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One of the great diagnostic challenges for children with pulmonary arterial hypertension is the need for general anesthesia (GA) to enable successful right heart catheterization. Here, for the first time, we describe how echocardiographic estimates of right ventricular function and pulmonary pressures change in pediatric patients during GA. [ABSTRACT FROM AUTHOR]

Purpose: Intra-Discal Vacuum phenomenon (IDVP) is well-recognised, yet poorly visualised and poorly understood radiological finding in disc degeneration, particularly with regard to its role in spinal alignment. CT analysis of the lumbar spine in an aging population aims to identify patterns associated with IDVP including lumbopelvic morphology and associated spinal diagnoses. Methods: An analysis was performed of an over-60s population sample of 2020 unrelated abdominal CT scans, without acute spinal presentations. Spinal analysis included sagittal lumbopelvic reconstructions to assess for IDVP and pelvic incidence (PI). Subjects with degenerative pathologies, including previous vertebral fractures, auto-fusion, transitional vertebrae, and listhesis, were also selected out and analysed separately. Results: The prevalence of lumbar spine IDVP was 50.3% (955/1898) and increased with age (125 exclusions). This increased in severity towards the lumbosacral junction (L1L2 8.3%, L2L3 10.9%, L3L4 11.5%, L4L5 23.9%, and L5S1 46.3%). A lower PI yielded a higher incidence of IDVP, particularly at L5S1 (p < 0.01). A total of 292 patients had IDVP with additional degenerative pathologies, which were more likely to occur at the level of isthmic spondylolisthesis, adjacent to a previous fracture or suprajacent to a lumbosacral transitional vertebra (p < 0.05). Conclusions: This study identified the prevalence and severity of IDVP in an aging population. Sagittal patterns that influence the pattern of IVDP, such as pelvic incidence and degenerative pathologies, provide novel insights into the function of aging spines. [ABSTRACT FROM AUTHOR]

Background: The instruction of empathy is challenging. Although several studies have addressed how art‐based education can foster empathy, there is a need for more evidence showing its impact and students' perceptions, especially in graduate education. Approach: We designed and implemented a virtual art‐based curriculum focused on fostering empathy—The Art of Empathy. This novel curriculum used diverse art‐based education methodologies to promote meticulous and collaborative observation and reflection, building on constructivism. Thirty‐six interns at the Brigham and Women's Hospital were invited to participate in the curriculum, while 34 served as control. Evaluation: We used mixed methods to explore interns' perceptions of the curriculum and assess its impact on their empathy. We used two quantitative instruments with known psychometric characteristics: the Toronto Empathy Questionnaire (TEQ) and the Jefferson Scale of Physicians Empathy (JSPE), which were distributed in a survey and completed by 31/99 (31.3%). We collected qualitative data from four interns using semi‐structured interviews. Thematic analysis showed how The Art of Empathy promoted interns' reflections and actions toward empathy. This was partially supported by the quantitative data that showed significantly higher scores on the 'Compassionate Care' subscale of the JSPE (p = 0.039) when compared with interns in the control group. The thematic analysis showed that interns appreciated the curriculum and valued its benefits while highlighting the limitations of the virtual delivery approach. Implications: Our curriculum was well received by interns and showed the potential of art‐based methodology to promote empathic capacities in graduate students. [ABSTRACT FROM AUTHOR]

In late 2020, the results of CASP14, the 14th event in a series of competitions to assess the latest developments in computational protein structure‐prediction methodology, revealed the giant leap forward that had been made by Google's Deepmind in tackling the prediction problem. The level of accuracy in their predictions was the first instance of a competitor achieving a global distance test score of better than 90 across all categories of difficulty. This achievement represents both a challenge and an opportunity for the field of experimental structural biology. For structure determination by macromolecular X‐ray crystallography, access to highly accurate structure predictions is of great benefit, particularly when it comes to solving the phase problem. Here, details of new utilities and enhanced applications in the CCP4 suite, designed to allow users to exploit predicted models in determining macromolecular structures from X‐ray diffraction data, are presented. The focus is mainly on applications that can be used to solve the phase problem through molecular replacement. [ABSTRACT FROM AUTHOR]

With the recent advancements in the field of wearable technologies, the opportunity to monitor stress continuously using different physiological variables has gained significant interest. The early detection of stress can help improve healthcare and minimizes the negative impact of long-term stress. This paper reports outcomes of a pilot study and associated stress-monitoring dataset, named the "Stress-Predict Dataset", created by collecting physiological signals from healthy subjects using wrist-worn watches with a photoplethysmogram (PPG) sensor. While wearing these watches, 35 healthy volunteers underwent a series of tasks (i.e., Stroop color test, Trier Social Stress Test and Hyperventilation Provocation Test), along with a rest period in-between each task. They also answered questionnaires designed to induce stress levels compatible with daily life. The changes in the blood volume pulse (BVP) and heart rate were recorded by the watch and were labelled as occurring during stress-inducing tasks or a rest period (no stress). Additionally, respiratory rate was estimated using the BVP signal. Statistical models and personalised adaptive reference ranges were used to determine the utility of the proposed stressors and the extracted variables (heart rate and respiratory rate). The analysis showed that the interview session was the most significant stress stimulus, causing a significant variation in heart rate of 27 (77%) participants and respiratory rate of 28 (80%) participants out of 35. The outcomes of this study contribute to the understanding the role of stressors and their association with physiological response and provide a dataset to help develop new wearable solutions for more reliable, valid, and sensitive physio-logical stress monitoring. [ABSTRACT FROM AUTHOR]

Background: Physicians need to learn and work amidst a plethora of uncertainties, which may drive burnout. Understanding differences in tolerance of uncertainty is an important research area. Objective: To examine factors associated with tolerance of uncertainty, including well-being metrics such as burnout. Design: Online confidential survey. Setting: The Massachusetts General Physicians Organization (MGPO). Participants: All 2172 clinically active faculty in the MGPO. Main Measures: We examined associations for tolerance of uncertainty with demographic information, personal and professional characteristics, and physician well-being metrics. Key Results: Two thousand twenty (93%) physicians responded. Multivariable analyses identified significant associations of lower tolerance of uncertainty with female gender (OR, 1.23; 95% CI, 1.03–1.48); primary care practice (OR, 1.56; 95% CI, 1.22–2.00); years since training (OR, 0.99; 95% CI, 0.98–0.995); and lacking a trusted advisor (OR, 1.25; 95% CI, 1.03–1.53). Adjusting for demographic and professional characteristics, physicians with low tolerance of uncertainty had higher likelihood of being burned-out (OR, 3.06; 95% CI, 2.41–3.88), were less likely to be satisfied with career (OR, 0.37; 95% CI, 0.26–0.52), and less likely to be engaged at work (RR, 0.87; 95% CI, 0.84–0.90). Conclusion: At a time when concern about physician well-being is high, with much speculation about causes of burnout, we found a strong relationship between tolerance of uncertainty and physician well-being, across specialties. Particular attention likely needs to be paid to those with less experience, those in specialties with high rates of undifferentiated illness and uncertainty, such as primary care, and ensuring all physicians have access to a trusted advisor. These results generate the potential hypothesis that efforts focused in understanding and embracing uncertainty could be potentially effective for reducing burnout. This concept should be tested in prospective trials. [ABSTRACT FROM AUTHOR]

