Search

People are routinely forced to undertake cognitive challenges under the effect of sleep deprivation, due to professional and social obligations forcing them to ignore their circadian clock. However, low intra-individual and high inter-individual differences in behavioural outcomes are known to occur when people are sleep deprived, leading to the conclusion that trait-like differences to sleep deprivation could explain the differing levels of resilience. Within this study we consider if trait-like resilience to sleep deprivation, measured using psychomotor vigilance tests over a 40 h protocol, could be associated with graph metrics (mean node strength, clustering coefficient, characteristic path length and stability) calculated from EEG functional networks acquired when participants ([Formula: see text]) are well rested (baseline). Furthermore, we investigated how stability (the consistency of a participant's functional network over time measured using 2-D correlation) changed over the constant routine. We showed evidence of strong significant correlations between high mean node strength, low characteristic path length and high stability at baseline with a general resilience to extended sleep deprivation, although the same features lead to vulnerability during the period of natural sleep onset, highlighting non-uniform correlations over time. We also show significant differences in the levels of stability between resilient and vulnerable groups., Competing Interests: Declarations Competing Interests W.W and J.R.T are co-founders of Neuronostics Ltd. C.A reports no conflicts of interests related to the data or results reported in this paper. In the interest of full disclosure: C.A has received a research award/prize from Sanofi-Aventis; contract research support from VicRoads/Department of Transport Victoria, Rio Tinto Coal Australia, National Transport Commission, Tontine/Pacific Brands, Transport Accident Commission, Takeda Pharmaceutical; and lecturing fees from Brown Medical School/Rhode Island Hospital, Ausmed, Healthmed and TEVA Pharmaceuticals; and reimbursements for conference travel expenses from Philips Healthcare. In addition, she has served as a consultant through her institution to the Rail, Bus and Tram Union, the Transport Accident Commission and the National Transportation Committee. She has also served as an expert witness and/or consultant in relation to fatigue and drowsy driving. C.A was a Theme Leader in the Cooperative Research Centre for Alertness, Safety and Productivity. S.F reports no conflicts of interests related to the data or results reported in this paper. In the interest of full disclosure: S.F reports receiving consultancy fees from Circadian Therapeutics and AMO Pharma. All other authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s).)

The use of circulating tumour DNA (ctDNA) to profile mutational signatures represents a non-invasive opportunity for understanding cancer mutational processes. Here we present MisMatchFinder, a liquid biopsy approach for mutational signature detection using low-coverage whole-genome sequencing of ctDNA. Through analysis of 375 plasma samples across 9 cancers, we demonstrate that MisMatchFinder accurately infers single-base and doublet-base substitutions, as well as insertions and deletions to enhance the detection of ctDNA and clinically relevant mutational signatures., Competing Interests: Competing interests The authors declare the following competing interests: S.-J.D. is an advisory board member for Adela. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body. We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-h constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [± SD] age = 25.4 ± 5.7 years, 5 women). Valid core body temperature data were available in 17/23 (mean [± SD] age = 25.6 ± 6.3 years, 1 woman). Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R 2  = 0.37, p = .009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R 2  = 0.47, p = .002). These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock., (© 2024. The Author(s).)

Sleep deprivation enhances risk for serious injury and fatality on the roads and in workplaces. To facilitate future management of these risks through advanced detection, we developed and validated a metabolomic biomarker of sleep deprivation in healthy, young participants, across three experiments. Bi-hourly plasma samples from 2 × 40-hour extended wake protocols (for train/test models) and 1 × 40-hour protocol with an 8-hour overnight sleep interval were analyzed by untargeted liquid chromatography-mass spectrometry. Using a knowledge-based machine learning approach, five consistently important variables were used to build predictive models. Sleep deprivation (24 to 38 hours awake) was predicted accurately in classification models [versus well-rested (0 to 16 hours)] (accuracy = 94.7%/AUC 99.2%, 79.3%/AUC 89.1%) and to a lesser extent in regression ( R 2 = 86.1 and 47.8%) models for within- and between-participant models, respectively. Metabolites were identified for replicability/future deployment. This approach for detecting acute sleep deprivation offers potential to reduce accidents through "fitness for duty" or "post-accident analysis" assessments.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies., (© 2024. The Author(s).)

