Drawing attention to previous studies can reduce confidence in a new research finding, even when confidence should increase.

People often learn of new scientific findings from brief news reports, and may discount or ignore prior research, potentially contributing to misunderstanding of findings. In this preregistered study, we investigated how people interpret a brief news report on a new drug for weight loss. Participants read an article that either highlighted the importance of prior research when judging the drug's effectiveness, or made no mention of this issue. For articles describing no prior research, mean confidence in the drug was 62%. For articles that noted prior research was conducted, confidence increased as the proportion of studies with positive findings increased. When prior research was highlighted, confidence decreased by a small amount, even when it should have increased (i.e., even when most of the evidence supported the drug's effectiveness). Thus, people's judgements were more sceptical, but not necessarily more accurate. Judgements were not affected by education level, statistics experience, or personal relevance of the research topic.

Maternal plasma cortisol's effect on offspring birth weight: a Mendelian Randomisation study.

BACKGROUND: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. METHODS: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. RESULTS: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. CONCLUSIONS: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

Identifying responders to elamipretide in Barth syndrome: Hierarchical clustering for time series data.

BACKGROUND: Barth syndrome (BTHS) is a rare genetic disease that is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities and often leads to death in childhood. Recently, elamipretide has been tested as a potential first disease-modifying drug. This study aimed to identify patients with BTHS who may respond to elamipretide, based on continuous physiological measurements acquired through wearable devices. RESULTS: Data from a randomized, double-blind, placebo-controlled crossover trial of 12 patients with BTHS were used, including physiological time series data measured using a wearable device (heart rate, respiratory rate, activity, and posture) and functional scores. The latter included the 6-minute walk test (6MWT), Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue score, SWAY Balance Mobile Application score (SWAY balance score), BTHS Symptom Assessment (BTHS-SA) Total Fatigue score, muscle strength by handheld dynamometry, 5 times sit-and-stand test (5XSST), and monolysocardiolipin to cardiolipin ratio (MLCL:CL). Groups were created through median split of the functional scores into "highest score" and "lowest score", and "best response to elamipretide" and "worst response to elamipretide". Agglomerative hierarchical clustering (AHC) models were implemented to assess whether physiological data could classify patients according to functional status and distinguish non-responders from responders to elamipretide. AHC models clustered patients according to their functional status with accuracies of 60-93%, with the greatest accuracies for 6MWT (93%), PROMIS (87%), and SWAY balance score (80%). Another set of AHC models clustered patients with respect to their response to treatment with elamipretide with perfect accuracy (all 100%). CONCLUSIONS: In this proof-of-concept study, we demonstrated that continuously acquired physiological measurements from wearable devices can be used to predict functional status and response to treatment among patients with BTHS.

Modification of the structural stability of human serum albumin in rheumatoid arthritis.

Differential scanning calorimetry (DSC) can indicate changes in structure and/or concentration of the most abundant proteins in a biological sample via heat denaturation curves (HDCs). In blood serum for example, HDC changes result from either concentration changes or altered thermal stabilities for 7-10 proteins and has previously been shown capable of differentiating between sick and healthy human subjects. Here, we compare HDCs and proteomic profiles of 50 patients experiencing joint-inflammatory symptoms, 27 of which were clinically diagnosed with rheumatoid arthritis (RA). The HDC of all 50 subjects appeared significantly different from expected healthy curves, but comparison of additional differences between the RA and the non-RA subjects allowed more specific understanding of RA samples. We used mass spectrometry (MS) to investigate the reasons behind the additional HDC changes observed in RA patients. The HDC differences do not appear to be directly related to differences in the concentrations of abundant serum proteins. Rather, the differences can be attributed to modified thermal stability of some fraction of the human serum albumin (HSA) proteins in the sample. By quantifying differences in the frequency of artificially induced post translational modifications (PTMs), we found that HSA in RA subjects had a much lower surface accessibility, indicating potential ligand or protein binding partners in certain regions that could explain the shift in HSA melting temperature in the RA HDCs. Several low abundance proteins were found to have significant changes in concentration in RA subjects and could be involved in or related to binding of HSA. Certain amino acid sites clusters were found to be less accessible in RA subjects, suggesting changes in HSA structure that may be related to changes in protein-protein interactions. These results all support a change in behavior of HSA which may give insight into mechanisms of RA pathology.

Rationed and satiated growth hormone transgenic Coho Salmon (Oncorhynchus kisutch) show tissue specific differences in energy stores.