This paper focuses on automatically assessing language proficiency levels according to linguistic complexity in learner English. We implement a supervised learning approach as part of an automatic essay scoring system. The objective is to uncover Common European Framework of Reference for Languages (CEFR) criterial features in writings by learners of English as a foreign language. Our method relies on the concept of microsystems with features related to learner-specific linguistic systems in which several forms operate paradigmatically. Results on internal data show that different microsystems help classify writings from A1 to C2 levels (82% balanced accuracy). Overall results on external data show that a combination of lexical, syntactic, cohesive and accuracy features yields the most efficient classification across several corpora (59.2% balanced accuracy). [ABSTRACT FROM AUTHOR]

Crystallographers have an array of search‐model options for structure solution by molecular replacement (MR). The well established options of homologous experimental structures and regular secondary‐structure elements or motifs are increasingly supplemented by computational modelling. Such modelling may be carried out locally or may use pre‐calculated predictions retrieved from databases such as the EBI AlphaFold database. MrParse is a new pipeline to help to streamline the decision process in MR by consolidating bioinformatic predictions in one place. When reflection data are provided, MrParse can rank any experimental homologues found using eLLG, which indicates the likelihood that a given search model will work in MR. Inbuilt displays of predicted secondary structure, coiled‐coil and transmembrane regions further inform the choice of MR protocol. MrParse can also identify and rank homologues in the EBI AlphaFold database, a function that will also interest other structural biologists and bioinformaticians. [ABSTRACT FROM AUTHOR]

In crystallography, the phase problem can often be addressed by the careful preparation of molecular‐replacement search models. This has led to the development of pipelines such as MrBUMP that can automatically identify homologous proteins from an input sequence and edit them to focus on the areas that are most conserved. Many of these approaches can be applied directly to cryo‐EM to help discover, prepare and correctly place models (here called cryo‐EM search models) into electrostatic potential maps. This can significantly reduce the amount of manual model building that is required for structure determination. Here, MrBUMP is repurposed to fit automatically obtained PDB‐derived chains and domains into cryo‐EM maps. MrBUMP was successfully able to identify and place cryo‐EM search models across a range of resolutions. Methods such as map segmentation are also explored as potential routes to improved performance. Map segmentation was also found to improve the effectiveness of the pipeline for higher resolution (<8 Å) data sets. [ABSTRACT FROM AUTHOR]

Primary Sj€ ogren syndrome is an autoimmune disease characterized by inflammation of the salivary and lacrimal exocrine glands but can also present with systemic extraglandular manifestations, including pulmonary disease. Commonly described pulmonary manifestations of Sjögren syndrome include airway disease, interstitial lung disease, pulmonary arterial hypertension, and lymphoproliferative disorders. However, diffuse alveolar hemorrhage as a sequela of Sj€ ogren syndrome has rarely been described in the adult literature and has never been described in a child. Here we report the case of an 11-year-old girl who presented with diffuse alveolar hemorrhage and was diagnosed with childhood-onset Sjöogren syndrome who otherwise lacked typical clinical features, such as sicca symptoms, at the time of presentation. She was successfully treated with corticosteroids and rituximab, with sustained pulmonary remission 1 year post diagnosis. Our case highlights the heterogenous presentation of Sj€ ogren syndrome in the pediatric population and the need for increased awareness among pediatric providers to recognize potential systemic manifestations of this disease to avoid delayed diagnosis. [ABSTRACT FROM AUTHOR]

The structured life-course modeling approach (SLCMA) is a theory-driven analytical method that empirically compares multiple prespecified life-course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. In this study, we performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genomewide DNA methylation (DNAm). Using simulations (n  = 700), we compared 5 statistical inference tests used with SLCMA, assessing the familywise error rate, statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effects—2 hallmark challenges of inference from -omics data. In the empirical analyses (n  = 703), we evaluated the time-dependent relationship between childhood abuse and genomewide DNAm. In simulations, selective inference and the max-| t |-test performed best: Both controlled the familywise error rate and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNAm. Our findings show that SLCMA, applied and interpreted appropriately, can be used in high-throughput settings to examine time-dependent effects underlying exposure-outcome relationships over the life course. We provide recommendations for applying the SLCMA in -omics settings and encourage researchers to move beyond analyses of exposed versus unexposed individuals. [ABSTRACT FROM AUTHOR]

The structured life-course modeling approach (SLCMA) is a theory-driven analytical method that empirically compares multiple prespecified life-course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. In this study, we performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genomewide DNA methylation (DNAm). Using simulations (n  = 700), we compared 5 statistical inference tests used with SLCMA, assessing the familywise error rate, statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effects—2 hallmark challenges of inference from -omics data. In the empirical analyses (n  = 703), we evaluated the time-dependent relationship between childhood abuse and genomewide DNAm. In simulations, selective inference and the max-| t |-test performed best: Both controlled the familywise error rate and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNAm. Our findings show that SLCMA, applied and interpreted appropriately, can be used in high-throughput settings to examine time-dependent effects underlying exposure-outcome relationships over the life course. We provide recommendations for applying the SLCMA in -omics settings and encourage researchers to move beyond analyses of exposed versus unexposed individuals. [ABSTRACT FROM AUTHOR]

To quantify the reliability of a commercially available auto-segmentation tool in locally advanced non-small cell lung cancer using serial four-dimensional computed tomography (4DCT) scans during conventionally fractionated radiotherapy. Eight patients with serial 4DCT scans (n = 44) acquired over the course of radiotherapy were assessed. Each 4DCT had a physician-defined primary tumour manual contour (MC). An auto-contour (AC) and a user-adjusted auto-contour (UA-AC) were created for each scan. Geometric agreement of the AC and the UA-AC to the MC was assessed using the dice similarity coefficient (DSC), the centre of mass (COM) shift from the MC and the structure volume difference from the MC. Bland Altman analysis was carried out to assess agreement between contouring methods. Dosimetric reliability was assessed by comparison of planning target volume dose coverage on the MC and UA-AC. The time trend analysis of the geometric accuracy measures from the initial planning scan through to the final scan for each patient was evaluated using a Wilcoxon signed ranks test to assess the reliability of the UA-AC over the duration of radiotherapy. User adjustment significantly improved all geometric comparison metrics over the AC alone. Improved agreement was observed in smaller tumours not abutting normal soft tissue and median values for geometric comparisons to the MC for DSC, tumour volume difference and COM offset were 0.80 (range 0.49–0.89), 0.8 cm3 (range 0.0–5.9 cm3) and 0.16 cm (range 0.09–0.69 cm), respectively. There were no significant differences in dose metrics measured from the MC and the UA-AC after Bonferroni correction. Variation in geometric agreement between the MC and the UA-AC were observed over the course of radiotherapy with both DSC (P = 0.035) and COM shift from the MC (ns) worsening. The median tumour volume difference from the MC improved at the later time point. These findings suggest that the UA-AC can produce geometrically and dosimetrically acceptable contours for appropriately selected patients with non-small cell lung cancer. Larger studies are required to confirm the findings. • User-adjustment of auto-contours improves geometric agreement towards the gold standard. • Appropriate case selection improves the accuracy of contours generated. • No significant dosimetric variations measured between PTVs generated from manual contours and user-adjusted auto-contours. • The unique dataset within the study seems to confirm the reliability of user-adjusted contours over time. • Longitudinal auto-contouring may have a role in biologically guided radiotherapy for non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