Objective: To investigate the influence of the degree of circadian adaptation to night work on sleep architecture following night shift., Methods: Thirty four night workers (11 females; 33.8 ± 10.1years) completed a simulated night shift following 2-7 typical night shifts. Participants completed a laboratory-based simulated night shift (21:00-07:00 hours), followed by a recovery sleep opportunity (∼09:00-17:00 hours), recorded using polysomnography. Urinary 6-sulphatoxymelatonin (aMT6s) rhythm acrophase was used as a marker of circadian phase. Sleep duration and architecture were compared between individuals with aMT6s acrophase before (unadapted group, n = 22) or after (partially adapted group, n = 12) bedtime., Results: Bedtime occurred on average 2.16 hours before aMT6s acrophase in the partially adapted group and 3.91 hours after acrophase in the unadapted group. The partially adapted group had more sleep during the week before the simulated night than the unadapted group (6.47 ± 1.02 vs. 5.26 ± 1.48 hours, p = .02). After the simulated night shift, both groups had similar total sleep time (partially adapted: 6.68 ± 0.80 hours, unadapted: 6.63 ± 0.88 hours, p > .05). The partially adapted group had longer total rapid eye movement sleep duration than the unadapted group (106.79 ± 32.05 minutes vs. 77.90 ± 28.86 minutes, p = .01). After 5-hours, rapid eye movement sleep accumulation was higher in the partially adapted compared to the unadapted group (p = .02). Sleep latency and other stages were not affected by circadian adaptation., Discussion: Partial circadian adaptation to night shift was associated with longer rapid eye movement sleep duration during daytime sleep, highlighting the influence of entrainment between the sleep-wake cycle and the circadian pacemaker in night workers. The findings have important implications for sleep and subsequent alertness associated with shift work., Competing Interests: Declaration of conflicts of interest Iona Zimberg, Suzanne Ftouni and Michelle Magee have no conflicts of interest to disclose. Sally Ferguson reports that through her institution she has received research grants from SafeWorkSA, Sleep Health Foundation; Australian Research Council, Australian Government Department of Industry, Innovation and Science; Defence, Science and Technology Organisation, Australian Maritime Safety Authority and Queensland Health. Steven Lockley has no conflicts of interests related to the research or results reported in this paper. In the interests of full disclosure, commercial interests are listed below. SWL has received consulting fees from the Atlanta Falcons, Atlanta Hawks, BHP Billiton, Noble Insights, Slingshot Insights and Team C Racing; honoraria and/or paid travel from BHP Billiton, DIN, Emory University, IES, Ineos, SLTBR, Solemma and Teague; has current consulting contracts with Akili Interactive, Apex2100 Ltd, Consumer Sleep Solutions, Headwaters Inc, Hintsa PERformance AG, LightCognitive, Lighting Science Group Corporation, Mental Workout, PlanLED, Six Senses, Stantec and Wyle Integrated Science and Engineering; has received unrestricted equipment gifts from Bionetics Corporation and F. Lux Software LLC and royalties from Oxford University Press; and has served as a paid expert in legal proceedings related to light, sleep and health. He holds a patent through Harvard University and Brigham and Women's Hospital for “Systems and Methods for Determining and/or Controlling Sleep Quality.” Shantha Rajaratnam reports unpaid appointments at the Cooperative Research Centre for Alertness, Safety and Productivity, Australia and the Sleep Health Foundation. Dr. Rajaratnam is supported on grants from Vanda Pharmaceuticals, Philips Respironics, Cephalon, Rio Tinto, BHP Billiton and Shell. Dr. Rajaratnam has received other support from Optalert, Compumedics, Teva Pharmaceuticals and Circadian Therapeutics, through his institution. He is a member of the National Sleep Foundation Sleep Timing Variability Consensus Panel, for which he was paid an honorarium through his institution. Tracey Sletten reports her institution has received equipment donations or other support from Philips Lighting, Philips Respironics, Optalert and Compumedics. Dr. Sletten was a Project Leader and received grants for research from the Cooperative Research Centre for Alertness, Safety and Productivity. Dr. Sletten has received consulting fees from Vanda Pharmaceuticals and is a member of the National Sleep Foundation Sleep Timing Variability Consensus Panel, for which she was paid an honorarium., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Circadian entrainment in mice relies primarily on photic cues that trigger the transcription of the core clock genes Period1/2 in the suprachiasmatic nucleus (SCN), thus aligning the phase of the clock with the dawn/dusk cycle. It has been shown previously that this pathway is directly regulated by adenosine signalling and that adenosine A 2A /A 1 receptor antagonists can both enhance photic entrainment and phase shift circadian rhythms of wheel-running behaviour in mice. In this study, we tested the ability of CT1500, a clinically safe adenosine A 2A /A 1 receptor antagonist to effect circadian entrainment. We show that CT1500 lengthens circadian period in SCN ex vivo preparations. Furthermore, we show in vivo that a single dose of CT1500 enhances re-entrainment to a shifted light dark cycle in a dose-dependent manner in mice and also phase shifts the circadian clock under constant dark with a clear time-of-day related pattern. The phase response curve shows CT1500 causes phase advances during the day and phase delays at dusk. Finally, we show that daily timed administration of CT1500 can entrain the circadian clock to a 24 h rhythm in free-running mice. Collectively, these data support the use of CT1500 in the treatment of disorders of circadian entrainment., Competing Interests: AJ, RF, and SV are co founders of Circadian Therapeutics, who funded this research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jagannath, Pretoro, Ebrahimjee, Ftouni, Taylor, Foster and Vasudevan.)

