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BackgroundPediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML.Methods/designChildren (age

ABSTRACTWe used Drosophila melanogaster to investigate how differences between Metarhizium species in growth rate and mechanisms of pathogenesis influence the outcome of infection. We found that the most rapid germinators and growers in vitro and on fly cuticle were the fastest killers, suggesting that pre-penetration competence is key to Metarhizium success. Virulent strains also induced the largest immune response, which did not depend on profuse growth within hosts as virulent toxin-producing strains only proliferated post-mortem while slow-killing strains that were specialized to other insects grew profusely pre-mortem. Metarhizium strains have apparently evolved resistance to widely distributed defenses such as the defensin Toll product drosomycin, but they were inhibited by Bomanins only found in Drosophila spp. Disrupting a gene (Dif), that mediates Toll immunity has little impact on the lethality of most Metarhizium strains (an exception being the early diverged M. frigidum and another insect pathogen Beauveria bassiana). However, disrupting the sensor of fungal proteases (Persephone) allowed rapid proliferation of strains within hosts (with the exception of M. album), and flies succumbed rapidly. Persephone also mediates gender differences in immune responses that determine whether male or female flies die sooner. We conclude that some strain differences in growth within hosts depend on immune-mediated interactions but intrinsic differences in pathogenic mechanisms are more important. Thus, Drosophila varies greatly in tolerance to different Metarhizium strains, in part because some of them produce toxins. Our results further develop D. melanogaster as a tractable model system for understanding insect-Metarhizium interactions.

We investigated genome folding across the eukaryotic tree of life. We find two types of three-dimensional (3D) genome architectures at the chromosome scale. Each type appears and disappears repeatedly during eukaryotic evolution. The type of genome architecture that an organism exhibits correlates with the absence of condensin II subunits. Moreover, condensin II depletion converts the architecture of the human genome to a state resembling that seen in organisms such as fungi or mosquitoes. In this state, centromeres cluster together at nucleoli, and heterochromatin domains merge. We propose a physical model in which lengthwise compaction of chromosomes by condensin II during mitosis determines chromosome-scale genome architecture, with effects that are retained during the subsequent interphase. This mechanism likely has been conserved since the last common ancestor of all eukaryotes.

Abstract Analyses of the factors shaping genetic variation in widespread plant species are important for understanding the evolutionary history and local adaptation and have applied significance for guiding conservation and restoration decisions. Thurber's needlegrass (Achnatherum thurberianum) is a widespread, locally abundant grass that inhabits heterogeneous arid environments of western North America and is of restoration significance. It is a common component of shrubland steppe communities in the Great Basin Desert, where drought, fire, and invasive grasses have degraded natural communities. Using a reduced representation sequencing approach, we generated SNP data at 5677 loci across 246 individuals from 17 A. thurberianum populations spanning five previously delineated seed zones from the western Great Basin. Analyses revealed a pronounced population genetic structure, with individuals forming consistent geographical clusters across a variety of population genetic analyses and spatial scales. Low levels of genetic diversity within populations, as well as high population estimates of linkage disequilibrium and relatedness, were consistent with self‐fertilization as a contributor to population differentiation. Variance partitioning and partial redundancy analysis (pRDA) indicated local adaptation to environment as additionally influencing the spatial distribution of genetic variation. The environmental variables driving these results were similar to those implicated in recent genecological work which inferred local adaptation for seed zone delineation. Our analyses also revealed a complex evolutionary history of A. thurberianum in the Great Basin, where previously delineated seed zones contain distantly related populations. Our results indicate evolutionary history, mating system, and differentiation across distinct geographic and environmental scales have shaped genetic variation in A. thurberianum and illustrate how numerous aspects of population genetic variation might require consideration for restoration planning.

Abstract Clinically relevant postoperative pancreatic fistula (CR-POPF) can significantly affect the treatment course and outcome in pancreatic cancer patients. Preoperative prediction of CR-POPF can aid the surgical decision-making process and lead to better perioperative management of patients. In this retrospective study of 108 pancreatic head resection patients, we present risk models for the prediction of CR-POPF that use combinations of preoperative computed tomography (CT)-based radiomic features, mesh-based volumes of annotated intra- and peripancreatic structures and preoperative clinical data. The risk signatures were evaluated and analysed in detail by visualising feature expression maps and by comparing significant features to the established CR-POPF risk measures. Out of the risk models that were developed in this study, the combined radiomic and clinical signature performed best with an average area under receiver operating characteristic curve (AUC) of 0.86 and a balanced accuracy score of 0.76 on validation data. The following pre-operative features showed significant correlation with outcome in this signature ( $$p < 0.05$$ p < 0.05 ) - texture and morphology of the healthy pancreatic segment, intensity volume histogram-based feature of the pancreatic duct segment, morphology of the combined segment, and BMI. The predictions of this pre-operative signature showed strong correlation (Spearman correlation co-efficient, $$\rho = 0.7$$ ρ = 0.7 ) with the intraoperative updated alternative fistula risk score (ua-FRS), which is the clinical gold standard for intraoperative CR-POPF risk stratification. These results indicate that the proposed combined radiomic and clinical signature developed solely based on preoperatively available clinical and routine imaging data can perform on par with the current state-of-the-art intraoperative models for CR-POPF risk stratification.