The conventional approach in molecular replacement is the use of a related structure as a search model. However, this is not always possible as the availability of such structures can be scarce for poorly characterized families of proteins. In these cases, alternative approaches can be explored, such as the use of small ideal fragments that share high, albeit local, structural similarity with the unknown protein. Earlier versions of AMPLE enabled the trialling of a library of ideal helices, which worked well for largely helical proteins at suitable resolutions. Here, the performance of libraries of helical ensembles created by clustering helical segments is explored. The impacts of different B‐factor treatments and different degrees of structural heterogeneity are explored. A 30% increase in the number of solutions obtained by AMPLE was observed when using this new set of ensembles compared with the performance with ideal helices. The boost in performance was notable across three different fold classes: transmembrane, globular and coiled‐coil structures. Furthermore, the increased effectiveness of these ensembles was coupled to a reduction in the time required by AMPLE to reach a solution. AMPLE users can now take full advantage of this new library of search models by activating the 'helical ensembles' mode. [ABSTRACT FROM AUTHOR]

The conventional approach to search‐model identification in molecular replacement (MR) is to screen a database of known structures using the target sequence. However, this strategy is not always effective, for example when the relationship between sequence and structural similarity fails or when the crystal contents are not those expected. An alternative approach is to identify suitable search models directly from the experimental data. SIMBAD is a sequence‐independent MR pipeline that uses either a crystal lattice search or MR functions to directly locate suitable search models from databases. The previous version of SIMBAD used the fast AMoRe rotation‐function search. Here, a new version of SIMBAD which makes use of Phaser and its likelihood scoring to improve the sensitivity of the pipeline is presented. It is shown that the additional compute time potentially required by the more sophisticated scoring is counterbalanced by the greater sensitivity, allowing more cases to trigger early‐termination criteria, rather than running to completion. Using Phaser solved 17 out of 25 test cases in comparison to the ten solved with AMoRe, and it is shown that use of ensemble search models produces additional performance benefits. [ABSTRACT FROM AUTHOR]

Molecular replacement (MR) is the predominant route to solution of the phase problem in macromolecular crystallography. Where the lack of a suitable homologue precludes conventional MR, one option is to predict the target structure using bioinformatics. Such modelling, in the absence of homologous templates, is called ab initio or de novo modelling. Recently, the accuracy of such models has improved significantly as a result of the availability, in many cases, of residue‐contact predictions derived from evolutionary covariance analysis. Covariance‐assisted ab initio models representing structurally uncharacterized Pfam families are now available on a large scale in databases, potentially representing a valuable and easily accessible supplement to the PDB as a source of search models. Here, the unconventional MR pipeline AMPLE is employed to explore the value of structure predictions in the GREMLIN and PconsFam databases. It was tested whether these deposited predictions, processed in various ways, could solve the structures of PDB entries that were subsequently deposited. The results were encouraging: nine of 27 GREMLIN cases were solved, covering target lengths of 109–355 residues and a resolution range of 1.4–2.9 Å, and with target–model shared sequence identity as low as 20%. The cluster‐and‐truncate approach in AMPLE proved to be essential for most successes. For the overall lower quality structure predictions in the PconsFam database, remodelling with Rosetta within the AMPLE pipeline proved to be the best approach, generating ensemble search models from single‐structure deposits. Finally, it is shown that the AMPLE‐obtained search models deriving from GREMLIN deposits are of sufficiently high quality to be selected by the sequence‐independent MR pipeline SIMBAD. Overall, the results help to point the way towards the optimal use of the expanding databases of ab initio structure predictions. [ABSTRACT FROM AUTHOR]

Discussing the uncertainty associated with a clinical decision is thought to be a critical element of shared decision-making. Yet, empirical evidence suggests that clinicians rarely communicate clinical uncertainty to patients, and indeed the culture within healthcare environments is often to equate uncertainty with ignorance or failure. Understanding the rationale for discussion of uncertainty along with the current evidence about approaches to communicating and managing uncertainty can advance shared decision-making as well as highlight gaps in evidence. With an increasing focus on personalized healthcare, and advances in genomics and new disease biomarkers, a more sophisticated understanding of how to communicate the limitations and errors that come from applying population-based, epidemiologic findings to predict individuals' futures is going to be essential. This article provides a narrative review of studies relating to the communication of uncertainty, highlighting current strategies together with challenges and barriers, and outlining a framework for future research. [ABSTRACT FROM AUTHOR]

Background: Communication and handoff failures are common causes of diagnostic errors in hospital. Human quest for certainty can increase the likelihood of premature closure in decision-making, the most common phenomenon in misdiagnosis. Little research exists on whether language choice in handoffs affects physicians' sense of uncertainty. Methods: Medical students from a large US medical school were randomized to receive one of four language variations describing a presumed diagnosis in hypothetical handoffs from emergency department (ED) to inpatient ward. The control language arm used the word 'diagnosis'; experimental arms replaced this word with either 'hypothesis', 'probability of 60%', or 'working diagnosis' with a short differential. Outcome measures were students' anxiety due to uncertainty (range 5–30; higher scores indicating higher stress from uncertainty) and clinical uncertainty about the ED provider's presumed diagnosis. Results: Mean anxiety due to uncertainty was significantly higher in subjects receiving the 'hypothesis' language arm compared to those receiving the control 'diagnosis' language [19.2 (4.6) vs. 15.5 (3.4); p<0.008]. Differences between subjects who received the probability language [17.2 (5.8) vs. 15.5 (3.4); p=0.26] and 'working diagnosis' language [16 (5) vs. 15.5 (3.4); p=0.69] were not statistically significant. There was no difference in items assessing clinical uncertainty after each scenario. Conclusions: The word 'hypothesis' increased anxiety due to uncertainty compared to the word 'diagnosis', but did not change assessments of clinical uncertainty. Further research is needed to assess how use of language in clinical handoffs may influence perceptions and anxiety related to uncertainty and whether optimal language can be identified that leads to recognition of uncertainty without maladaptive stress or anxiety due to uncertainty. [ABSTRACT FROM AUTHOR]

