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.

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.

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.

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.

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.

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.

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.

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.

CCP4i2: the new graphical user interface to the CCP4 program suite.

The CCP4 (Collaborative Computational Project, Number 4) software suite for macromolecular structure determination by X-ray crystallography groups brings together many programs and libraries that, by means of well established conventions, interoperate effectively without adhering to strict design guidelines. Because of this inherent flexibility, users are often presented with diverse, even divergent, choices for solving every type of problem. Recently, CCP4 introduced CCP4i2, a modern graphical interface designed to help structural biologists to navigate the process of structure determination, with an emphasis on pipelining and the streamlined presentation of results. In addition, CCP4i2 provides a framework for writing structure-solution scripts that can be built up incrementally to create increasingly automatic procedures.

Lung involvement in inflammatory rheumatic diseases.

This chapter describes the involvement of the lung in systemic inflammatory joint disease (IJD) with a particular focus on rheumatoid arthritis, although the topics of pulmonary involvement in ankylosing spondylitis and psoriatic arthritis are also addressed. Interstitial lung disease is the most lethal pulmonary complication of IJD and the chapter describes recent advances in both our understanding of this complication and the therapeutic options that offer real hope for improved outcomes. Although less well recognised, airways disease is just as common and its association with IJD is described in some detail, with a section devoted to the recent surge in interest in bronchiectasis. Acute pulmonary infection is common in IJD and its management is reviewed in some detail. Although pleural disease is less common than it once was, its treatment is explored. We conclude by reviewing the relationship between the drug therapies employed in IJD and their effects on the lung.

Assessment of the cortisol awakening response: Real-time analysis and curvilinear effects of sample timing inaccuracy.

The cortisol awakening response (CAR) is typically measured in the domestic setting. Moderate sample timing inaccuracy has been shown to result in erroneous CAR estimates and such inaccuracy has been shown partially to explain inconsistency in the CAR literature. The need for more reliable measurement of the CAR has recently been highlighted in expert consensus guidelines where it was pointed out that less than 6% of published studies provided electronic-monitoring of saliva sampling time in the post-awakening period. Analyses of a merged data-set of published studies from our laboratory are presented. To qualify for selection, both time of awakening and collection of the first sample must have been verified by electronic-monitoring and sampling commenced within 15min of awakening. Participants (n=128) were young (median age of 20 years) and healthy. Cortisol values were determined in the 45min post-awakening period on 215 sampling days. On 127days, delay between verified awakening and collection of the first sample was less than 3min ('no delay' group); on 45days there was a delay of 4-6min ('short delay' group); on 43days the delay was 7-15min ('moderate delay' group). Cortisol values for verified sampling times accurately mapped on to the typical post-awakening cortisol growth curve, regardless of whether sampling deviated from desired protocol timings. This provides support for incorporating rather than excluding delayed data (up to 15min) in CAR analyses. For this population the fitted cortisol growth curve equation predicted a mean cortisol awakening level of 6nmols/l (±1 for 95% CI) and a mean CAR rise of 6nmols/l (±2 for 95% CI). We also modelled the relationship between real delay and CAR magnitude, when the CAR is calculated erroneously by incorrectly assuming adherence to protocol time. Findings supported a curvilinear hypothesis in relation to effects of sample delay on the CAR. Short delays of 4-6min between awakening and commencement of saliva sampling resulted in an overestimated CAR. Moderate delays of 7-15min were associated with an underestimated CAR. Findings emphasize the need to employ electronic-monitoring of sampling accuracy when measuring the CAR in the domestic setting.

Does breast composition influence late adverse effects in breast radiotherapy?

