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Mullite-glass composites were obtained by solid-state reactive sintering of kaolinite clay and kaolin waste mixtures with waste additions up to 100 wt%. The structural and microstructural analysis of starting powders and sintered samples were evaluated by X-ray diffractometry (XRD) and field-emission scanning electron microscopy (FESEM). The mechanical properties were evaluated by measuring the flexural strength of sintered bodies. Electrical properties of the composites were assessed by impedance spectroscopy (at 30 °C and from 400 to 700 °C) in air. A viscous flux mechanism resulting from the glassy phase filled up the open porosity and increased the mechanical strength. Electrical conductivity, dielectric constant and dielectric loss were strongly dependent on the microstructural features, namely glassy phase and porosity. The activation energies (0.89–0.99 eV) for electrical conduction were lower than typical literature values of mullite-based materials. The results indicated that the herein synthesized mullite-glass composites with up to 53.6 wt% mullite are promising low-cost materials for electronics-related applications. • Mullite-glass composites from kaolin waste-based formulations. • Effect of microstructure on properties of mullite-glass composites. • Electrical and dielectric properties by impedance spectroscopy. • Low-cost material for electronics-related applications. [ABSTRACT FROM AUTHOR]

The United Kingdom Childhood Cancer Study (UKCCS) is a national multi-centre case - control study that was designed to evaluate the potential aetiological role of prenatal events in childhood cancer. The obstetric records of 2692 mothers of children diagnosed with cancer and 4864 mothers of children without cancer were available for analysis. Overall, 1754 (65%) case mothers and 3220 (66%) control mothers had at least one prior pregnancy before the birth of the index child. Of these, 12 (0.68%) of the former and 9 (0.28%) of the latter had a prior molar pregnancy (odds ratio 2.5, 95% confidence interval 1.1 - 6.1). Both childhood cancer and molar pregnancy are rare neoplastic events, and the numbers are small. Nonetheless, whilst the associations were strongest for common precursor B-cell acute lymphoblastic leukaemia (OR 5.2, 95% CI 1.9 - 14.7) and sarcoma (OR 6.2, 95% CI 1.3 - 30.3), the spread across the remaining diagnostic groups suggests that the relationship, if confirmed, may be of a generalized, rather than specific, type.This is the first time that an association between childhood cancer and hydatidiform mole has been reported. The UKCCS's systematic use of clinical records permitted a more precise characterization of reproductive events than is possible in investigations that rely on individuals own accounts, and we are confident that our findings cannot be explained by recall bias or other methodological limitations. Accordingly, we suggest that there may be an aetiologic connection between molar pregnancy and childhood cancer, and speculate here on the various genetic/epigenetic mechanisms that could be involved. [ABSTRACT FROM AUTHOR]

Sickle Cell Disease (SCD) carries a significant risk for poor vascular health and vascular dysfunction. High levels of vascular reactive oxygen species (ROS) as well as elevated plasma endothelin-1 (ET-1), a potent vasoconstrictor with actions via the ETA receptor, are both common phenotypes in SCD. Alpha-1 adrenergic receptor activation is a major mediator of stress-induced vasoconstriction. However, the mechanism of the SCD enhanced vasoconstrictive response is unknown.  We hypothesized that SCD induces enhanced alpha-1 adrenergic mediated vasoconstriction through the ET-1/ETA receptor pathway in arterial tissues. Utilizing humanized SCD (HbSS) and genetic control (HbAA) mice, alpha-1a, but not alpha-1b or alpha-1d, receptor expression was significantly greater in aortic tissue from HbSS mice compared to HbAA mice. Significantly enhanced vasoconstriction in aortic and carotid arterial segments were observed from HbSS mice compared to HbAA mice. Treatment with ambrisentan, a selective ETA receptor antagonist, and a ROS scavenger normalized the aortic vasoconstrictive response in HbSS mice. In a randomized translational study, patients with SCD were treated with placebo or ambrisentan for 3 months, with the treatment group showing an increase in the percent brachial arterial diameter. Taken together, these data suggest that the ETA receptor pathway interaction with the adrenergic receptor pathway contributes to enhanced aortic vasoconstriction in SCD. Findings indicate the potential of ETA antagonism as a therapeutic avenue for improving vascular health in SCD., (Copyright 2024 The Author(s).)