School-based social and emotional learning programs aim to provide students with the skills they need to deal with life challenges, thereby enhancing their social and emotional wellbeing, academic outcomes, and reducing their risk of mental health difficulties. While there is a robust evidence base on the effectiveness of these programs originating from the US, there is a relative paucity of research on how these programs impact young people in other county contexts, especially for older adolescents and those at higher risk. This study sets out to address this research gap by evaluating the effectiveness of a social emotional learning program designed for older adolescents in Ireland, the MindOut program. MindOut is a universal school-based social and emotional learning program designed for older adolescents in Ireland which was developed based on a common elements approach underpinned by CASEL's framework. Employing a cluster randomized-controlled trial, data on social and emotional skills, academic performance and mental health outcomes were collected from students (n = 497; 51.1% female) ages 15–18 years in 32 disadvantaged schools. There were significant improvements in intervention students' social and emotional skills including, reduced suppression of emotions (p = 0.035), use of more positive coping strategies [reduced avoidance coping p = < 0.001) and increased social support coping p = 0.044)]. Improvements in mental health and wellbeing were also found with significantly reduced levels of stress (p = 0.017) and depressive symptoms (p = 0.030) as well as reduced anxiety scores for females students (p = 0.044). These short-term evaluation findings support the positive impact of school-based social and emotional learning programs, such as MindOut, when designed to be both age and culturally appropriate and delivered to older adolescents in disadvantaged schools. [ABSTRACT FROM AUTHOR]

Purpose: The ability of healthcare systems to deliver world-class compassionate care depends on the quality of training and education of staff. Matching student-centered learning with patient-centered care is the focus for much curricula reform. This study explores the effect a novel longitudinal curriculum had on medical students' attitudes and experiences to better identify central tenets needed in our education system. Methods: Single-center, qualitative focus-group study conducted in 2017 of medical students in a longitudinally integrated clinical apprenticeship at a large UK medical school. Students were randomly assigned to focus groups to describe their educational journey and explore how longitudinal learning prepared them for a medical career, valuing their unique position as student participants in the healthcare system. Results: Four themes emerged from students' experiences: navigating the patient journey, their professional development, their learning journey, and the healthcare system. Conclusions: Listening to student voices lends insights for educators refining educational models to produce doctors of tomorrow. This project identified the educational value of students having authentic roles in helping patients navigate the healthcare system and the benefits of consistent mentorship and greater autonomy. The gulf between gaining skills as a future doctor and gaining skills to pass summative exams calls into question assessment methods. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Sex differences in measures of cardiovascular health in adults are well documented. However, the sex-specific aetiology of cardiovascular health across childhood and adolescence is poorly understood. Methods We examined sex differences in trajectories of 11 measures of cardiovascular health from birth to 18 years, in a contemporary birth cohort study in England (N participants per outcomes: 662-13,985, N repeated measures per outcome: 1,831-112,768). Outcomes were measured over varying time spans from birth or mid-childhood to age 18 and with different numbers of repeated measures per outcome. Analyses were performed using fractional polynomial and linear spline multilevel models. Results Females had higher mean BMI, height-adjusted fat mass, pulse rate, insulin, triglycerides, and non-high-density lipoprotein cholesterol (HDL-c) and lower mean height-adjusted lean mass from birth or from mid-childhood to age 18. For example, mean non-HDL-c was 0.07 mmol/l (95% confidence interval (CI), 0.04, 0.10) higher in females compared with males at birth. By age 18, this difference persisted and widened to 0.19 mmol/l (95% CI, 0.16, 0.23) higher non-HDL-c in females compared with males. Females had lower levels of glucose from mid-childhood and developed lower systolic blood pressure and higher HDL-c from mid-adolescence onward. For example, females had 0.08 mmol/l (95% CI, 0.05, 0.10) lower mean glucose compared with males at age seven which widened to a difference of 0.22 mmol/l (95% CI, 0.25, 0.19) at age 18. Conclusions Sex differences in measures of cardiovascular health are apparent from birth or mid-childhood and change during early life. These differences may have implications for sex-specific disease risk in future adult populations. Highlights • Sex differences in measures of cardiovascular health are well established in adulthood. • Few studies have examined sex-specific change in cardiovascular risk in childhood. • Our findings show that sex differences in cardiovascular health begin at birth. • These sex differences change further throughout childhood and adolescence. • Early life factors may play a role in sex differences in cardiometabolic disease. [ABSTRACT FROM AUTHOR]

Why Do Physicians Pursue Cascades of Care After Incidental Findings? Census region data were not available for zip codes reported by 6 physicians in the sample SP ‡ sp Area-level education derived using the American Community Survey linked to physician-reported practice zip code. Of the remaining 41.4%, the most common reasons to pursue follow-up were practice/community norms (49.7%), concern about a lawsuit (35.7%), another doctor's advice (26.0%), and patient request (24.2%) (not mutually exclusive). [Extracted from the article]

Estimating velocity and acceleration trajectories allows novel inferences in the field of longitudinal data analysis, such as estimating change regions rather than change points, and testing group effects on nonlinear change in an outcome (ie, a nonlinear interaction). In this article, we develop derivative estimation for 2 standard approaches—polynomial mixed models and spline mixed models. We compare their performance with an established method—principal component analysis through conditional expectation through a simulation study. We then apply the methods to repeated blood pressure (BP) measurements in a UK cohort of pregnant women, where the goals of analysis are to (i) identify and estimate regions of BP change for each individual and (ii) investigate the association between parity and BP change at the population level. The penalized spline mixed model had the lowest bias in our simulation study, and we identified evidence for BP change regions in over 75% of pregnant women. Using mean velocity difference revealed differences in BP change between women in their first pregnancy compared with those who had at least 1 previous pregnancy. We recommend the use of penalized spline mixed models for derivative estimation in longitudinal data analysis. [ABSTRACT FROM AUTHOR]

