 3.45, p=0.009), and diarrhea (RR 2.12, 95% CI 1.10, 4.08, p=0.02). Azithromycin improves lung function of CF patients, especially in the subgroup colonized with Pseudomonas. However, nausea and diarrhea are significantly more frequent with azythromycin.

Cigarette smoking significantly alters sperm DNA methylation patterns.

Numerous health consequences of tobacco smoke exposure have been characterized, and the effects of smoking on traditional measures of male fertility are well described. However, a growing body of data indicates that pre-conception paternal smoking also confers increased risk for a number of morbidities on offspring. The mechanism for this increased risk has not been elucidated, but it is likely mediated, at least in part, through epigenetic modifications transmitted through spermatozoa. In this study, we investigated the impact of cigarette smoke exposure on sperm DNA methylation patterns in 78 men who smoke and 78 never-smokers using the Infinium Human Methylation 450 beadchip. We investigated two models of DNA methylation alterations: (i) consistently altered methylation at specific CpGs or within specific genomic regions and (ii) stochastic DNA methylation alterations manifest as increased variability in genome-wide methylation patterns in men who smoke. We identified 141 significantly differentially methylated CpGs associated with smoking. In addition, we identified a trend toward increased variance in methylation patterns genome-wide in sperm DNA from men who smoke compared with never-smokers. These findings of widespread DNA methylation alterations are consistent with the broad range of offspring heath disparities associated with pre-conception paternal smoke exposure and warrant further investigation to identify the specific mechanism by which sperm DNA methylation perturbation confers risk to offspring health and whether these changes can be transmitted to offspring and transgenerationally.

Cytotoxicity and accumulation of ganciclovir triphosphate in bystander cells cocultured with herpes simplex virus type 1 thymidine kinase-expressing human glioblastoma cells.

The ability of herpes simplex virus type 1 thymidine kinase (HSV-TK)-expressing cells incubated with ganciclovir (GCV) to induce cytotoxicity in neighboring HSV-TK-negative (bystander) cells has been well documented. Although it has been suggested that this bystander cell killing occurs through the transfer of phosphorylated GCV, there is little direct proof that bystander cells can accumulate GCV nucleotides. We have studied the ability of U251 human glioblastoma cells expressing HSV-TK (U251tk cells) to induce cytotoxicity in neighboring U251 bystander cells that lack the viral kinase (U251beta gal cells) and evaluated whether this bystander cell killing is mediated by GCV nucleotides. The cytotoxicity studies demonstrated that the ratio of HSV-TK-expressing cells:bystander cells was important in determining the sensitivity of both cell types to GCV. U251tk cells cocultured with an equal number of U251beta gal cells (a 50:50 ratio) exhibited a sensitivity to GCV similar to that observed in the absence of bystander cells, with >99.8% cell kill at 1 microm GCV. However, in cultures with 10% U251tk cells and 90% bystander cells (a 10:90 ratio), 1 microM GCV decreased the survival of U251tk cells by only 54%. Strong bystander cell killing was observed at both ratios. In a 50:50 coculture of U251tk and U251beta gal cells, the survival of bystander cells was decreased by >99.5% with 3 microM GCV, whereas 30 microM GCV was required to effect a similar decrease in bystander cell survival when 90% of the culture consisted of U251beta gal cells. To determine whether this bystander cell killing may be mediated by GCV nucleotides, we developed a technique to separate the two cell populations after coculture. A U251 bystander cell line was developed from the parental cell line by transfection with the cDNA coding for green fluorescent protein (U251gfp cells), which permitted the separation of U251gfp cells from nonfluorescing U251tk cells by flow cytometry with cell sorting. With this technique, bystander cells were isolated in a viable state with >97% purity within 1 h after harvest, permitting analysis of the nucleotide pools for the presence of phosphorylated GCV. The results demonstrated that significant levels of the triphosphate of GCV (GCVTP) accumulated in bystander cells within 4 h of coculture, and this accumulation was dependent upon the percentage of HSV-TK-expressing cells as well as the concentration of GCV and the length of incubation. The proportion of GCVTP in bystander cells was consistently 50-80% of that in HSV-TK-expressing cells in the 50:50 or 10:90 cocultures, suggesting a facile transfer of phosphorylated GCV. However, the actual amount of GCVTP was as much as 8-fold lower in both the U251tk and U251beta gal cells cocultured at a ratio of 10:90 compared to those cocultured at a ratio of 50:50, which is consistent with the lesser effect on cell survival. When U251tk and U251gfp cells were cultured with 1-beta-D-arabinofuranosylthymine (araT), the 5'-triphosphate of araT accumulated in the bystander cells, demonstrating that the transfer of phosphorylated compounds between these cell types is not restricted to GCV nucleotides. However, the proportion of araT-5'-triphosphate in bystander cells compared to that in HSV-TK-expressing cells was lower than that for GCVTP, and the amount was not sufficient to decrease survival in the bystander population.