Growth hormone transgenic coho salmon experience increased growth rates, driven primarily through elevated feed intake and feed conversion. However, neuropeptides that signal appetite stimulation have been shown to exhibit variable responses across fed states, suggesting a more complex system mediating growth in these fish. Studies have proposed that growth hormone may have a modulatory role on the energy reserves of fish, possibly through AMP-activated protein kinase (AMPK) activation. AMPK, an energy sensor in cells, has previously been shown to be upregulated in growth hormone transgenic salmon when compared to wild type, however, whether this effect is seen across fed states is unknown. Here, we tested the hypothesis that growth hormone induces an energetic deficit in metabolic tissues, leading to constitutive AMPK activation in growth hormone transgenic salmon. This study compared AMPK activity, ATP, and glycogen, of the liver, heart, and muscle of wild-type, and growth hormone transgenic salmon either fed to satiation or a wild-type ration. The results suggest that white muscle ATP levels in growth hormone salmon are elevated in satiation and rationed conditions. In the liver, growth hormone transgenic salmon fed a rationed wild-type diet experience reductions in ATP level and glycogen. In none of the tissues examined, did AMPK activity change. Taken together, these results indicate that growth hormone transgenic salmon experience metabolic duress when not fed to satiation.

Youth screen use in the ABCD® study.

Adolescent screen usage is ubiquitous and influences development and behavior. Longitudinal screen usage data coupled with psychometrically valid constructs of problematic behaviors can provide insights into these relationships. We describe methods by which the screen usage questionnaire was developed in the Adolescent Brain Cognitive Development (ABCD) Study, demonstrate longitudinal changes in screen usage via child report and describe data harmonization baseline-year 2. We further include psychometric analyses of adapted social media and video game addiction scales completed by youth. Nearly 12,000 children ages 9-10 years at baseline and their parents were included in the analyses. The social media addiction questionnaire (SMAQ) showed similar factor structure and item loadings across sex and race/ethnicities, but that item intercepts varied across both sex and race/ethnicity. The videogame addiction questionnaire (VGAQ) demonstrated the same configural, metric and scalar invariance across racial and ethnic groups, however differed across sex. Video gaming and online social activity increased over ages 9/10-11/12 (p's < 0.001). Compared with boys, girls engaged in greater social media use (p < .001) and demonstrated higher ratings on the SMAQ (p < .001). Compared with girls, boys played more video games (p < .001) and demonstrated higher ratings on the VGAQ (p < .001). Time spent playing video games increased more steeply for boys than girls from age 9/10-11/12 years (p < .001). Black youth demonstrated significantly higher SMAQ and VGAQ scores compared to all other racial/ethnic groups. These data show the importance of considering different screen modalities beyond total screen use and point towards clear demographic differences in use patterns. With these comprehensive data, ABCD is poised to address critical questions about screen usage changes across adolescence.

Climate resilience and the human-water dynamics. The case of tomato production in Morocco.

In Morocco, droughts are an increasing threat affecting water availability, agricultural production and producers' livelihoods. Moreover, water demand for irrigation has led to overexploitation of the groundwater table causing significant natural resource management challenges. The combination of groundwater changes and increasing drought risk raises concerns about the ability of agricultural producers to be resilient against drought. In this study, we describe the interactions of environmental and socioeconomic processes which influence farmers' livelihoods involved in tomato production in Morocco. Building on system dynamics modelling tools, we aim to improve the understanding of the long-term dynamic behavior of water management and to explore plausible policy scenarios necessary for sustainable and resilient water resource management and agricultural development. Our results show that tomato production is not yet severely impacted by droughts. However, droughts are accelerating the process of groundwater depletion, impacting farmers' livelihoods, by decreasing crop productivity and reducing farmer's revenue over a longer time period, especially since tomatoes are a high-value crop. Therefore, integrated and effective policies are presented as a set of measures for a systemic enhancement of resilience. We conclude that a more radical approach toward water resource conservation and upholding the most vulnerable producers has to be adopted in order to enhance a sustainable and inclusive resilience of the tomato production in Morocco.

First Leptophobic Dark Matter Search from the Coherent-CAPTAIN-Mills Liquid Argon Detector.

We report the first results of a search for leptophobic dark matter (DM) from the Coherent-CAPTAIN-Mills (CCM) liquid argon (LAr) detector. An engineering run with 120 photomultiplier tubes (PMTs) and 17.9×10^{20} protons on target (POT) was performed in fall 2019 to study the characteristics of the CCM detector. The operation of this 10-ton detector was strictly light based with a threshold of 50 keV and used coherent elastic scattering off argon nuclei to detect DM. Despite only 1.5 months of accumulated luminosity, contaminated LAr, and nonoptimized shielding, CCM's first engineering run has already achieved sensitivity to previously unexplored parameter space of light dark matter models with a baryonic vector portal. With an expected background of 115 005 events, we observe 115 005+16.5 events which is compatible with background expectations. For a benchmark mediator-to-DM mass ratio of m_{V_{B}}/m_{χ}=2.1, DM masses within the range 9 MeV≲m_{χ}≲50 MeV are excluded at 90% C. L. in the leptophobic model after applying the Feldman-Cousins test statistic. CCM's upgraded run with 200 PMTs, filtered LAr, improved shielding, and 10 times more POT will be able to exclude the remaining thermal relic density parameter space of this model, as well as probe new parameter space of other leptophobic DM models.

