Heavy-element production in a compact object merger observed by JWST.

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs)1, sources of high-frequency gravitational waves (GWs)2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process)3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers4-6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7-12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe.

Digital Informed Consent: Modernising Information Sharing in Surgery to Empower Patients.

BACKGROUND: Despite the 2015 Montgomery Ruling highlighting key requisites for informed consent, little has changed to modernise data-sharing and documentation of the consent process. It can be difficult to gauge patient understanding and address all patient concerns in time-limited appointments. We aimed to assess the feasibility of a digital information-sharing platform to support a move towards a digital informed consent process. METHODS: All adult patients referred to a single centre with symptomatic gallstones were invited to use a digital information-sharing platform to support the informed consent process prior to their first surgical clinic appointment. The platform provided patients with multimedia information on gallstones and available treatment options. It recorded the time spent accessing information, asked patients multiple choice questions (MCQs) to allow a self-test of understanding, documented a summary medical history, and allowed free text for patient questions. This information was summarised into a clinical report to support outpatient clinic consultations. RESULTS: Of the 349 patients registered to use the digital platform, 203 (58.2%) [165 (81.3%) female, mean age 47.6 years (range 19-84 years)] completed all modules necessary to generate a clinical report. Some 130 patients (64.0%) answered all 10 MCQs correctly and spent a mean of 18.7 min (range 3-88 min) reading the consent information. Most patient-reported medical histories were deemed to be accurate. CONCLUSION: Despite difficulties with access, resulting in drop-outs, patients welcomed the opportunity to receive information digitally, prior to their consultation. Patients described feeling empowered and better informed to be involved in decision-making.

Relationship between post-awakening salivary cortisol and melatonin secretion in healthy participants.

We report the relationship between patterns of post-awakening salivary melatonin and cortisol secretion in healthy participants (n = 51; mean age 21.6 ± 5.0 years). Saliva samples were collected within the domestic setting, at 0-, 15-, 30-, and 45-min post-awakening on 2 consecutive typical weekdays. Analyses were undertaken on data with electronically verified sample timing accuracy (<5-min delay between awakening and the start of saliva sampling). Melatonin secretion declined linearly by an average of 29% within the first 45-min post-awakening. In contrast, there was a marked 112% surge in cortisol, characteristic of the cortisol awakening response. No day differences in melatonin or cortisol secretion were observed but melatonin concentrations were lower with later awakening. Despite contrasting post-awakening changes in these hormones, there was a lack of relationship between overall levels or patterns of melatonin and cortisol during this period.

Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.

Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of beta-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.

The cortisol awakening response predicts same morning executive function: results from a 50-day case study.

A relationship between individual differences in trait estimates of the cortisol-awakening response (CAR) and indices of executive function (EF) has been reported. However, it is difficult to determine causality from such studies. The aim of the present study was to capitalise upon state variation in both variables to seek stronger support for causality by examining daily co-variation. A 50 days researcher-participant case study was employed, ensuring careful adherence to the sampling protocol. A 24-year-old healthy male collected saliva samples and completed an attention-switching index of EF on the morning of each study day. Subsidiary control measures included wake time, sleep duration, morning fatigue, and amount of prior day exercise and alcohol consumption. As the CAR preceded daily measurement of EF, we hypothesised that, over time, a greater than average CAR would predict better than average EF. This was confirmed by mixed regression modelling of variation in cortisol concentrations, which indicated that the greater the increase in cortisol concentrations from 0 to 30 min post-awakening (CAR) the better was subsequent EF performance at 45 min post-awakening (t = 2.29, p = 0.024). This effect was independent of all potential confounding measures. Results are discussed in terms of implications for the understanding of the relationship between the CAR and the cognitive function, and the previously suggested role of the CAR in "boosting" an individual's performance for the day ahead.

The effect of progressive muscle relaxation on daily cortisol secretion.