BACKGROUND: Large breast size is associated with increased risk of late adverse effects after surgery and radiotherapy for early breast cancer. It is hypothesised that effects of radiotherapy on adipose tissue are responsible for some of the effects seen. In this study, the association of breast composition with late effects was investigated along with other breast features such as fibroglandular tissue distribution, seroma and scar. METHODS: The patient dataset comprised of 18 cases with changes in breast appearance at 2 years follow-up post-radiotherapy and 36 controls with no changes, from patients entered into the FAST-Pilot and UK FAST trials at The Royal Marsden. Breast composition, fibroglandular tissue distribution, seroma and scar were assessed on planning CT scan images and compared using univariate analysis. The association of all features with late-adverse effect was tested using logistic regression (adjusting for confounding factors) and matched analysis was performed using conditional logistic regression. RESULTS: In univariate analyses, no statistically significant differences were found between cases and controls in terms of breast features studied. A statistically significant association (p < 0.05) between amount of seroma and change in photographic breast appearance was found in unmatched and matched logistic regression analyses with odds ratio (95% CI) of 3.44 (1.28-9.21) and 2.57 (1.05-6.25), respectively. CONCLUSIONS: A significant association was found between seroma and late-adverse effects after radiotherapy although no significant associations were noted with breast composition in this study. Therefore, the cause for large breast size as a risk factor for late effects after surgery and optimally planned radiotherapy remains unresolved.

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.

Assessment of the cortisol awakening response: Expert consensus guidelines.

The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.

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.

Detailed time course of the cortisol awakening response in healthy participants.

The cortisol awakening response (CAR) can be assessed from saliva samples collected at home, which confers ecological validity but lacks researcher oversight. Participant non-adherence to requested saliva sampling regimes leads to inaccurate CAR estimates. Moderate sampling delays of just 8 (5-15) min between awakening and commencement of saliva sampling are reported to result in over-estimated CAR magnitude and earlier peaking. This has been attributed to an observed 'latent' period in which cortisol secretion does not increase for up to 10-min after awakening. Replication of this finding is essential as the findings have considerable implications for CAR research. Healthy participants (n=26) collected saliva samples at 5-min intervals for 60min on 2 consecutive typical weekdays. Full electronic monitoring of awakening and sampling enabled exclusion of non-adherent data (i.e., delays of greater than 5min between awakening and collection of the first sample). In the 0-15min post awakening segment of the CAR a quadratic effect was observed, with no difference between the awakening and 5 and 10min samples. Moderate sampling delays will shift assessment of the CAR just sufficiently along the time axis to not impact upon measurement of the first sample but to remove the immediate post-awakening latent period from CAR estimates-whilst retaining later estimates of elevated cortisol secretion. The implication from these results is that accurate CAR measures can only be determined from data with strict adherence to commencement of saliva sampling following awakening.

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.

Post awakening salivary cortisol secretion and trait well-being: The importance of sample timing accuracy.

Indices of post awakening cortisol secretion (PACS), include the rise in cortisol (cortisol awakening response: CAR) and overall cortisol concentrations (e.g., area under the curve with reference to ground: AUCg) in the first 30-45 min. Both are commonly investigated in relation to psychosocial variables. Although sampling within the domestic setting is ecologically valid, participant non-adherence to the required timing protocol results in erroneous measurement of PACS and this may explain discrepancies in the literature linking these measures to trait well-being (TWB). We have previously shown that delays of little over 5 min (between awakening and the start of sampling) to result in erroneous CAR estimates. In this study, we report for the first time on the negative impact of sample timing inaccuracy (verified by electronic-monitoring) on the efficacy to detect significant relationships between PACS and TWB when measured in the domestic setting. Healthy females (N=49, 20.5±2.8 years) selected for differences in TWB collected saliva samples (S1-4) on 4 days at 0, 15, 30, 45 min post awakening, to determine PACS. Adherence to the sampling protocol was objectively monitored using a combination of electronic estimates of awakening (actigraphy) and sampling times (track caps). Relationships between PACS and TWB were found to depend on sample timing accuracy. Lower TWB was associated with higher post awakening cortisol AUCg in proportion to the mean sample timing accuracy (p<.005). There was no association between TWB and the CAR even taking into account sample timing accuracy. These results highlight the importance of careful electronic monitoring of participant adherence for measurement of PACS in the domestic setting. Mean sample timing inaccuracy, mainly associated with delays of >5 min between awakening and collection of sample 1 (median=8 min delay), negatively impacts on the sensitivity of analysis to detect associations between PACS and TWB.

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.