Effect of Lipoprotein Apheresis on Progression of Carotid Intima-Media Thickness in Patients with Severe Hypercholesterolemia.

The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular risk-reduction. We hypothesized that regular lipoprotein apheresis over the course of 10 years might slow down progression of CIMT in patients with severe hypercholesterolemia. This case series describes 10 Caucasian patients (mean age 60 ± 9 years, 70% female, 80% statin intolerant) with a severe hypercholesterolemia phenotype treated with lipoprotein apheresis between 2005 and 2020 (mean duration, 10 ± 4 years). The median pretreatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/100 ml (95% confidence interval, 145 to 248), lipoprotein(a) (Lp[a]), 26 mg/100 ml (15 to 109; 40% with Lp(a)>60 mg/100 ml). Three patients were diagnosed with a monogenic cause. The baseline mean CIMT was 850 ± 170 µm, and maximum CIMT was 1,040 ± 220 µm across the age range of 46 to 70 years. Acute effects of lipoprotein apheresis determined as a difference before and immediately after the procedure were estimated as a median of 72 ± 8% and 75 ± 7% reduction in the LDL-C and Lp(a) levels, respectively. Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and Lp(a) were 141 mg/100 ml (interquartile range, 89 to 152; 38% reduction from the baseline) and 24 mg/100 ml (interquartile range, 12 to 119; 19% reduction from baseline), respectively. The number of patients with CIMT above their "vascular age" decreased from 80% to 30% over the treatment course. In conclusion, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with lipoprotein apheresis with an estimated annual rate of change in mean common CIMT of -4 µm/y and maximum CIMT of -3 µm/y.

The antidepressant venlafaxine perturbs cardiac development and function in larval zebrafish.

Venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is a highly prescribed antidepressant and is detected at µg/L concentrations in waterways receiving municipal wastewater effluents. We previously showed that early-life venlafaxine exposure disrupted the normal development of the nervous system and reduces larval activity in zebrafish (Danio rerio). However, it is unclear whether the reduced swimming activity may be associated with impaired cardiac function. Here we tested the hypothesis that zygotic exposure to venlafaxine impacts the development and function of the larval zebrafish heart. Venlafaxine (0, 1 or 10 ng) was administered by microinjection into freshly fertilized zebrafish embryos (1-4 cell stage) to assess heart development and function during early-life stages. Venlafaxine deposition in the zygote led to precocious development of the embryo heart, including the timing of the first heartbeat, increased heart size, and a higher heart rate at 24- and 48-hours post-fertilization (hpf). Also, waterborne exposure to environmental levels of this antidepressant during early development increased the heart rate at 48 hpf of zebrafish larvae mimicking the zygotic deposition. The venlafaxine-induced higher heart rate in the embryos was abolished in the presence of NAN-190, an antagonist of the 5HT1A receptor. Also, heart rate dropped below control levels in the 10 ng, but not 1 ng venlafaxine group at 72 and 96 hpf. An acute stressor reduced the venlafaxine-induced heart rate at 48 hpf but did not affect the already reduced heart rate at 72 and 96 hpf in the 10 ng venlafaxine group. Our results suggest that the higher heart rate in the venlafaxine group may be due to an enhanced serotonin stimulation of the 5HT1A receptor. Taken together, early-life venlafaxine exposure disrupts cardiac development and has the potential to compromise the cardiovascular performance of larval zebrafish.

Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis.

OBJECTIVE: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). METHODS: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1ß (IL)-1ß for 24 or 48 h to investigate gene and protein expression. RESULTS: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1ß treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1ß, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1ß-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. CONCLUSIONS: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P < 0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose-response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence.

Acceptance of anomalous research findings: explaining treatment implausibility reduces belief in far-fetched results.