Acoustic stimulation has been shown to enhance slow wave sleep and in turn, cognition, and now cardiac outcomes in young adults. With the emergence of commercial acoustic devices in the home, we sought to examine the impact of an acoustic, slow wave enhancing device on heart rate variability in healthy, middle-aged males (n = 24, 39.92 ± 4.15 years). Under highly controlled conditions, the participants were randomised to receive closed-loop brain state-dependent stimulation in the form of auditory tones (STIM), or no tones (SHAM), in a crossover design, separated by a 1 week washout period. STIM and SHAM were compared on measures of heart rate variability for the whole night and over the first three sleep cycles. We found an increase in slow wave activity following STIM compared with SHAM. There was a significant increase in high frequency power and standard deviation of the normalised RR-intervals (SDNN) during the STIM condition compared with SHAM (p < 0.05), due to changes observed specifically during N3. In conclusion, heart rate variability appears to improve following acoustic slow wave sleep enhancement., (© 2022 European Sleep Research Society.)

There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003)., Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007., (©2022 American Association for Cancer Research.)

Background: Research exploring the impact of the COVID-19 pandemic on sleep in people with disabilities has been scarce. This study provides a preliminary assessment of sleep in people with disabilities, across two timepoints during the pandemic, with a focus on those with visual impairment (VI). Methods: Two online surveys were conducted between April 2020 and March 2021 to explore sleep quality using the Pittsburgh Sleep Quality Index (PSQI). A convenience sample of 602 participants completed the first survey and 160 completed the follow-up survey. Results: Across both timepoints, participants with disabilities reported significantly poorer global sleep quality and higher levels of sleep disturbance, use of sleep medication and daytime dysfunction than those with no disabilities. Participants with VI reported significantly higher levels of sleep disturbance and use of sleep medication at both timepoints, poorer global sleep quality, sleep duration and latency at time 1, and daytime dysfunction at time 2, than those with no disabilities. Global sleep quality, sleep duration, sleep efficiency, and self-rated sleep quality deteriorated significantly in participants with no disabilities, but daytime dysfunction increased in all three groups. Disability and state anxiety were significant predictors of sleep quality across both surveys. Conclusion: While sleep was consistently poorer in people with disabilities such as VI, it appears that the COVID-19 pandemic has had a greater impact on sleep in people with no disabilities. State anxiety and, to a lesser extent, disability, were significant predictors of sleep across both surveys, suggesting the need to address anxiety in interventions targeted toward improving sleep., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heinze, Hussain, Castle, Godier-McBard, Kempapidis, Ftouni, Espie and Gomes.)