Genome-wide DNA methylation profiling in zebrafish.

Genomic DNA methylation functions to repress gene expression by interfering with transcription factor binding and/or recruiting repressive chromatin machinery. Recent data support contribution of regulated DNA methylation to embryonic pluripotency, development, and tissue differentiation; this important epigenetic mark is chemically stable yet enzymatically reversible-and heritable through the germline. Importantly, all the major components involved in dynamic DNA methylation are conserved in zebrafish, including the factors that "write, read, and erase" this mark. Therefore, the zebrafish has become an excellent model for studying most biological processes associated with DNA methylation in mammals. Here we briefly review the zebrafish model for studying DNA methylation and describe a series of methods for performing genome-wide DNA methylation analysis. We address and provide methods for methylated DNA immunoprecipitation followed by sequencing (MeDIP-Seq), bisulfite sequencing (BS-Seq), and reduced representation bisulfite sequencing (RRBS-Seq).

Implementing international sexual counselling guidelines in hospital cardiac rehabilitation: development of the CHARMS intervention using the Behaviour Change Wheel.

BACKGROUND: Decreased sexual activity and sexual problems are common among people with cardiovascular disease, negatively impacting relationship satisfaction and quality of life. International guidelines recommend routine delivery of sexual counselling to cardiac patients. The Cardiac Health and Relationship Management and Sexuality (CHARMS) baseline study in Ireland found, similar to international findings, limited implementation of sexual counselling guidelines in practice. The aim of the current study was to develop the CHARMS multi-level intervention to increase delivery of sexual counselling by healthcare professionals. We describe the methods used to develop the CHARMS intervention following the three phases of the Behaviour Change Wheel approach: understand the behaviour, identify intervention options, and identify content and implementation options. Survey (n = 60) and focus group (n = 14) data from two previous studies exploring why sexual counselling is not currently being delivered were coded by two members of the research team to understand staff's capability, opportunity, and motivation to engage in the behaviour. All potentially relevant intervention functions to change behaviour were identified and the APEASE (affordability, practicability, effectiveness, acceptability, side effects and equity) criteria were used to select the most appropriate. The APEASE criteria were then used to choose between all behaviour change techniques (BCTs) potentially relevant to the identified functions, and these BCTs were translated into intervention content. The Template for Intervention Description and Replication (TIDieR) checklist was used to specify details of the intervention including the who, what, how and where of proposed intervention delivery. RESULTS: Providing sexual counselling group sessions by cardiac rehabilitation staff to patients during phase III cardiac rehabilitation was identified as the target behaviour. Education, enablement, modelling, persuasion and training were selected as appropriate intervention functions. Twelve BCTs, linked to intervention functions, were identified for inclusion and translated into CHARMS intervention content. CONCLUSIONS: This paper details the use of Behaviour Change Wheel approach to develop an implementation intervention in an under-researched area of healthcare provision. The systematic and transparent development of the CHARMS intervention will facilitate the evaluation of intervention effectiveness and future replication and contribute to the advancement of a cumulative science of implementation intervention design.

Incidence and severity of keratoconus in Asir province, Saudi Arabia.