Research findings are best understood by considering contextual factors such as treatment plausibility: how likely it is that a studied treatment or manipulation is effective, based on theory and data. If a treatment is implausible, then more evidence should be required before believing it has an effect. The current study assessed the extent to which the interpretation of a research finding is affected by treatment plausibility. Participant age varied from 18 to 82 (M = 27.4, SD = 9.4), and about half of the participants (53%) were college students. A total of 600 participants read a brief news article about an experiment with a new type of psychotherapy for weight loss. The current study used a 2 (treatment plausibility) × 3 (results type) between-subjects factorial design. Treatment plausibility had two levels: (1) a plausible cognitive behavioral therapy and (2) an implausible "psychic reinforcement therapy" that was described as employing psychic messages to promote weight loss. The three levels of the results type factor varied how the study results were presented in the article: (1) standard results with no mention of treatment plausibility, (2) standard results followed by interpretive statements focused on treatment plausibility, and (3) no results-the study was described as still in progress. Participants rated their belief in the effectiveness of the therapy on a scale of 0 to 100% in 10% increments. When treatment plausibility was not discussed in the article, average ratings for the implausible therapy were relatively high (M = 63.1%, SD = 25.0, 95% CI% [58.2-68.1]) and similar to those for the plausible therapy (M = 69.2%, SD = 21.5, 95% CI% [65.0-73.5]). Ratings for the implausible treatment were moderately lower when the article explained why the results supporting it were questionable (M = 48.5%, SD = 26.6, 95% CI% [43.2-53.8]). The findings of the current study suggest that students and other members of the public may draw incorrect inferences from research partly because they do not appreciate the importance of treatment plausibility. This could be remedied, though not completely, by explicitly discussing the plausibility of the treatment based on theory and prior data.

Venlafaxine deposition in the zygote disrupts the endocrine control of growth in juvenile zebrafish.

The antidepressant venlafaxine can be found at levels nearing µg/L in waterways receiving municipal wastewater effluent, exposing non-target organisms, such as fish, to this chemical. We showed previously that zygotic exposure to venlafaxine alters neurodevelopment and behaviour in zebrafish (Danio rerio) larvae. Here, we tested the hypothesis that the zygotic deposition of venlafaxine disrupts endocrine pathways related to growth in zebrafish. This was carried out by microinjecting embryos (1-4 cell stage) with either 0, 1, or 10 ng venlafaxine. Zygotic venlafaxine deposition reduced the growth of fish after 30 days post-fertilization. Specific growth rate was particularly impacted by 1 ng venlafaxine. This growth retardation corresponded with the disruption of endocrine pathways involved in growth and metabolism. Venlafaxine exposed embryos displayed reduced transcript abundance of key genes involved in anabolic hormone action. Early-life venlafaxine exposure also reduced whole-body insulin and glucose content in juveniles. Target-tissue glucose uptake measurements indicated that high venlafaxine deposition preferentially increased glucose uptake to the brain. Zygotic venlafaxine did not affect feed intake nor altered the transcript abundance of key feeding-related peptides. Taken together, zygotic venlafaxine deposition compromises zebrafish growth by disrupting multiple endocrine pathways, and this study has identified key markers for potential use in risk assessment.

Suppression of cancer-associated bone loss through dynamic mechanical loading.

Patients afflicted with or being treated for cancer constitute a distinct and alarming subpopulation who exhibit elevated fracture risk and heightened susceptibility to developing secondary osteoporosis. Cancer cells uncouple the regulatory processes central for the adequate regulation of musculoskeletal tissue. Systemically taxing treatments to target tumors or disrupt the molecular elements driving tumor growth place considerable strain on recovery efforts. Skeletal tissue is inherently sensitive to mechanical forces, therefore attention to exercise and mechanical loading as non-pharmacological means to preserve bone during treatment and in post-treatment rehabilitative efforts have been topics of recent focus. This review discusses the dysregulation that cancers and the ensuing metabolic dysfunction that confer adverse effects on musculoskeletal tissues. Additionally, we describe foundational mechanotransduction pathways and the mechanisms by which they influence both musculoskeletal and cancerous cells. Functional and biological implications of mechanical loading at the tissue and cellular levels will be discussed, highlighting the current understanding in the field. Herein, in vitro, translational, and clinical data are summarized to consider the positive impact of exercise and low magnitude mechanical loading on tumor-bearing skeletal tissue.

Distinct Regionalization Patterns of Cortical Morphology are Associated with Cognitive Performance Across Different Domains.