The military population face a unique set of risk factors that may increase the risk of being diagnosed with dementia. Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) have a higher prevalence in this group in comparison to the civilian population. By delving into the individual relationships between TBI and dementia, and PTSD and dementia, we are able to better explore dementia in the military and veteran populations. While there are some inconsistencies in results, the TBI-dementia association has become more widely accepted. Moderate-to-severe TBI has been found to increase the risk of being diagnosed with Alzheimer's disease. A correlation between PTSD and dementia has been established, however, whether or not it is a causal relationship remains unclear. Factors such as blast, combat and chemical exposure may occur during a deployment, along with TBI and/or PTSD diagnosis, and can impact the risk of dementia. However, there is a lack of literature exploring the direct effects of deployment on dementia risk. Sleep problems have been observed to occur in those following TBI, PTSD and deployment. Poor sleep has been associated with possible dementia risk. Although limited studies have focused on the link between sleep and dementia in military and veteran populations, sleep is a valuable factor to study due to its association and interconnection with other military/veteran factors. This review aims to inform of various risk factors to the cognitive health of military members and veterans: TBI, PTSD, deployment, and sleep., (© 2021. The Author(s).)

Objectives: To determine whether continuous eye blink measures could identify drowsiness in patients with obstructive sleep apnea (OSA) during a week of naturalistic driving., Design: Observational study comparing OSA patients and healthy controls., Setting: Regular naturalistic driving across one week., Participants: Fifteen untreated moderate to severe OSA patients and 15 age (± 5 years) and sex (female = 6) matched healthy controls., Measurements: Participants wore an eye blink drowsiness recording device during their regular driving for one week., Results: During regular driving, the duration of time with no ocular movements (quiescence), was elevated in the OSA group by 43% relative to the control group (mean [95% CI] 0.20[0.17, 0.25] vs 0.14[0.12, 0.18] secs, P = .011). During long drives only, the Johns Drowsiness Scale was also elevated and increased by 62% in the OSA group relative to the control group (1.05 [0.76, 1.33] vs 0.65 [0.36, 0.93], P = .0495). Across all drives, critical drowsiness events (defined by a Johns Drowsiness Scale score ≥2.6) were twice as frequent in the OSA group than the control group (rate ratio [95% CI] =1.93 [1.65, 2.25], P ≤ .001)., Conclusions: OSA patients were drowsier than healthy controls according to some of the continuous real time eye blink drowsiness measures. The findings of this pilot study suggest that there is potential for eye blink measures to be utilized to assess fitness to drive in OSA patients. Future work should assess larger samples, as well as the relationship of eye blink measures to conventional fitness to drive assessments and crash risk., Competing Interests: Declaration of Competing Interest Jennifer M Cori, Andrew Vakulin, Suzanne Ftouni and Mark E Howard have received financial support from the Cooperative Research Centre for Alertness, Safety and Productivity for projects not related to this work. Jennifer M Cori, Andrew Vakulin, Suzanne Ftouni and Mark E Howard have also received technical support, software and equipment in-kind from Optalert Ltd for this and other projects. Sophie Turner, Justine Westlake, Aqsa Naqvi, Vanessa Wilkinson and Fergal J. O'Donoghue report no conflict of interest. Jennifer M Cori and Mark E Howard have also received equipment support from Seeing Machines for unrelated work. Andrew Vakulin reports research funding from the National Health Medical Research Council (NHMRC) for unrelated work., (Copyright © 2021 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