AIM: To assess the incidence and associated signs and symptoms of patients with keratoconus in Asir Province, Saudi Arabia. METHODS: 125 new keratoconus patients (51 male, 74 female; mean age 18.5 (SD 3.8) years; range 8--28 years) were recruited from referrals to the department of ophthalmology, Asir Central Hospital, over a 1 year period. Age, visual acuity, and keratometry were recorded along with clinical signs and symptoms. RESULTS: The incidence of keratoconus in Asir Province is 20 cases per 100,000 population. Also, the disease severity is high, as indicated by an early mean age (17.7 (3.6) years) with advanced stage keratoconus. Visual acuity, with either spectacles or rigid contact lenses, was 6/12 or better in 98% of eyes measured. Just over half (56%) of patients had atopic ocular disease. 16% of patients had a positive family history of the disease and 16% had atopic dermatitis (eczema and/or vitiligo). CONCLUSION: The incidence and severity of keratoconus in Asir Province, Saudi Arabia, is high with an early onset and more rapid progress to the severe disease stage at a young age. This might reflect the influence of genetic and/or environmental factor(s) in the aetiology of keratoconus.

A model for the catabolism of rhizopine in Rhizobium leguminosarum involves a ferredoxin oxygenase complex and the inositol degradative pathway.

Rhizopines are nodule-specific compounds that confer an intraspecies competitive nodulation advantage to strains that can catabolize them. The rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolic moc gene cluster mocCABRDE(F) in Rhizobium leguminosarum bv. viciae strain 1a is located on the Sym plasmid. MocCABR are homologous to the mocCABR gene products from Sinorhizobium meliloti. MocD and MocE contain motifs corresponding to a TOL-like oxygenase and a [2Fe-2S] Rieske-like ferredoxin, respectively. The mocF gene encodes a ferredoxin reductase that would complete the oxygenase system, but is not essential for rhizopine catabolism. We propose a rhizopine catabolic model whereby MocB transports rhizopine into the cell and MocDE and MocF (or a similar protein elsewhere in the genome), under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine (SI). MocA, an NAD(H)-dependent dehydrogenase, and MocC continue the catabolic process. Compounds formed then enter the inositol catabolic pathway.

Character displacement in polyphenic tadpoles.

Biologists have long known that closely related species are often phenotypically different where they occur together, but are indistinguishable where they occur alone. The causes of such character displacement are controversial, however. We used polyphenic spadefoot toad tadpoles (Spea bombifrons and S. multiplicata) to test the hypothesis that character displacement evolves to minimize competition for food. We also sought to evaluate the role of phenotypic plasticity in the mediation of competitive interactions between these species. Depending on their diet, individuals of both species develop into either a small-headed omnivore morph, which feeds mostly on detritus, or a large-headed carnivore morph, which specializes on shrimp. Laboratory experiments and surveys of natural ponds revealed that the two species were more dissimilar in their tendency to produce carnivores when they occurred together than when they occurred alone. This divergence in carnivore production was expressed as both character displacement (where S. multiplicata's propensity to produce carnivores was lower in sympatry than in allopatry) and as phenotypic plasticity (where S. multiplicata facultatively enhanced carnivore production in S. bombifrons, and S. bombifrons facultatively suppressed carnivore production in S. multiplicata). In separate experiments, we established that S. bombifrons (the species for which carnivore production was enhanced) was the superior competitor for shrimp. Conversely, S. multiplicata (the species for which carnivore production was suppressed and omnivore production enhanced) was the superior competitor for detritus. These results therefore demonstrate that selection to minimize competition for food can cause character displacement. They also suggest that both character displacement and phenotypic plasticity may mediate competitive interactions between species.

Genetic relationships among rhizopine-producing Rhizobium strains.

Chromosomal and symbiosis-related genotypes of rhizopine-producing and non-producing isolates of Rhizobium meliloti and Rhizobium leguminosarum were examined by multilocus enzyme electrophoresis and RFLP. The distribution of rhizopine production in both species was found to be independent of host genotype. Conversely, rhizopine production was associated with particular symbiotic plasmid types. This association may explain the observed distribution of rhizopine production in R. leguminosarum and R. meliloti. Rhizopine synthesis (mos) genes showed greater sequence divergence than rhizopine catabolism (moc) genes in both R. meliloti and R. leguminosarum. Furthermore, mos and moc genes were less divergent in R. leguminosarum than R. meliloti, suggesting a more recent evolution in the former species.