Abbreviated progressive muscle relaxation (APMR) is a much used stress-management technique. Its efficacy relevant to placebo control is already established in the literature and the primary aim of the present study was to ascertain whether its proven impact on psychological stress measures is matched by a decrease in prevailing levels of the stress-associated hormone cortisol, using accurate and robust measurement based on multiple sampling of full diurnal cortisol secretion profiles. First-year university students can face significant stress in adjustment to academic demands and immersion in a novel social network and provided a convenient study population. One hundred and one first-year students completed APMR with prevailing stress levels assessed a week before and after intervention. Both cortisol and self-report measures were significantly reduced post-intervention by 8% and 10%, respectively. The efficacy of the intervention was independent of, and not modulated by neuroticism, gender, age and smoking status. We also demonstrated that cortisol reduction was unlikely to have been a consequence of adaptation to any initial cortisol elevation prompted by the challenge of the demanding saliva collection protocol. We conclude that the efficacy of APMR in this population extends to reduction in biologically expressed stress levels as well as levels based solely on self-report.

Anxious attachment style predicts an enhanced cortisol response to group psychosocial stress.

Insecure attachment style is associated with poor health outcomes. A proposed pathway implicates the hypothalamic-pituitary-adrenal axis (HPA-axis), dysregulation of which is associated with a wide range of mental and physical ill-health. However, data on stress reactivity in relation to attachment style is contradictory. This relationship was examined using the novel Trier Social Stress Test for groups (TSST-G): a group-based acute psychosocial stressor. Each participant, in the presence of other group members, individually performed public speaking and mental arithmetic tasks. Seventy-eight healthy young females (20.2 ± 3.2 years), in groups of up to six participants completed demographic information and the Vulnerable Attachment Style Questionnaire (VASQ), and were then exposed to the TSST-G. Physiological stress reactivity was assessed using salivary cortisol concentrations, measured on seven occasions at 10-min intervals. Vulnerable attachment predicted greater cortisol reactivity independent of age, smoking status, menstrual phase and body mass index. Supplementary analysis indicated that insecure anxious attachment style (high scores on the insecurity and proximity-seeking sub-scales of the VASQ) showed greater cortisol reactivity than participants with secure attachment style. Avoidant attachment style (high scores for insecurity and low scores for proximity seeking) was not significantly different from the secure attachment style. Attachment style was not associated with the timing of the cortisol peak or post-stress recovery in cortisol concentrations. These findings in healthy young females indicate subtle underlying changes in HPA axis function in relation to attachment style and may be important for future mental health and well-being.

Reduced memory skills and increased hair cortisol levels in recent Ecstasy/MDMA users: significant but independent neurocognitive and neurohormonal deficits.

OBJECTIVES: The goals of this study were to measure the neurocognitive performance of recent users of recreational Ecstasy and investigate whether it was associated with the stress hormone cortisol. METHODS: The 101 participants included 27 recent light users of Ecstasy (one to four times in the last 3 months), 23 recent heavier Ecstasy users (five or more times) and 51 non-users. Rivermead paragraph recall provided an objective measure for immediate and delayed recall. The prospective and retrospective memory questionnaire provided a subjective index of memory deficits. Cortisol levels were taken from near-scalp 3-month hair samples. RESULTS: Cortisol was significantly raised in recent heavy Ecstasy users compared with controls, whereas hair cortisol in light Ecstasy users was not raised. Both Ecstasy groups were significantly impaired on the Rivermead delayed word recall, and both groups reported significantly more retrospective and prospective memory problems. Stepwise regression confirmed that lifetime Ecstasy predicted the extent of these memory deficits. CONCLUSIONS: Recreational Ecstasy is associated with increased levels of the bio-energetic stress hormone cortisol and significant memory impairments. No significant relationship between cortisol and the cognitive deficits was observed. Ecstasy users did display evidence of a metacognitive deficit, with the strength of the correlations between objective and subjective memory performances being significantly lower in the Ecstasy users.

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain.