The conventional approach to finding structurally similar search models for use in molecular replacement (MR) is to use the sequence of the target to search against those of a set of known structures. Sequence similarity often correlates with structure similarity. Given sufficient similarity, a known structure correctly positioned in the target cell by the MR process can provide an approximation to the unknown phases of the target. An alternative approach to identifying homologous structures suitable for MR is to exploit the measured data directly, comparing the lattice parameters or the experimentally derived structure‐factor amplitudes with those of known structures. Here, SIMBAD, a new sequence‐independent MR pipeline which implements these approaches, is presented. SIMBAD can identify cases of contaminant crystallization and other mishaps such as mistaken identity (swapped crystallization trays), as well as solving unsequenced targets and providing a brute‐force approach where sequence‐dependent search‐model identification may be nontrivial, for example because of conformational diversity among identifiable homologues. The program implements a three‐step pipeline to efficiently identify a suitable search model in a database of known structures. The first step performs a lattice‐parameter search against the entire Protein Data Bank (PDB), rapidly determining whether or not a homologue exists in the same crystal form. The second step is designed to screen the target data for the presence of a crystallized contaminant, a not uncommon occurrence in macromolecular crystallography. Solving structures with MR in such cases can remain problematic for many years, since the search models, which are assumed to be similar to the structure of interest, are not necessarily related to the structures that have actually crystallized. To cater for this eventuality, SIMBAD rapidly screens the data against a database of known contaminant structures. Where the first two steps fail to yield a solution, a final step in SIMBAD can be invoked to perform a brute‐force search of a nonredundant PDB database provided by the MoRDa MR software. Through early‐access usage of SIMBAD, this approach has solved novel cases that have otherwise proved difficult to solve. [ABSTRACT FROM AUTHOR]

Background:Controlling for maturational status and timing is crucial in lifecourse epidemiology. One popular non-invasive measure of maturity is the age at peak height velocity (PHV). There are several ways to estimate age at PHV, but it is unclear which of these to use in practice. Aim:To find the optimal approach for estimating age at PHV. Subjects and methods:Methods included the Preece & Baines non-linear growth model, multi-level models with fractional polynomials, SuperImposition by Translation And Rotation (SITAR) and functional data analysis. These were compared through a simulation study and using data from a large cohort of adolescent boys from the Christ’s Hospital School. Results:The SITAR model gave close to unbiased estimates of age at PHV, but convergence issues arose when measurement error was large. Preece & Baines achieved close to unbiased estimates, but shares similarity with the data generation model for our simulation study and was also computationally inefficient, taking 24 hours to fit the data from Christ’s Hospital School. Functional data analysis consistently converged, but had higher mean bias than SITAR. Almost all methods demonstrated strong correlations (r > 0.9) between true and estimated age at PHV. Conclusions:Both SITAR or the PBGM are useful models for adolescent growth and provide unbiased estimates of age at peak height velocity. Care should be taken as substantial bias and variance can occur with large measurement error. [ABSTRACT FROM AUTHOR]

Time-sensitive emergencies in areas of low population density have statistically poorer outcomes. This includes incidents of major trauma. This study assesses the effect that population density at a receiving hospital of a major trauma patient has on survival. Patients meeting Trauma Audit Research Network criteria for major trauma from 2016 to 2020 in Ireland were included in this retrospective observational study. Incident data were retrieved from the Major Trauma Audit, while data on population density were calculated from Irish state sources. The primary outcome measure of survival to discharge was compared to population density using logistic regression, adjusted for demographic and incident variables. Records were divided into population density tertiles to assess for between-group differences in potential predictor variables. Population density at a receiving hospital had no impact on mortality in Irish major trauma patients from our logistic regression model (OR = 1.01, 95% CI 0.98–1.05, p = 0.53). Factors that did have an impact were age, Charlson Comorbidity Index, Injury Severity Score, and the presence of an Orthopaedic Surgery service at the receiving hospital (all p < 0.001). Age and Charlson Comorbidity Index differed slightly by population density tertile; both were higher in areas of high population density (all p < 0.001). Survival to discharge in Irish major trauma patients does not differ substantially based on population density. This is an important finding as Ireland moves to a new trauma system, with features based on population distribution. An Orthopaedic Surgery service is an important feature of a major trauma receiving hospital and its presence improves outcomes. • Population density has no impact on survival of major trauma patients in Ireland. • Risk of mortality reduced by 44% in hospitals with an Orthopaedic Surgery service. • These findings are notable as Ireland introduces a new major trauma system. [ABSTRACT FROM AUTHOR]

The article points out that individuals who suffer from both addiction and mental health problems are very prone to stigma. Topics discussed include definition of stigma, explanation on stigma in mental illness and substance use disorder (SUD), and characteristics of stigma among those with a diagnosis of both disorders.

Broiler chicken flocks are a significant source of Campylobacter jejuni and Campylobacter coli that result in the major public health problem of campylobacteriosis. Accurate estimates of the prevalence of both C. coli and C. jejuni in flocks would enhance epidemiological understanding, risk assessment and control options. This study combined results from a panel of 10 detection tests (direct culture, enrichment and PCR) on caecal samples from flocks at slaughter. A parallel interpretation approach was used to determine the presence of Campylobacter spp. and for C. jejuni and C. coli individually. The sample was considered positive if at least one method detected the target and this interpretation was taken to represent a 'proxy gold standard' for detection in the absence of a gold standard reference test. The sensitivity of each individual method to detect Campylobacter spp., C. jejuni and C. coli was then estimated relative to the proxy gold standard. Enrichment in adapted Exeter broth (deficient in polymyxin B) with a resuscitation step was 100% sensitive, whilst direct culture on modified charcoal cefoperazone deoxycholate agar ( mCCDA) was highly sensitive (97.9%). Enrichment methods using Preston broth and Bolton broth were significantly less sensitive. Enrichment in Exeter broth promoted the recovery of C. jejuni, whilst enrichment in Bolton broth favoured C. coli. A RT- PCR detection test could identify 80% of flocks that were co-colonised with both species. This study found that 76.3% ( n = 127) of flocks were colonised with Campylobacter spp. The majority (95.9%) of Campylobacter-positive flocks were colonised with C. jejuni; however, approximately one-third of positive flocks were simultaneously colonised with both C. jejuni and C. coli. The findings highlight the impact of different detection methodologies on the accuracy of the estimated incidence of both C. jejuni and C. coli entering the abattoir within broiler flocks and the associated public health risks. [ABSTRACT FROM AUTHOR]

Background: Statistical models that use an individual's DNA methylation levels to estimate their age (known as epigenetic clocks) have recently been developed, with 96% correlation found between epigenetic and chronological age. We postulate that differences between estimated and actual age [age acceleration (AA)] can be used as a measure of developmental age in early life.Methods: We obtained DNA methylation measures at three time points (birth, age 7 years and age 17 years) in 1018 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Using an online calculator, we estimated epigenetic age, and thus AA, for each child at each time point. We then investigated whether AA was prospectively associated with repeated measures of height, weight, body mass index (BMI), bone mineral density, bone mass, fat mass, lean mass and Tanner stage.Results: Positive AA at birth was associated with higher average fat mass [1321 g per year of AA, 95% confidence interval (CI) 386, 2256 g] from birth to adolescence (i.e. from age 0-17 years) and AA at age 7 was associated with higher average height (0.23 cm per year of AA, 95% CI 0.04, 0.41 cm). Conflicting evidence for the role of AA (at birth and in childhood) on changes during development was also found, with higher AA being positively associated with changes in weight, BMI and Tanner stage, but negatively with changes in height and fat mass.Conclusions: We found evidence that being ahead of one's epigenetic age acceleration is related to developmental characteristics during childhood and adolescence. This demonstrates the potential for using AA as a measure of development in future research. [ABSTRACT FROM AUTHOR]