Abstract We found that Drosophila species vary in their susceptibility to the broad-spectrum entomopathogen, Metarhizium anisopliae (strain Ma549). Generalist species were generally more resistant than dietary specialists, with the cactophilic Drosophila buzzatii and Drosophila sechellia, a specialist of the Morinda citrifolia (Morinda) fruit, being most susceptible. Morinda fruit is reported to be toxic to most herbivores because it contains Octanoic Acid (OA). We confirmed that OA is toxic to Drosophila spp., other than D. sechellia, and we also found that OA is highly toxic to entomopathogenic fungi including Ma549 and Beauveria bassiana. Drosophila sechellia fed a diet containing OA, even at levels much less than found in Morinda fruit, had greatly reduced susceptibility to Ma549. This suggests that specializing to Morinda may have provided an enemy-free space, reducing adaptive prioritization on a strong immune response. Our results demonstrate that M. anisopliae and Drosophila species with divergent lifestyles provide a versatile model system for understanding the mechanisms of host–pathogen interactions at different scales and in environmental context.

Abstract We present pycoMeth, a toolbox to store, manage and analyze DNA methylation calls from long-read sequencing data obtained using the Oxford Nanopore Technologies sequencing platform. Building on a novel, rapid-access, read-level and reference-anchored methylation storage format MetH5, we propose efficient algorithms for haplotype aware, multi-sample consensus segmentation and differential methylation testing. We show that MetH5 is more efficient than existing solutions for storing Oxford Nanopore Technologies methylation calls, and carry out benchmarking for pycoMeth segmentation and differential methylation testing, demonstrating increased performance and sensitivity compared to existing solutions designed for short-read methylation data.

Abstract Background A ketogenic diet (KD) reduces daily carbohydrates (CHOs) ingestion by replacing most calories with fat. KD is of increasing interest among athletes because it may increase their maximal oxygen uptake (VO2max), the principal performance limitation at high-altitudes (1500–3500 m). We examined the tolerance of a 4-week isocaloric KD (ICKD) under simulated hypoxia and the possibility of evaluating ICKD performance benefits with a maximal graded exercise bike test under hypoxia and collected data on the effect of the diet on performance markers and arterial blood gases. Methods In a randomised single-blind cross-over model, 6 recreational mountaineers (age 24–44 years) completed a 4-week ICKD followed or preceded by a 4-week usual mixed Western-style diet (UD). Performance parameters (VO2max, lactate threshold [LT], peak power [Ppeak]) and arterial blood gases (PaO2, PaCO2, pH, HCO3 −) were measured at baseline under two conditions (normoxia and hypoxia) as well as after a 4-week UD and 4-week ICKD under the hypoxic condition. Results We analysed data for all 6 participants (BMI 19.9–24.6 kg m−2). Mean VO2max in the normoxic condition was 44.6 ml kg−1 min−1. Hypoxia led to decreased performance in all participants. With the ICKD diet, median values for PaO2 decreased by − 14.5% and VO2max by + 7.3% and Ppeak by + 4.7%. Conclusion All participants except one could complete the ICKD. VO2max improved with the ICKD under the hypoxia condition. Therefore, an ICKD is an interesting alternative to CHOs dependency for endurance performance at high-altitudes, including high-altitude training and high-altitude races. Nevertheless, decreased PaO2 with ICKD remains a significant limitation in very-high to extreme altitudes (> 3500 m). Trial registration Clinical trial registration Nr. NCT05603689 (Clinicaltrials.gov). Ethics approval CER-VD, trial Nr. 2020-00427, registered 18.08.2020—prospectively registered.

Objective: Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to co mpare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates. Design: Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019. Methods: Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses. Results: Thirty-five patients were included. A significantly higher incre ase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)). Conclusions: Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferati on, and testicular descent, with both treatment modalities.