The cortisol awakening response (CAR) is the most prominent, dynamic and variable part of the circadian pattern of cortisol secretion. Despite this, its precise purpose is unknown. Aberrant patterns of the CAR are associated with impaired physical and mental health and reduced cognitive function, suggesting that it may have a pervasive role or roles. It has been suggested that the CAR primes the brain for the expected demands of the day but the mechanisms underlying this process are unknown. We examined temporal covariation of the CAR and rapid transcranial magnetic stimulation (rTMS)-induced long term depression (LTD)-like responses in the motor cortex. Plasticity was evaluated across 180 measures from five time points on four sessions across nine healthy researcher participants, mean age 25 ± 2.5 years. Plasticity estimates were obtained in the afternoon after measurement of the CAR on 4 days, at least 3 days apart. As both CAR magnitude and rTMS-induced responses are variable across days, we hypothesized that days with larger than individual average CARs would be associated with a greater than individual average plasticity response. This was confirmed by mixed regression modelling where variation in the CAR predicted variation in rTMS-induced responses (df: 1, 148.24; F: 10.41; p = 0.002). As the magnitude of the CAR is regulated by the "master" circadian CLOCK, and synaptic plasticity is known to be modulated by peripheral "slave" CLOCK genes, we suggest that the CAR may be a mediator between the master and peripheral circadian systems to entrain daily levels of synaptic plasticity.

State variation in the cortisol awakening response.

The cortisol awakening response (CAR) is a much studied but poorly understood aspect of the circadian pattern of cortisol secretion. A Scopus search of "cortisol" and "awakening" reveals 666 publications in this area since 1997 when it was first identified by Pruessner and colleagues as a "reliable biomarker of adrenocortical activity". The primary focus of the majority of these studies is centered on its utility as a biomarker associated with a range of psychosocial, physical and mental health variables. Such studies typically examine differences in the CAR (studied on 1 or 2 days) between healthy participants and other comparator groups of interest. Fewer studies (25 in our estimation) have examined correlates of day-to-day variation in the CAR in healthy participants, informing its role and regulation within the healthy circadian pattern of cortisol secretion. This is the first review to examine these studies which, although limited in number, offer a relatively coherent emerging story about state factors that influence the CAR and the impact of the CAR on daily functioning. Greater understanding of these issues helps illuminate the utility of the CAR as a promising biomarker in psychophysiological and epidemiological research. The review also highlights areas that require greater clarification and points to potentially fruitful areas of further research.

The CCP4 suite: integrative software for macromolecular crystallography.

The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.

Social network characteristics and salivary cortisol in healthy older people.

Psychobiological research on aging in humans has been confounded by individual differences that have not been adequately characterized in the literature. This paper is an attempt to shed light on this issue by examining the impact of social network characteristics predictive of successful aging on salivary cortisol among 78 older Chinese people in Hong Kong. Eight salivary cortisol samples were collected each day for two consecutive days from immediately after awakening to 12 hours later. Two components of the cortisol diurnal cycle, response to awakening and diurnal decline, were examined in relation to social network characteristics including size, emotional support, and cultivation. ANOVAs with repeated measured were run to examine influences of the three social network characteristics on the cortisol awakening response and diurnal decline, with the effects of gender, age, socioeconomic status, and waking time controlled. Results indicated that those who spent more time and effort in developing and strengthening their social ties (i.e., those high in "cultivation") exhibited a significantly greater rise in cortisol in the morning and a significantly steeper decline over the day, thus attesting to more effective activation and deactivation of the HPA axis. Network cultivation reflected a positive motivation to nurture social relationships more than the other two network characteristics. Its effect on cortisol might stem from the positivity underlying the motivation.

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects.

Belumosudil is a selective Rho-associated coiled-coil containing protein kinase 2 inhibitor. A capsule formulation was used during early clinical development of belumosudil; it was later replaced by a tablet formulation, which mimicked the capsule's release properties and facilitated manufacturing scalability. To assess belumosudil's pharmacokinetics, including potential food effects, and evaluate the relative bioavailability of the 2 formulations, 2 phase 1 clinical trials were conducted. Administration of both belumosudil tablets and capsules with food increased exposure ≈2× as compared to the fasted state and delayed time to maximum concentration by 0.5 hour, indicating a decrease in the rate but increase in the extent of absorption with fed administration. Relative bioavailability was slightly higher when belumosudil was administered as tablets vs capsules, although the difference was not clinically meaningful. Safety and tolerability were generally consistent with the known safety profile of belumosudil. The results of these studies support administration of belumosudil with food.

Evaluation and update of the expert consensus guidelines for the assessment of the cortisol awakening response (CAR).