Purpose:There is concern among physicians that the rising use of technology in medicine may have a negative impact on compassionate patient-centered care. This study explores medical student attitudes and ideas about technology in medicine in order to consider ways to achieve symbiosis between technology use and the delivery of humanistic, patient-centered care. Methods:This qualitative study uses data from 138 essays written by medical students in the United States and Canada responding to the prompt “Using a real life experience, describe how technology played a role, either negatively or positively, in the delivery of humanistic patient care.” Data were analyzed for themes about technology and the impact on humanistic patient care. Results:Seven themes emerged from the medical students’ essays: Patient Perspective; Life-Giving versus Life-Prolonging; Boundaries between Human and Technology; Distancing versus Presence; Adapting to Change; Tools to Enhance Care; and Definitions of Technology. Conclusion:Listening to medical students lends insight into ways to integrate technology into the healthcare environment, to ensure that physicians’ ability to deliver compassionate care is enhanced, not hindered. Utilizing perceptions of the next generation of physicians, educational and developmental strategies are proposed to ensure the successful integration of technology with humanistic patient-centered care. [ABSTRACT FROM PUBLISHER]

Objective To determine whether there are differences in prostate-specific antigen ( PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer ( PCa). Subjects and Methods We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. Results The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/ mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. Conclusion We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies. [ABSTRACT FROM AUTHOR]

Background: Uncertainty remains about the true extent by which alcohol consumption causes a number of health outcomes. Genetic variants, or combinations of variants built into a polygenic risk score (PGRS), can be used in an instrumental variable framework to assess causality between a phenotype and disease outcome of interest, a method known as Mendelian randomisation (MR). We aimed to identify genetic variants involved in the aetiology of alcohol consumption, and develop a PGRS for alcohol. Methods: Repeated measures of alcohol consumption from mothers and their offspring were collected as part of the Avon Longitudinal Study of Parents and Children. We tested the association between 89 SNPs (identified from either published GWAS data or from functional literature) and repeated measures of alcohol consumption, separately in mothers (from ages 28–48) and offspring (from ages 15–21) who had ever reported drinking. We modelled log units of alcohol using a linear mixed model and calculated beta coefficients for each SNP separately. Cross-validation was used to determine an allelic score for alcohol consumption, and the AVENGEME algorithm employed to estimate variance of the trait explained. Results: Following correction for multiple testing, one SNP (rs1229984) showed evidence for association with alcohol consumption (β = -0.177, SE = 0.042, p = <0.0001) in the mothers. No SNPs showed evidence for association in the offspring after correcting for multiple testing. The optimal allelic score was generated using p-value cut offs of 0.5 and 0.05 for the mothers and offspring respectively. These scores explained 0.3% and 0.7% of the variance. Conclusion: Our PGRS explains a modest amount of the variance in alcohol consumption and larger sample sizes would be required to use our PGRS in an MR framework. [ABSTRACT FROM AUTHOR]

We aimed to examine associations of salivary and hair cortisol with emotional exhaustion (EE) and depersonalization (DP) (measures of burnout) and association of urinary oxytocin with connection and trust among clinicians. Hair cortisol concentrations were obtained from the 3 cm most proximal to the scalp reflecting prior three-month cortisol levels.[3] Because of this lag, an additional hair sample was collected three months after initial collection. Professional burnout has adverse consequences for healthcare quality and safety and staff wellbeing.[1] Efforts to address burnout are hampered by challenges in conceptualizing and measuring burnout, in part because of inadequate understanding of its pathophysiology.[2] Because burnout and stress are conceptually linked, neuro-hormonal changes in response to stress (such as cortisol levels) may provide novel avenues for understanding the pathophysiology of burnout and for improving measurement using biomarkers. [Extracted from the article]

The article focuses on several Contemporary Choral Music members including Karen P. Thomas; Colin Eatock and Carlos Cordero.

Serial measurements of prostate-specific antigen (PSA) are used as a biomarker for men diagnosed with prostate cancer following an active monitoring programme. Distinguishing pathological changes from natural age-related changes is not straightforward. Here, we compare four approaches to modelling age-related change in PSA with the aim of developing reference ranges for repeated measures of PSA. A suitable model for PSA reference ranges must satisfy two criteria. First, it must offer an accurate description of the trend of PSA on average and in individuals. Second, it must be able to make accurate predictions about new PSA observations for an individual and about the entire PSA trajectory for a new individual. [ABSTRACT FROM AUTHOR]

Background Patients with acute decompensated heart failure with diuretic resistance (ADHF-DR) have a poor prognosis. The aim of this study was to assess in patients with ADHF-DR, whether haemodynamic changes during ultrafiltration (UF) are associated with changes in renal function (Δcreatinine) and whether Δcreatinine post UF is associated with mortality. Methods Seventeen patients with ADHF-DR underwent 20 treatments with UF. Serial bloods (4–6 hourly) from the onset of UF treatment were measured for renal function, electrolytes and central venous saturation (CVO 2 ). Univariate and multivariate analysis were performed to assess the relationship between changes in markers of haemodynamics [heart rate (HR), systolic blood pressure (SBP), packed cell volume (PCV) and CVO 2 ] and Δcreatinine. Patients were followed up and mortality recorded. Cox-regression survival analysis was performed to determine covariates associated with mortality. Results Renal function worsened after UF in 17 of the 20 UF treatments (baseline vs. post UF creatinine: 164 ± 58 vs. 185 ± 69 μmol/l, P < 0.01). ΔCVO 2 was significantly associated with Δcreatinine [β-coefficient of − 1.3 95%CI (− 1.8 to − 0.7), P < 0.001] and remained significantly associated with Δcreatinine after considering changes in SBP, HR and PCV [P < 0.001]. Ten (59%) patients died at 1-year and 15(88%) by 2-years. Δcreatinine was independently associated with mortality (adjusted-hazard ratio 1.03 (1.01 to 1.07) per 1 μmol/l increase in creatinine; P = 0.02). Conclusions Haemodynamic changes during UF as measured by the surrogate of cardiac output was associated with Δcreatinine. Worsening renal function at end of UF treatment occurred in the majority of patients and was associated with mortality. [ABSTRACT FROM AUTHOR]

Background: Proteins produced by bacteriophages can have potent antimicrobial activity. The study of phage-host interactions can therefore inform small molecule drug discovery by revealing and characterising new drug targets. Here we characterise in silico the predicted interaction of gene protein 0.4 (GP0.4) from the Escherichia coli (E. coli) phage T7 with E. coli filamenting temperature-sensitive mutant Z division protein (FtsZ). FtsZ is a tubulin homolog which plays a key role in bacterial cell division and that has been proposed as a drug target. Results: Using ab initio, fragment assembly structure modelling, we predicted the structure of GP0.4 with two programs. A structure similarity-based network was used to identify a U-shaped helix-turn-helix candidate fold as being favoured. ClusPro was used to dock this structure prediction to a homology model of E. coli FtsZ resulting in a favourable predicted interaction mode. Alternative docking methods supported the proposed mode which offered an immediate explanation for the anti-filamenting activity of GP0.4. Importantly, further strong support derived from a previously characterised insertion mutation, known to abolish GP0.4 activity, that is positioned in close proximity to the proposed GP0.4/FtsZ interface. Conclusions: The mode of interaction predicted by bioinformatics techniques strongly suggests a mechanism through which GP0.4 inhibits FtsZ and further establishes the latter's druggable intrafilament interface as a potential drug target. [ABSTRACT FROM AUTHOR]

The article evaluates Project: Encore, a catalog of contemporary choral music reviewed and endorsed by a panel of renowned conductors.