Illusion processing in hemispatial neglect.

Twelve patients with hemispatial neglect and two control groups were tested to examine the effects of the Müller-Lyer and Judd illusions on bisection behaviour. The studies were designed to investigate whether neglect patients were indeed unaware of the left sides of the illusory figures. In Experiment 1, participants were asked to describe the illusory figures prior to bisection, whereas in Experiment 2, they compared two illusions whose fins, in the critical condition, differed on the left and then performed the bisection. It was found that the illusions worked equally well in all three groups. Interestingly, apart from one exception, almost all neglect patients explicitly reported the left-sided fins in Experiment 1. Only five patients failed to do so but only on an average of 16% of trials. In Experiment 2, six patients made errors in the comparison task but four of these patients did not neglect any left-sided fins in Experiment 1 (with the exception of three overall trials for LC and EdR). This finding seems a good indication that the two tasks differ in their requirements. The comparison task may be perceived as harder as it requires discrimination rather than detection and thus lead to more neglect type errors than the bisection task. In one neglect patient, the illusions consistently failed to work. This patient presented with an occipito-temporal and basal ganglia lesion and the mechanisms responsible for the processing of simple visual features might have possibly been impaired in her case.

Modification of visually guided saccades by a nonvisual afferent feedback signal.

PURPOSE: To investigate the role of extraocular muscle afferent signals in the control of saccadic eye movements. METHODS: A suction scleral contact lens was used to impede the movements of the right eye while subjects executed visually guided saccades to briefly presented targets. Movements of the left eye were measured using infrared oculography. Saccade amplitude, peak velocity, and duration were analyzed trial by trial and compared before, during, and after the right eye was impeded. RESULTS: When the right eye was impeded, the amplitudes of saccades executed by the left eye were reduced. There was no alteration in the main sequence relationships. The amplitude effect had a rapid onset and offset. There was no evidence that the effects built up over a number of trials, nor was there evidence that individual saccades were modified on-line. CONCLUSIONS: These results are consistent with the hypothesis that extraocular muscle afferent signals provide a feedback signal of the movements of the eyes that is used to produce rapid adjustments of oculomotor output when required.

Nighttime drop in body temperature: a physiological trigger for sleep onset?

Relationships between changes in the slope of the body temperature (BT) and the initiation of sleep were examined in 44 subjects ranging from 19 to 82 years of age. Following an adaptation night, subjects remained in the laboratory for a baseline night and 72 hours in temporal and social isolation, with strictly limited behavioral options ("disentrainment") during which continuous electroencephalograph (EEG) and BT were recorded. Polysomnographic sleep variables (e.g. sleep onset, percentage of each sleep stage) were determined for nighttime sleep periods at baseline and during the disentrainment period. Periods of the BT curve surrounding these sleep bouts were examined for minute to minute changes, and the time at which the maximum rate of decline (MROD) in temperature occurred was compared with the time of sleep onset (SO) and sleep quality parameters. On the baseline night, the MROD occurred, on average, 60 minutes prior to SO. During disentrainment, the MROD occurred, on average, 44 minutes prior to SO. The proximity of MROD to SO did not affect subsequent sleep quality on the baseline night, but during disentrainment, there were significant correlations between the interval from MROD to sleep onset and the amount of slow-wave sleep (SWS) obtained during the sleep bout. There were no significant age differences on variables related to MROD on baseline night, but the timing of both MROD and SO were significantly advanced in older, relative to younger, subjects during the disentrainment period. It is suggested that a rapid decline in core body temperature increases the likelihood of sleep initiation and may facilitate an entry into the deeper stages of sleep.

Etiology and treatment of intrinsic circadian rhythm sleep disorders.

Some individuals experience an acute or chronic sleep disturbance, associated with a misalignment between the timing of their sleep and the sleep-wake cycle that is desired, or considered normal by society. It is estimated that 5-10% of insomniacs seeking treatment have this type of disorder, collectively called circadian rhythm sleep disorders. This paper reviews circadian rhythm sleep disorders of the intrinsic type, which include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome, and irregular sleep-wake pattern. For each disorder, we present data addressing its pathophysiology and potential treatments, including the use of behavioral measures and chronotherapy, bright light treatment and pharmacological treatments such as melatonin. We conclude by addressing some of the limitations and drawbacks of the various treatments.