We aimed to investigate the impact of the Wake Maintenance Zone (WMZ) on measures of drowsiness, attention, and subjective performance under rested and sleep deprived conditions. We studied 23 healthy young adults (18 males; mean age = 25.41 ± 5.73 years) during 40 hr of total sleep deprivation under constant routine conditions. Participants completed assessments of physiological drowsiness (EEG-scored slow eye movements and microsleeps), sustained attention (PVT), and subjective task demands every two hours, and four-hourly ocular motor assessment of inhibitory control (inhibition of reflexive saccades on an anti-saccade task). Tests were analyzed relative to dim light melatonin onset (DLMO); the WMZ was defined as the 3 hr prior to DLMO, and the preceding 3 hr window was deemed the pre-WMZ. The WMZ did not mitigate the adverse impact of ~37 hr sleep deprivation on drowsiness, sustained attention, response inhibition, and self-rated concentration and difficulty, relative to rested WMZ performance (~13 hr of wakefulness). Compared to the pre-WMZ, though, the WMZ improved measures of sustained attention, and subjective concentration and task difficulty, during sleep deprivation. Cumulatively, these results expand on previous work by characterizing the beneficial effects of the WMZ on operationally-relevant indices of drowsiness, inhibitory attention control, and self-rated concentration and task difficulty relative to the pre-WMZ during sleep deprivation. These results may inform scheduling safety-critical tasks at more optimal circadian times to improve workplace performance and safety., (© 2021 European Sleep Research Society.)

Sleep-restriction therapy (SRT) has been shown to improve insomnia symptoms by restricting sleep opportunity. Curtailment of time in bed affects the duration and consolidation of sleep, but also its timing. While recent work suggests that people with insomnia are characterised by misalignment between circadian and behavioural timing of sleep, no study has investigated if SRT modifies this relationship. The primary aim of the present study was to examine change in phase angle after 2 weeks of SRT. As a secondary aim, we also sought to assess the effect of SRT on psychomotor vigilance. Following a 1-week baseline phase, participants implemented SRT for 2 consecutive weeks. Phase angle was derived from the difference between the decimal clock time of dim light melatonin onset (DLMO) and attempted sleep time. Secondary outcomes included vigilance (assessed via hourly measurement during the DLMO laboratory protocol), sleep continuity (assessed via sleep diary and actigraphy), and insomnia severity. Eighteen participants meeting insomnia criteria (mean [SD] age 37.06 [8.99] years) took part in the study. Consistent with previous research, participants showed robust improvements in subjective and objective sleep continuity, as well as reductions in insomnia severity. The primary outcome (phase angle) was measurable in 15 participants and revealed an increase of 34.8 min (~0.58 hr; 95% confidence interval [CI] 0.01-1.15) from baseline to post-treatment (mean [SD] 2.27 [0.94] versus 2.85 [1.25] hr). DLMO remained relatively stable (20:49 versus 21:01 hours), while attempted sleep was 46.8 min later (~0.78 hr; 95%CI 0.41-1.15; 23:05 versus 23:52 hours). For psychomotor vigilance, reaction time was delayed (by 52.71 ms, 95% CI 34.44-70.97) and number of lapses increased (by 5.84, 95% CI 3.93-7.75) after SRT. We show that SRT increases phase angle during treatment, principally by delaying the timing of sleep attempt. Future studies are needed to test if an increase in phase angle is linked to clinical improvement. Finally, reduction in vigilance after SRT appears to be of similar magnitude to normal sleepers undergoing experimental sleep restriction, reinforcing the importance of appropriate safety advice during implementation., (© 2020 European Sleep Research Society.)