Context Many men with clinically localized prostate cancer are being monitored as part of active surveillance (AS) programs, but little is known about reasons for receiving radical treatment. Objectives A systematic review of the evidence about AS was undertaken, with a meta-analysis to identify predictors of radical treatment. Evidence acquisition A comprehensive search of the Embase, MEDLINE and Web of Knowledge databases to March 2014 was performed. Studies reporting on men with localized prostate cancer followed by AS or monitoring were included. AS was defined where objective eligibility criteria, management strategies, and triggers for clinical review or radical treatment were reported. Evidence synthesis The 26 AS cohorts included 7627 men, with a median follow-up of 3.5 yr (range of medians 1.5–7.5 yr). The cohorts had a wide range of inclusion criteria, monitoring protocols, and triggers for radical treatment. There were eight prostate cancer deaths and five cases of metastases in 24 981 person-years of follow-up. Each year, 8.8% of men (95% confidence interval 6.7–11.0%) received radical treatment, most commonly because of biopsy findings, prostate-specific antigen triggers, or patient choice driven by anxiety. Studies in which most men changed treatment were those including only low-risk Gleason score 6 disease and scheduled rebiopsies. Conclusions The wide variety of AS protocols and lack of robust evidence make firm conclusions difficult. Currently, patients and clinicians have to make judgments about the balance of risks and benefits in AS protocols. The publication of robust evidence from randomized trials and longer-term follow-up of cohorts is urgently required. Patient summary We reviewed 26 studies of men on active surveillance for prostate cancer. There was evidence that studies including men with the lowest risk disease and scheduled rebiopsy had higher rates of radical treatment. [ABSTRACT FROM AUTHOR]

The timing of the internal circadian clock shows large inter-individual variability across the lifespan. Although the sleep-wakefulness pattern of most toddlers includes an afternoon nap, the association between napping and circadian phase in early childhood remains unexplored. This study examined differences in circadian phase and sleep between napping and non-napping toddlers. Data were collected on 20 toddlers (34.2±2.0 months; 12 females; 15 nappers). Children followed their habitual napping and non-napping sleep schedules (monitored with actigraphy) for 5 days before an in-home salivary dim light melatonin onset (DLMO) assessment. On average, napping children fell asleep during their nap opportunities on 3.6±1.2 of the 5 days before the DLMO assessment. For these napping children, melatonin onset time was 38 min later (p = 0.044; d = 0.93), actigraphically-estimated bedtime was 43 min later (p = 0.014; d = 1.24), sleep onset time was 59 min later (p = 0.006; d = 1.46), and sleep onset latency was 16 min longer (p = 0.030; d = 1.03) than those not napping. Midsleep and wake time did not differ by napping status. No difference was observed in the bedtime, sleep onset, or midsleep phase relationships with DLMO; however, the wake time phase difference was 47 min smaller for napping toddlers (p = 0.029; d = 1.23). On average, nappers had 69 min shorter nighttime sleep durations (p = 0.006; d = 1.47) and spent 49 min less time in bed (p = 0.019; d = 1.16) than non-nappers. Number of days napping was correlated with melatonin onset time (r = 0.49; p = 0.014). Our findings indicate that napping influences individual variability in melatonin onset time in early childhood. The delayed bedtimes of napping toddlers likely permits light exposure later in the evening, thereby delaying the timing of the clock and sleep. Whether the early developmental trajectory of circadian phase involves an advance associated with the decline in napping is a question necessitating longitudinal data as children transition from a biphasic to monophasic sleep-wakefulness pattern. [ABSTRACT FROM AUTHOR]

Aims There is increasing evidence of Gleason score ( GS) drift in prostatic core biopsies during the last two decades. The Protec T study is a randomized controlled study and provides an excellent cohort to study the effect of time, prostate-specific antigen ( PSA) level, perineural invasion, tumour length and age on GS. Methods and results The Protec T study recruited men in the United Kingdom between 1999 and 2010. The Gleason scores were grouped into four categories ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4 for analysis. Data from England between 2000 and 2012 were also available. A total of 3282 biopsies containing cancer were analysed. For each year of the ProtecT study, the odds of being diagnosed with a higher GS category increased by 4.9%. Higher GS was also associated with perineural invasion, increasing tumour length, age and PSA level. While biopsy GS from England was incomplete, it also showed a marked decrease in GS five and six tumours during the same period. Conclusion There was GS drift from 3 + 3 to 3 + 4 with time in the ProtecT study, but there appeared to be no significant change in percentage of GS 4 + 3 or higher. This drift was less dramatic when compared to GS in the rest of England. [ABSTRACT FROM AUTHOR]