Abstract Aim To examine the association between breastfeeding self‐efficacy (BSE) and breastmilk feeding at discharge from the neonatal intensive care unit among mothers of preterm infants. Design Secondary analysis of the Family Integrated Care (FICare) cluster randomized controlled trial. Methods Data from 221 mothers of preterm infants who participated in the standard care group of the trial were analysed. BSE at admission was assessed using the modified Breastfeeding Self‐Efficacy Scale–Short Form (BSES‐SF). Breastmilk feeding was assessed using 24 hr maternal recall at discharge. Results Mothers who were exclusively breastmilk feeing their infants at discharge had statistically significantly higher mean BSES‐SF scores at admission (68.4, SD = 13.7) than those providing a combination of breastmilk and formula or only formula (59.6, SD = 14.7; p

Abstract Background We determined direct medical costs, overhead costs, societal costs, and personnel requirements for the provision of antiretroviral therapy (ART) to patients with AIDS in Haiti. Methods We examined data from 218 treatment-naïve adults who were consecutively initiated on ART at the GHESKIO Center in Port-au-Prince, Haiti between December 23, 2003 and May 20, 2004 and calculated costs and personnel requirements for the first year of ART. Results The mean total cost of treatment per patient was $US 982 including $US 846 in direct costs, $US 114 for overhead, and $US 22 for societal costs. The direct cost per patient included generic ART medications $US 355, lab tests $US 130, nutrition $US 117, hospitalizations $US 62, pre-ART evaluation $US 58, labor $US 51, non-ART medications $US 39, outside referrals $US 31, and telephone cards for patient retention $US 3. Higher treatment costs were associated with hospitalization, change in ART regimen, TB treatment, and survival for one year. We estimate that 1.5 doctors and 2.5 nurses are required to treat 1000 patients in the first year after initiating ART. Conclusion Initial ART treatment in Haiti costs approximately $US 1,000 per patient per year. With generic first-line antiretroviral drugs, only 36% of the cost is for medications. Patients who change regimens are significantly more expensive to treat, highlighting the need for less-expensive second-line drugs. There may be sufficient health care personnel to treat all HIV-infected patients in urban areas of Haiti, but not in rural areas. New models of HIV care are needed for rural areas using assistant medical officers and community health workers.

Objectives: To test whether older adults' pain was bidirectionally associated with nighttime sleep disturbances and whether daily positive encounters attenuated these associations. Methods: Participants (N = 292, mean = 73.71 years old) from the Daily Experiences and Well-being Study indicated pain and positive encounters with close partners (e.g., family and friends) and nonclose partners (e.g., acquaintances and service providers) every 3 hours throughout each day across 4-6 days. They also reported nighttime sleep disturbances the following morning. Results: Multilevel models revealed that participants with more prior nighttime sleep disturbances reported more severe pain the next day. This link was attenuated on days when participants had a greater proportion of positive encounters or viewed encounters as more pleasant, especially when these encounters occurred with close partners. Discussion: This study identifies benefits of positive encounters to older adults and sheds light on ways that may alleviate their pain from a social perspective.

The prevalence of telogen effluvium (TE) has increased during COVID-19. In this study we describe the clinical characteristics of patients with COVID-19-related TE and review the current literature on COVID-19-associated TE. We conducted a retrospective chart review of 66 patients, all of which had COVID-19 infection (confirmed by PCR or antibodies) and had either non-scarring hair loss or TE in Elmhurst, Queens. Our data suggest that this form of TE is similar to other forms of TE, after which many patients experience regrowth within several months.

A vast majority of social science students experience statistics anxiety in their statistics class, a course often perceived as the most difficult one of their academic paths. The present study examines the role of attitudes towards statistics, cognitive emotion regulation strategies, and satisfaction of psychological needs in the prediction of statistics anxiety as well as the contribution of gender onto statistics anxiety. Two hundred forty-two undergraduate social sciences students in Canada completed the study. Positive attitude towards statistics, fewer maladaptive emotion regulation strategies, and satisfaction of psychological needs were related to less statistics anxiety; adaptive emotion regulation strategies, however, were not. Furthermore, women experienced more statistics anxiety than men. Results provide insight about individual differences that may impact experiences of statistics anxiety and overall learning in the context of a statistics course.

The Quantum Instrumentation Control Kit (QICK) is a standalone open-source qubit controller that was first introduced in 2022. In this follow-up work, we present recent upgrades to the QICK and the experimental use cases they uniquely enabled for superconducting qubit systems. These include multiplexed signal generation and readout, mixer-free readout, predistorted fast flux pulses, and phase-coherent pulses for parametric operations, including high-fidelity parametric entangling gates. We explain in detail how the QICK was used to enable these experiments.

Over the past 20 years, interest in the impact of space on teaching and learning has grown, and higher education institutions have responded by creating Active Learning Classrooms (ALCs)--spaces designed to promote active, student-centred learning. While ALC research has explored teaching methods, student experience, and student learning, less is known about how teaching in these spaces affects instructors. We contribute to this discussion by investigating teachers' educational development in these spaces. We asked new instructors to reflect on their ALC experiences, exploring their pre-course preparation and their perceptions about themselves, their students, and teaching and learning. Their reflections revealed key differences between knowing and learning: Although all participants knew about and were dedicated to student-centred pedagogy before teaching in the ALCs, teaching in these spaces prompted transformative learning through which they shifted both their behaviours and perceptions about student learning and about their own roles in the classroom.

IntroductionInjectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer.MethodsRelugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT.ResultsBetween July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively.DiscussionRelugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix’s potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations.

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain’s response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.

Whole Person Care (WPC) is an emerging framework that emphasises the clinician’s role in empowering patient healing. However, reliably translating a framework’s theory into practice is a recognised challenge for clinicians. Observational studies have revealed discrepancies between a clinician’s stated values in theory and how these may be implemented in practice. The aim of this qualitative study is to bridge the gap between the theory of WPC and its practical implementation by clinicians. We interviewed a diverse group of 34 clinicians attending the 2017 International Whole Person Care Congress to explore (1) their conceptions of WPC in theory as well as (2) how they monitor their practice in real time. Data were analysed using Grounded Theory Methodology. Preliminary results were presented in the form of a workshop at the 2019 International Whole Person Care Congress to validate our findings with relevant stakeholders. The results revealed a vision of WPC that highlighted themes of the clinician’s way of being, seeing the person beyond the disease, and the clinician–patient relationship. Our results demonstrate that clinicians use a range of strategies to monitor their practice in real time. Mindfulness and self-awareness were frequently cited as being crucial to this ability of self-regulating their practice. This study helps establish a unifying framework of WPC based on a diverse range of clinician-reported experiences. More importantly, it sheds light on the range of strategies employed by clinicians who monitor their practice in real time. These collected insights will be of interest to any clinician interested in translating their stated values into their clinical practice more reliably.

RATIONALE: Work is a common source of stress for many adults, arising from situations that occur at work (e.g., job demands) as well as the worries and responsibilities that people take home with them (negative work-family spillover). Over time, work-related stress may impact physical health. OBJECTIVE: The current study prospectively examined the effects of job demands and negative work-family spillover (NWFS) on three self-reported physical health measures. METHOD: Participants in the Midlife in the United States (MIDUS) survey (N = 4200) reported their job demands and negative work-family spillover at wave 1. They also reported on their health across three waves of data collection. RESULTS: Higher levels of NWFS at baseline were related to a higher number of self-reported chronic illnesses, greater functional limitation, and poorer self-rated health approximately 10 and 20 years later. In contrast, job demands were unrelated to any health indices at baseline or at the approximately 10- and 20-year follow-ups. CONCLUSIONS: Findings suggest that NWFS is a unique form of stress with long-lasting and detrimental effects on physical health.

Recent declines of wild pollinators and infections in honey, bumble and other bee species have raised concerns about pathogen spillover from managed honey and bumble bees to other pollinators. Parasites of honey and bumble bees include trypanosomatids and microsporidia that often exhibit low host specificity, suggesting potential for spillover to co-occurring bees via shared floral resources. However, experimental tests of trypanosomatid and microsporidial cross-infectivity outside of managed honey and bumble bees are scarce. To characterize potential cross-infectivity of honey and bumble bee-associated parasites, we inoculated three trypanosomatids and one microsporidian into five potential hosts - including four managed species - from the apid, halictid and megachilid bee families. We found evidence of cross-infection by the trypanosomatids Crithidia bombi and C. mellificae, with evidence for replication in 3/5 and 3/4 host species, respectively. These include the first reports of experimental C. bombi infection in Megachile rotundata and Osmia lignaria, and C. mellificae infection in O. lignaria and Halictus ligatus. Although inability to control amounts inoculated in O. lignaria and H. ligatus hindered estimates of parasite replication, our findings suggest a broad host range in these trypanosomatids, and underscore the need to quantify disease-mediated threats of managed social bees to sympatric pollinators.

The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C-C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C-C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C-C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.

The brain-gut-microbiome axis is an emerging area of study, particularly in vertebrate systems. Existing evidence suggests that gut microbes can influence basic physiological functions and that perturbations to the gut microbiome can have deleterious effects on cognition and lead to neurodevelopmental disorders. While this relationship has been extensively studied in vertebrate systems, little is known about this relationship in insects. We hypothesized that because of its importance in bee health, the gut microbiota influences learning and memory in adult bumble bees. As an initial test of whether there is a brain-gut-microbiome axis in bumble bees, we reared microbe-inoculated and microbe-depleted bees from commercial Bombus impatiens colonies. We then conditioned experimental bees to associate a sucrose reward with a color and tested their ability to learn and remember the rewarding color. We found no difference between microbe-inoculated and microbe-depleted bumble bees in performance during the behavioral assay. While these results suggest that the brain-gut-microbiome axis is not evident in Bombus impatiens, future studies with different invertebrate systems are needed to further investigate this phenomenon.