Acute hepatitis E by a new isolate acquired in the United States.

OBJECTIVE: To report the first case of acute hepatitis E by a novel isolate acquired in the United States and confirmed by nucleotide sequencing. MATERIAL AND METHODS: We describe the clinical manifestations and the results of associated laboratory studies in a man who was found to have acute hepatitis E infection. RESULTS: A 62-year-old man was hospitalized because of fever, abdominal pain, and jaundice. After an initial evaluation did not provide a cause, his serum was found to be positive for IgG anti-hepatitis E virus (HEV) by three antibody assays. Serum was also positive for HEV RNA by reverse transcriptase polymerase chain reaction (PCR). Sequencing results from the PCR products demonstrated substantial differences at the nucleotide level between this strain and the known Mexican and Burmese strains. CONCLUSION: On the basis of this initial report, HEV should be considered an etiologic agent in patients with acute non-ABC hepatitis in the United States.

Homologous blood transfusion as a risk factor for postoperative infection after coronary artery bypass graft operations.

Homologous transfusions are immunosuppressive and associated with a higher risk of postoperative infection. In this retrospective analysis, we studied 238 consecutive patients who underwent first-time coronary operations by a single surgeon in 1988 to 1989 and collected clinical and laboratory data relevant to postoperative infections including pulmonary, urinary, and wound sites. Culture-proved postoperative infections occurred in 16 of the 238 patients (6.7%), with only 3 (1.3%) being deep sternal wound infections. Seven of 16 (44%) of the infections were away from the wound sites, suggesting that nonsurgical variables contributed to at least some infections. Factors significantly associated with an increased risk of postoperative infection by univariate analysis included female sex, diabetes mellitus, and transfusion dose. Infections occurred in 3.9% of patients receiving up to 2 units of red cells and whole blood, 6.9% receiving 3 to 5 units, and 22% of those receiving 6 units or more. Multiple linear and logistic regression analysis showed that transfusion dose was the most significant predictor of infection, days of fever, days of antibiotic therapy, and length of hospital stay. Homologous transfusion is associated (in a dose-dependent fashion) with a threefold to eightfold increased risk of postoperative infection in patients undergoing coronary artery operations. This increased risk of infection may be due to transfusion-induced immunosuppression of the patient.

Relationships between sleep and body temperature in middle-aged and older subjects.

OBJECTIVES: Although changes in the circadian timing system are thought to be a major factor in the decline of sleep quality that often accompanies aging, few reports have actually examined this relationship in detail. Because some treatments for age-related insomnia are based on putative circadian changes, it is important to expand the limited database that specifically addresses this issue. This study examined age-related changes in sleep, and relationships between those sleep changes and alterations in the circadian timing system, in a group of middle-aged and older subjects. DESIGN: Sixty healthy men and women between the ages of 40 and 84 were studied. A subset of older subjects (< 65 years) had reported sleep disturbance for at least 1 year before participation. Polysomnography was obtained, and body core temperature was recorded continuously for 24 hours. All recordings took place in the Laboratory of Human Chronobiology, Department of Psychiatry, Cornell University Medical College. RESULTS: There were no differences in sleep quality between middle-aged and non-sleep-disturbed older subjects. However, timing of the minimum body temperature was earlier in the older non-sleep-disturbed subjects than in the middle-aged group. In contrast, sleep-disturbed older people had shorter total sleep times, reduced sleep efficiency, more waking time after sleep onset, and a reduced proportion of REM sleep compared with non-sleep-disturbed older subjects. Yet, there were no differences between the two older groups in the rhythm of body temperature. For the entire group, age was correlated negatively with total sleep time, sleep efficiency, percentage of stage 2 sleep, and the timing of the temperature minimum. CONCLUSION: The results support the widely held notion that sleep and circadian rhythm changes occur with aging. However, the hypothesis that age-related changes in sleep may be associated with aging of the circadian system was supported only to a limited degree, suggesting that age-related sleep disturbance is likely to have multiple causes. Thus, treatment strategies that incorporate a combination of interventions may be the most effective.