The cortisol awakening response (CAR) is frequently assessed in psychobiological (stress) research. Obtaining reliable CAR data, however, requires careful attention to methodological detail. To promote best practice, expert consensus guidelines on the assessment of the CAR were published (Stalder et al., 2016, PNEC). However, it is unclear whether these highly cited guidelines have resulted in actual methodological improvements. To explore this, the PNEC editorial board invited the present authors to conduct a critical evaluation and update of current CAR methodology, which is reported here. (i) A quantitative evaluation of methodological quality of CAR research published in PNEC before and after the guidelines (2013-2015 vs. 2018-2020) was conducted. Disappointingly, results reveal little improvement in the implementation of central recommendations (especially objective time verification) in recent research. (ii) To enable an update of guidelines, evidence on recent developments in CAR assessment is reviewed, which mostly confirms the accuracy of the majority of the original guidelines. Moreover, recent technological advances, particularly regarding methods for the verification of awakening and sampling times, have emerged and may help to reduce costs in future research. (iii) To aid researchers and increase accessibility, an updated and streamlined version of the CAR consensus guidelines is presented. (iv) Finally, the response of the PNEC editorial board to the present results is described: potential authors of future CAR research to be published in PNEC will be required to submit a methodological checklist (based on the current guidelines) alongside their article. This will increase transparency and enable reviewers to readily assess the quality of the respective CAR data. Combined, it is hoped that these steps will assist researchers and reviewers in assuring higher quality CAR assessments in future research, thus yielding more reliable and reproducible results and helping to further advance this field of study.

Overview of the CCP4 suite and current developments.

The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallography is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package.

Smaller Cortisol Awakening Responses Are Associated with Greater Visual Dependence in Postural Control.

There are known links between the hypothalamic-pituitary-adrenal (HPA) axis and systems responsible for regulating posture. Our aim was to explore directly, for the first time, whether an aspect of circadian HPA axis activity (the cortisol awakening response: CAR) was associated with greater visual dependency in postural control. For measurement of the CAR, electronically monitored saliva samples were collected by participants following morning awakening in their home environment. On the afternoons of the same days, postural sway was measured in the laboratory by exposing participants to static (control) and moving visual stimuli whilst standing still and upright on a force platform. Visual dependence was assessed as the increase in postural sway (path length) during exposure to the moving compared with the static condition. The 44 measurement days were derived from four days for each of eleven healthy participants (mean ± SD age: 51.18 ± 3.3 years). As expected, postural sway was greater when exposed to moving versus static cues. Mixed regression modelling showed that participants with smaller four day average CARs had greater deterioration in postural sway when presented with moving stimuli. These data are the first to document associations between the CAR and visual dependency in postural sway.

The cortisol awakening response predicts a same-day index of executive function in healthy young adults.

The cortisol awakening response (CAR) is associated with various aspects of cognition, including executive function, in older adult and clinical samples. However, the association between these variables in the healthy functioning population is not well understood due to the limited number of appropriately controlled studies. This study explored the association between the CAR and a set shifting index of executive function in 55 (44 females) healthy participants aged 20.2 ± 3.0 years. Notoriously, assessment of the CAR from self-collected saliva samples within the domestic setting is subject to sample timing error, so electronic monitoring of both awakening and sampling times were employed. Participants attended the laboratory in the afternoon of CAR assessment for testing on the Attention Switching Task of the CANTAB neuropsychological testing battery. A positive association was found between CAR magnitude and attention-switching performance in the afternoon of the same day. This was independent of known relevant CAR covariates, but only evident in CAR data collected without delay exceeding 8 min post-awakening. These findings offer insight into a potential role for the CAR in modulating cognitive functions associated with the pre-frontal cortex.

Is There a Difference in the Diagnostic Outcomes of Calcifications Initially Identified on Synthetic Tomosynthesis Versus Full-Field Digital Mammography Screening?