Background/Aims: Donohue and Rabson-Mendenhall syndrome are rare autosomal recessive disorders caused by mutations in the insulin receptor gene, INSR. Phenotypic features include extreme insulin resistance, linear growth retardation, paucity of fat and muscle, and soft tissue overgrowth. The insulin receptor is also expressed in the kidney, where animal data suggest it plays a role in glomerular function and blood pressure (BP) regulation, yet such a role in the human kidney is untested. Patients with biallelic INSR mutations provide a rare opportunity to ascertain its role in man. Methods: Retrospective review of patients with INSR mutations. Data for BP, renal imaging, plasma creatinine and electrolyte levels, as well as urine protein, albumin and calcium excretion were sought from the treating clinicians. Results: From 33 patients with INSR mutations, data were available for 17 patients. Plasma creatinine was low (mean ± SD: 25 ± 9 μmol/l) and mean plasma electrolyte concentrations were within the normal range (n = 13). Systolic BP ranged between the 18th and 91st percentile for age, sex, height and weight (n = 9; mean ± SD: 49 ± 24). Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all (mean ± SD: 0.32 ± 0.17 mmol/kg/day; normal <0.1). Nephrocalcinosis was present in all patients (n = 17). Urinary albumin excretion (n = 7) ranged from 4.3-122.5 μg/min (mean ± SD: 32.4 ± 41.0 μg/min; normal <20). Conclusions: INSR dysfunction is associated with hypercalciuria and nephrocalcinosis. No other consistent abnormality of renal function was noted. Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recent innovations in computational structural biology have opened an opportunity to revise our current understanding of the structure and function of clinically important proteins. This study centres on human Oca2 which is located on mature melanosomal membranes. Mutations of Oca2 can result in a form of oculocutanous albinism, which is the most prevalent and visually identifiable form of albinism. Sequence analysis predicts Oca2 to be a member of the SLC13 transporter family, but it has not been classified into any existing SLC families. The modelling of Oca2 with AlphaFold2 and other advanced methods show that, like SLC13 members, it consists of a scaffold and transport domain and displays a pseudo inverted repeat topology that includes re-entrant loops. This finding contradicts the prevailing consensus view of its topology. In addition to the scaffold and transport domains, the presence of a cryptic GOLD domain is revealed that is likely responsible for its trafficking fromthe endoplasmic reticulum to the Golgi prior to localisation at the melanosomes. The GOLD domain harbours some known glycosylation sites. Analysis of the putative ligand binding site of the model shows the presence of highly conserved key asparagine residues that suggest Oca2 may be a Na+/dicarboxylate symporter. Known critical pathogenic mutations map to structural features present in the repeat regions that form the transport domain. Exploiting the AlphaFold2 multimeric modelling protocol in combination with conventional homology modelling allowed the building of plausible homodimers in both inward- and outward-facing conformations, supporting an elevator-type transport mechanism. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Early right-sided heart failure (RHF) was seen in 22% of recipients of a left ventricular assist device (LVAD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). However, the optimal treatment of post-LVAD RHF is not well known. Levosimendan has proven to be effective in patients with cardiogenic shock and in those with end-stage heart failure. We sought to evaluate the efficacy of levosimendan on post-LVAD RHF and 30-day and 1-year mortality. METHODS The EUROMACS Registry was used to identify adults with mainstream continuous-flow LVAD implants who were treated with preoperative levosimendan compared to a propensity matched control cohort. RESULTS In total, 3661 patients received mainstream LVAD, of which 399 (11%) were treated with levosimendan pre-LVAD. Patients given levosimendan had a higher EUROMACS RHF score [4 (2– 5.5) vs 2 (2– 4); P  < 0.001], received more right ventricular assist devices (RVAD) [32 (8%) vs 178 (5.5%); P  = 0.038] and stayed longer in the intensive care unit post-LVAD implant [19 (8–35) vs 11(5–25); P  < 0.001]. Yet, there was no significant difference in the rate of RHF, 30-day, or 1-year mortality. Also, in the matched cohort (357 patients taking levosimendan compared to an average of 622 controls across 20 imputations), we found no evidence for a difference in postoperative severe RHF, RVAD implant rate, length of stay in the intensive care unit or 30-day and 1-year mortality. CONCLUSIONS In this analysis of the EUROMACS registry, we found no evidence for an association between levosimendan and early RHF or death, albeit patients taking levosimendan had much higher risk profiles. For a definitive conclusion, a multicentre, randomized study is warranted. [ABSTRACT FROM AUTHOR]

The article explains the need to focus on diagnostic reasoning in internal medicine training. Physicians are advised to enhance their competency in internal medicine training in order to help them the challenges in the health care environment. Some recommendations for rebuilding the focus on diagnostic reasoning in internal medicine training are enumerated, including changing the teaching conferences and structure of teaching rounds.

The article focuses on development of the Integrated Clinical Apprenticeship (ICA) for assistance of medical students in their transformation to student doctors. Topics discussed include association of the Imperial College London in an introduction of ICA along with on-job training; assessment of the ICA's curriculum y comparison of ICA students with other medical students; and increment in an exposure for medical care services by ICA towards undergraduate primary care students.

The authors share their thoughts on the revolutionary change required for cultivating a tolerance of uncertainty in medicine's cultural attitude and approach to uncertainty. Topics mentioned include a shift toward the acknowledgment and acceptance of uncertainty for physicians and their patients, the need for doctors to make decisions on the basis of imperfect data and limited knowledge, and the maladaptive responses of doctors to uncertainty and its impact on work-related stress.

Chronotype is a construct reflecting individual differences in diurnal preference. Although chronotype has been studied extensively in schoolage children, adolescents and adults, data on young children are scarce. This study describes chronotype and its relationship to the timing of the circadian clock and sleep in 48 healthy children aged 30-36 months (33.4 ± 2.1 months; 24 males). Parents completed the Children's Chronotype Questionnaire (CCTQ) ~2 weeks before the start of the study. The CCTQ provides three measures of chronotype: midsleep time on free days, a multi-item morningness/eveningness score and a single item chronotype score. After 5 days of sleeping on their habitual schedule (assessed with actigraphy and sleep diaries), children participated in an in-home salivary dim light melatonin onset assessment. Average midsleep time on free days was 1:47 ± 0:35, and the average morningness/eveningness score was 26.8 ± 4.3. Most toddlers (58.4%) were rated as 'definitely a morning type' or 'rather morning than evening type', while none (0%) were rated as 'definitely evening type'. More morning types (midsleep time on free days and morningness/eveningness score, respectively) had earlier melatonin onset times (r = 0.45, r = 0.26), earlier habitual bedtimes (r = 0.78, r = 0.54), sleep onset times (r = 0.80, r = 0.52), sleep midpoint times (r = 0.90, r = 0.53) and wake times (r = 0.74, r = 0.34). Parent ratings using the single-item chronotype score were associated with melatonin onset (r = 0.32) and habitual bedtimes (r = 0.27), sleep onset times (r = 0.33) and sleep midpoint times (r = 0.27). Morningness may best characterize circadian preference in early childhood. Associations between chronotype and circadian physiology and sleep timing suggest adequate validity for the CCTQ in this age group. These findings have important implications for understanding the marked variability in sleep timing during the early years of life. [ABSTRACT FROM AUTHOR]

Aims To look at the incidence of tip margin involvement in skin excisions for basal cell carcinomas (BCCs) and to examine if any factors might be used to predict margin involvement. Methods and results All reports of BCCs by a single dermatopathologist were reviewed and 793 excisions were included from 642 patients. Whether there was BCC in the tip and whether this tip was involved were recorded together with macroscopic and microscopic factors based on the Royal College of Pathologists' (RCPath) dataset. Statistical analysis was carried out to determine associations between these factors and tip involvement. In 43 (5%) specimens the tip margin was involved and in 35 (4%) cases the peripheral lateral margin was involved. Risk factors for tip margin involvement were a lesion that was non-discernible macroscopically and most importantly, involvement of a peripheral lateral margin. Conclusions The incidence of tip margin involvement is small and it appears unnecessary to embed the tips unless the lesion is non-discernible macroscopically or if the peripheral lateral margin is involved. [ABSTRACT FROM AUTHOR]