Cognitive performance in children is predictive of academic and social outcomes; therefore, understanding neurobiological mechanisms underlying individual differences in cognition during development may be important for improving quality of life. The belief that a single, psychological construct underlies many cognitive processes is pervasive throughout society. However, it is unclear if there is a consistent neural substrate underlying many cognitive processes. Here, we show that a distributed configuration of cortical surface area and apparent thickness, when controlling for global imaging measures, is differentially associated with cognitive performance on different types of tasks in a large sample (N = 10 145) of 9-11-year-old children from the Adolescent Brain and Cognitive DevelopmentSM (ABCD) study. The minimal overlap in these regionalization patterns of association has implications for competing theories about developing intellectual functions. Surprisingly, not controlling for sociodemographic factors increased the similarity between these regionalization patterns. This highlights the importance of understanding the shared variance between sociodemographic factors, cognition and brain structure, particularly with a population-based sample such as ABCD.

The importance of evaluating specific myeloid malignancies in epidemiological studies of environmental carcinogens.

INTRODUCTION: Although myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN) - including chronic myeloid leukemia (CML) - and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are largely clinically distinct myeloid malignancies, epidemiological studies rarely examine them separately and often combine them with lymphoid malignancies, limiting possible etiological interpretations for specific myeloid malignancies. METHODS: We systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes "myeloid malignancies." Literature searches of IARC Monographs and PubMed identified 85 studies that we critically assessed, and for appropriate subsets, summarized results using meta-analysis. RESULTS: Only two epidemiological studies on 1,3-butadiene were identified, but reported findings were inadequate to evaluate specific myeloid malignancies. Studies on formaldehyde reported results for AML and CML - and not for MDS or MPN - but reported no increased risks. For benzene, several specific myeloid malignancies were evaluated, with consistent associations reported with AML and MDS and mixed results for CML. Studies of tobacco smoking examined all major myeloid malignancies, demonstrating consistent relationships with AML, MDS and MPN, but not with CML. CONCLUSIONS: Surprisingly few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. This exercise illustrates that even for agents classified as having sufficient evidence of causing "myeloid malignancies," the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent. Future epidemiological studies should report findings for the specific myeloid malignancies, as combining them post hoc - where appropriate - always remains possible, whereas disaggregation may not. Furthermore, combining results across possibly discrete diseases reduces the chances of identifying important malignancy-specific causal associations.

Do you hear what you see? Utilizing phonocardiography to enhance proficiency in cardiac auscultation.

INTRODUCTION: Cardiac auscultation skills have proven difficult to train and maintain. The authors investigated whether using phonocardiograms as visual adjuncts to audio cases improved first-year medical students' cardiac auscultation performance. METHODS: The authors randomized 135 first-year medical students using an email referral link in 2018 and 2019 to train using audio-only cases (audio group) or audio with phonocardiogram tracings (combined group). Training included 7 cases with normal and abnormal auscultation findings. The assessment included feature identification and diagnostic accuracy using 14 audio-only cases, 7 presented during training, and 7 alternate versions of the same diagnoses. The assessment-administered immediately after training and repeated 7 days later-prompted participants to identify the key features and diagnoses for 14 audio-only cases. Key feature scores and diagnostic accuracy were compared between groups using repeated measures ANOVA. RESULTS: Mean key feature scores were statistically significantly higher in the combined group (70%, 95% CI 67-75%) compared to the audio group (61%, 95% CI 56-66%) (F(1,116) = 6.144, p = 0.015, ds = 0.45). Similarly, mean diagnostic accuracy in the combined group (68%, 95% CI 62-73%) was significantly higher than the audio group, although with small effect size (59%, 95% CI 54-65%) (F(1,116) = 4.548, p = 0.035, ds = 0.40). Time on task for the assessment and prior auscultation experience did not significantly impact performance on either measure. DISCUSSION: The addition of phonocardiograms to supplement cardiac auscultation training improves diagnostic accuracy and heart sound feature identification amongst novice students compared to training with audio alone.

A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism.

PURPOSE: To evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane. METHODS: We performed a randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin. In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale. RESULTS: In part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters. CONCLUSION: In this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.

The discerning ear: cardiac auscultation in the era of artificial intelligence and telemedicine.

Heart murmur, a thoracic auscultatory finding of cardiovascular origin, is extremely common in childhood and can appear at any age from premature newborn to late adolescence. The objective of this review is to provide a modern examination and update of cardiac murmur auscultation in this new era of artificial intelligence (AI) and telemedicine. First, we provide a comprehensive review of the causes and differential diagnosis, clinical features, evaluation, and long-term management of paediatric heart murmurs. Next, we provide a brief history of computer-assisted auscultation and murmur analysis, along with insight into the engineering design of the digital stethoscope. We conclude with a discussion of the paradigm shifting impact of deep learning on murmur analysis, AI-assisted auscultation, and the implications of these technologies on telemedicine in paediatric cardiology. It is our hope that this article provides an updated perspective on the impact of AI on cardiac auscultation for the modern paediatric cardiologist.