PURPOSE: To compare the outcomes of microcalcifications recalled on full-field digital (FFDM) and FFDM and combined tomosynthesis (Combo) to synthetic (SM) screening mammograms. METHOD: We reviewed medical records, radiology, and pathology reports of all patients found to have abnormal calcifications requiring further evaluation on mammography screening at our institution between 11/1/2016-11/1/2018 and collected patient demographics, calcification morphology and distribution, and mammography technique (SM, FFDM, or Combo). We used biopsy pathology or at least 1-year imaging follow-up to establish overall diagnostic outcome (benign or malignant). Fisher's exact test was used to compare validation rates at diagnostic work-up, BI-RADS category, and final outcome of calcifications identified on each screening technique. T-test was used for continuous variables. RESULTS: Of 699 calcifications in 596 women recalled, 176 (30%) of 596 were from SM and 420 (70%) FFDM/Combo. There was a significantly higher rate of calcifications unvalidated at diagnostic work-up for SM compared to FFDM/Combo (0.8% vs. 10%, p < 0.0001). SM calcifications were more likely to receive BI-RADS 2/3 at diagnostic work-up compared to FFDM/Combo ones (55% vs. 42%, p = 0.003). Of 346 (49%) calcifications that underwent biopsy, 88 (25%) were malignant (36% of SM vs. 22% of FFDM/Combo, OR:0.5 [95% CI: 0.3, 0.8] p = 0.01). Of 622 lesions with established diagnostic outcome, there was no difference between having an overall benign or malignant outcome between SM and FFDM/Combo (17% vs. 13%, OR: 0.8 [95% Cl: 0.5, 1.2] p = 0.27). CONCLUSIONS: Synthetic tomosynthesis screening results in a higher rate of false positive and unvalidated calcification recalls compared to FFDM/Combo.

Use of a single case study design to examine state variation in the cortisol awakening response: relationship with time of awakening.

Recent evidence suggests that the cortisol awakening response (CAR) on any single day is determined by a combination of trait and state factors; however, the nature of such state associations remains largely unexplored. In this study we examined day-to-day changes in the CAR and their covariance with simultaneous changes in sleep-related variables, alcohol consumption, and motility levels. We employed a novel approach to this field of research in the form of a detailed case study of a 27-year-old healthy male (TS) over 50 measurement days, occurring at 3-day intervals. On each measurement day, salivary free cortisol was determined at 0, 15, 30, and 45min post-awakening and sleep-related variables, alcohol consumption on the previous evening, and post-awakening motility were measured. Our findings show considerable day-to-day variability in the CAR, particularly the dynamic increase, which averaged 17.2nmol/l and ranged from 3.6 to 39.0nmol/l (max-min values). We also report a strong relationship between changes in awakening time and changes in the first waking sample (explaining approximately 38% of its variability) such that later awakening was associated with a higher first waking sample. This relationship was found to be stronger on days when awakening time was earlier in the morning than on days when it was later. Our findings also provide a preliminary indication for an inverse association between alcohol consumption on the evening before a sampling day and the dynamic of the AUC(I), while no associations between sleep quality, post-awakening motility levels, and mode of awakening and measures of the CAR were found.

The cortisol awakening response, seasonality, stress and arousal: a study of trait and state influences.

The aim of this study was to investigate the relationship between the cortisol awakening response (CAR) and two key state variables (morning stress and arousal) and the trait-like variable of seasonality as recent evidence suggests that the CAR is subject to both state and trait influences. The CAR was examined across two consecutive winter days in 50 healthy participants. Participants collected saliva samples in the domestic setting immediately on awakening, then at 15, 30 and 45min post-awakening on the two study days. Concomitant trait and state measures were examined, notably seasonal changeability in mood as a trait, and self-reported stress and arousal as state measures. Although there was correlational stability for measures of the CAR across days, there was a significant difference in the magnitude of the increase in cortisol levels following awakening between the two study days, being greater on the first sampling day. This reduction in the magnitude of cortisol increase was significantly associated with an observed reduction across the 2 days in self-reported arousal assessed at 45min following awakening. Participants reported greater arousal (more alert, active, energetic and stimulated, less drowsy, tired and sluggish) on the first study day than the second. Average CAR across days was associated with seasonality score, greater propensity for seasonal changes in mood being associated with smaller average CAR. High seasonality scorers were also more likely as a group to show a strong association between daily changes in state arousal and CAR. This study supports the view that the CAR is, in part, susceptible to short-term changes in state variables, notably perceived arousal, while observing a novel link between CAR and the trait variable of perceived seasonality. Finally a tentative finding suggests the importance of examining for possible interaction between trait and state effects, evidenced by a significantly greater association between state arousal changes and cortisol response changes in those with high (trait) seasonality.