Background: The human microbiome plays an important role in cancer. Accumulating evidence indicates that commensal microbiome-derived DNA may be represented in minute quantities in the cell-free DNA of human blood and could possibly be harnessed as a new cancer biomarker. However, there has been limited use of rigorous experimental controls to account for contamination, which invariably affects low-biomass microbiome studies., Results: We apply a combination of 16S-rRNA-gene sequencing and droplet digital PCR to determine if the specific detection of cell-free microbial DNA (cfmDNA) is possible in metastatic melanoma patients. Compared to matched stool and saliva samples, the absolute concentration of cfmDNA is low but significantly above the levels detected from negative controls. The microbial community of plasma is strongly influenced by laboratory and reagent contaminants introduced during the DNA extraction and sequencing processes. Through the application of an in silico decontamination strategy including the filtering of amplicon sequence variants (ASVs) with batch dependent abundances and those with a higher prevalence in negative controls, we identify known gut commensal bacteria, such as Faecalibacterium, Bacteroides and Ruminococcus, and also other uncharacterised ASVs. We analyse additional plasma samples, highlighting the potential of this framework to identify differences in cfmDNA between healthy and cancer patients., Conclusions: Together, these observations indicate that plasma can harbour a low yet detectable level of cfmDNA. The results highlight the importance of accounting for contamination and provide an analytical decontamination framework to allow the accurate detection of cfmDNA for future biomarker studies in cancer and other diseases.

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV 1-5 . In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population 6-10 , we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34-3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection.

Background: Metastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients., Methods and Findings: Two hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1-46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. In parallel, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up., Conclusion: In this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: M.A.D. has been a member of advisory boards for CTX CRC, Storm Therapeutics, Celgene, Cambridge Epigenetix, and GSK. S. L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merk, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly. She has acted as a consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech. She has acted as a consultant (paid to her institution) to Aduro Biotech. S.Q.W. has received travel support from BioRad. S-J. D. has received research funding to her institution from Roche-Genentech and CTX CRC. She has been a member of advisory boards for AstraZeneca.

Introduction: Many sleep and circadian studies require participants to adhere to structured sleep-wake schedules designed to stabilize sleep outcomes and circadian phase prior to in-laboratory testing. The effectiveness of this approach has not been rigorously evaluated, however. We therefore investigated the differences between participants' unstructured and structured sleep over a three-week interval., Methods: Twenty-three healthy young adults completed three weeks of sleep monitoring, including one week of unstructured sleep and two weeks of structured sleep with consistent bed and wake times. Circadian phase was assessed via salivary dim light melatonin onset (DLMO) during both the unstructured and structured sleep episodes., Results: Compared to their unstructured sleep schedule, participants' bed- and wake times were significantly earlier in their structured sleep, by 34 ± 44 mins (M ± SD) and 44 ± 41 mins, respectively. During structured sleep, circadian phase was earlier in 65% of participants (40 ± 32 mins) and was later in 35% (41 ± 25 mins) compared to unstructured sleep but did not change at the group level. While structured sleep reduced night-to-night variability in sleep timing and sleep duration, and improved the alignment (phase angle) between sleep onset and circadian phase in the most poorly aligned individuals (DLMO < 1h or > 3h before sleep onset time; 25% of our sample), sleep duration and quality were unchanged., Conclusion: Our results show adherence to a structured sleep schedule results in more regular sleep timing, and improved alignment between sleep and circadian timing for those individuals who previously had poorer alignment. Our findings support the use of structured sleep schedules prior to in-laboratory sleep and circadian studies to stabilize sleep and circadian timing in healthy volunteers., Competing Interests: “No author’s commercial affiliation/s alters our adherence to PLOS ONE policies on sharing data and materials”.

In a visually stimulating environment with competing stimuli, we continually choose where to allocate attention, and what to ignore. Wake and circadian-dependent modulation of attentional control and resolution of conflict is poorly understood. Twenty-two participants (17males; 25.6 ± 5.6 years) completed ocular motor tasks throughout 40 hours of sleep deprivation under constant routine conditions. A prosaccade task required a reflexive saccade toward a stimulus (no conflict), while an antisaccade task required inhibiting a reflexive saccade to the peripheral stimulus, and looking in the mirror opposite instead (conflict resolution). Antisaccade inhibitory errors showed circadian modulation, being highest in the morning, progressively decreasing until melatonin onset, before returning to the prior morning's peak throughout the biological night. This diurnal rhythm was blunted by sleep loss (>24 hours), with inhibitory control remaining impaired across the second biological day. For prosaccade, responses slowed down during the biological night. Taken together, we provide evidence for a circadian modulation of attentional bias: the morning being biased toward reflexive responding, and the evening toward higher inhibitory control. Our data show that sleep loss and circadian timing differentially impact attention, depending on whether a response conflict is present (antisaccade) or absent (prosaccade).

Study Objectives: As slow-wave activity (SWA) is critical for cognition, SWA-enhancing technologies provide an exciting opportunity to improve cognitive function. We focus on improving cognitive function beyond sleep-dependent memory consolidation, using an automated device, and in middle-aged adults, who have depleted SWA yet a critical need for maximal cognitive capacity in work environments., Methods: Twenty-four healthy adult males aged 35-48 years participated in a randomized, double-blind, cross-over study. Participants wore an automated acoustic stimulation device that monitored real-time sleep EEG. Following an adaptation night, participants were exposed to either acoustic tones delivered on the up phase of the slow-wave (STIM) or inaudible "tones" during equivalent periods of stimulation (SHAM). An executive function test battery was administered after the experimental night., Results: STIM resulted in an increase in delta (0.5-4 Hz) activity across the full-night spectra, with enhancement being maximal at 1 Hz. SWA was higher for STIM relative to SHAM. Although no group differences were observed in any cognitive outcomes, due to large individual differences in SWA enhancement, higher SWA responders showed significantly improved verbal fluency and working memory compared with nonresponders. Significant positive associations were found between SWA enhancement and improvement in these executive function outcomes., Conclusions: Our study suggests that (1) an automated acoustic device enhances SWA; (2) SWA enhancement improves executive function; (3) SWA enhancement in middle-aged men may be an important therapeutic target for enhancing cognitive function; and (4) there is a need to examine interindividual responses to acoustic stimulation and its effect on subsequent cognitive function., Clinical Trial Registration: This study has been registered with the Australian New Zealand Clinical Trials Registry. "The efficacy of acoustic tones in slow-wave sleep enhancement and cognitive function in healthy adult males". https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371548&isReview=true., Registration: ACTRN12617000399392., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

A neural network model was previously developed to predict melatonin rhythms accurately from blue light and skin temperature recordings in individuals on a fixed sleep schedule. This study aimed to test the generalizability of the model to other sleep schedules, including rotating shift work. Ambulatory wrist blue light irradiance and skin temperature data were collected in 16 healthy individuals on fixed and habitual sleep schedules, and 28 rotating shift workers. Artificial neural network models were trained to predict the circadian rhythm of (i) salivary melatonin on a fixed sleep schedule; (ii) urinary aMT6s on both fixed and habitual sleep schedules, including shift workers on a diurnal schedule; and (iii) urinary aMT6s in rotating shift workers on a night shift schedule. To determine predicted circadian phase, center of gravity of the fitted bimodal skewed baseline cosine curve was used for melatonin, and acrophase of the cosine curve for aMT6s. On a fixed sleep schedule, the model predicted melatonin phase to within ± 1 hour in 67% and ± 1.5 hours in 100% of participants, with mean absolute error of 41 ± 32 minutes. On diurnal schedules, including shift workers, the model predicted aMT6s acrophase to within ± 1 hour in 66% and ± 2 hours in 87% of participants, with mean absolute error of 63 ± 67 minutes. On night shift schedules, the model predicted aMT6s acrophase to within ± 1 hour in 42% and ± 2 hours in 53% of participants, with mean absolute error of 143 ± 155 minutes. Prediction accuracy was similar when using either 1 (wrist) or 11 skin temperature sensor inputs. These findings demonstrate that the model can predict circadian timing to within ± 2 hours for the vast majority of individuals on diurnal schedules, using blue light and a single temperature sensor. However, this approach did not generalize to night shift conditions.