In medicine, difficulty integrating work and home can lead to decreased job satisfaction, diminished well-being, and increased turnover. Understanding the experience of pediatric hospitalists can provide insights into building a stable, long-term workforce. We aim to examine gender differences in work-life balance and parental leave for physicians practicing Pediatric Hospital Medicine., Methods: This was a cross-sectional survey study of 1096 pediatric hospitalists. Responses were collected via an online survey platform and summarized using descriptive statistics, including frequency distributions and measures of central tendency. A multivariable logistic regression was used to examine associated variables and work-life balance satisfaction. We analyzed free responses on parental leave to provide nuance to quantitative survey data., Results: Five hundred and sixty-five respondents (52% response rate) completed the survey with 71% women. 343 (62%) prioritize work-life balance in career decision-making. Women report taking on more household responsibilities than their partners (41.4% vs. 8.4%; p < .001) including a larger percentage of caregiving and domestic tasks. Female gender and performing <50% caregiving were associated with decreased work-life balance satisfaction; performing <50% domestic tasks increased satisfaction. Median parental leaves were 4 weeks, with men taking significantly shorter leaves (3.5 vs. 6 weeks; p < .001) and more "paid back" time off., Conclusion: Work-life balance is an important factor in career decisions for men and women. Women perceive carrying a larger load at home. Qualitative results suggest that parental leave may be inadequate in length and salary support for men and women. This study adds insights into work-life integration in PHM., (© 2024 Society of Hospital Medicine.)

Background and Objectives: Clinical practice guidelines (CPGs) have significantly influenced medical practice worldwide. Nevertheless, the authorship of CPGs produced by several medical societies has not been representative of the field and population they address, as women and individuals from racial and ethnic minority groups have been underrepresented as authors. We hypothesized that women and individuals from minoritized racial and ethnic groups would also be underrepresented as authors of CPGs produced by the American Academy of Pediatrics (AAP). Methods: In this cross-sectional study, the gender, race, and ethnic composition of authors and subcommittee participants of AAP-produced CPGs published from January 2010 through May 2023 were analyzed and compared to the 2010 and 2021 U.S. population and 2010 and 2022 U.S. medical school pediatric faculty. Results: Women (39.7%, 127/320 of all positions, and 42.5%, 85/200 of named author positions) and women physicians (35.2%, 101/287 of all positions, and 36.4%, 64/176 of named author positions) were significantly underrepresented-while men and men physicians were significantly overrepresented-from their respective composition in the U.S. Census and pediatric faculty. Women and women physicians from all racial and ethnic groups and men and men physicians from minority racial and ethnic groups were significantly underrepresented-from their respective composition in the U.S. Census and pediatric faculty. No Black man was identified as an author. Conclusions: Medical societies that produce CPGs should be cognizant of these inequities and ensure appropriate authorship diversity.

Objectives: Gender-based disparities in salary exist in multiple fields of medicine. However, there is limited data examining gender inequities in salary in pediatric hospital medicine (PHM). Our primary objective was to assess whether gender-based salary differences exist in PHM. The secondary objective was to assess if, among women, the differences in salary varied on the basis of leadership positions or self-identified race and ethnicity., Methods: We conducted a survey-based, cross-sectional study of pediatric hospitalists in December 2021. Our primary outcomes were base and total salary, adjusted for the reported number of average weekly work hours. We performed subanalyses by presence of a leadership position, as well as race. We used a weighted t test using inverse probability weighting to compare the outcomes between genders., Results: A total of 559 eligible people responded to our survey (51.0%). After propensity score weighting, women's mean base salary was 87.7% of men's base (95% confidence interval [CI] 79.8%-96.4%, P < .01), and women's total salary was 85.6% of men's total (95% CI 73.2%-100.0%, P = .05) salary. On subgroup analysis of respondents with a leadership position, women's total salary was 80.6% of men's total salary (95% CI 68.7%-94.4%, P < .01). Although women who identified as white had base salaries that were 86.6% of white men's base salary (95% CI 78.5%-95.5%, P < .01), there was no gender-based difference noted between respondents that identified as nonwhite (88.4% [69.9%-111.7%] for base salary, 80.3% [57.2% to 112.7%])., Conclusions: Gender-based discrepancies in salary exists in PHM, which were increased among those with leadership roles. Continued work and advocacy are required to achieve salary equity within PHM., (Copyright © 2024 by the American Academy of Pediatrics.)

Background and Objectives: Gender-based communication differences are described in educational online communities, but have not been rigorously evaluated in medical online communities. Understanding gender differences in communication may provide insight into gender disparities in the medical profession. Our objective was to describe gender differences in post frequency, content, and language styles on the American Academy of Pediatrics Section on Hospital Medicine (SOHM) listserv., Methods: Posts were obtained from publicly available SOHM listserv archives. The first month of every quarter of 2019 and 2020 were reviewed. Two reviewers assigned a post topic (clinical, research, etc) and format (question vs statement) to all deidentified original posts (K = 1.0 topic, 0.89 format). Six trained reviewers assigned language styles (intraclass coefficient = 0.73, indicating good agreement)., Results: We analyzed 1592 posts: 287 original posts and 1305 responses. Frequency: Women authored 50% of posts. The 9 most frequent posters (7 men, 2 women) accounted for 19.5% of posts. Content: Men's posts had more words than women's (132.51 vs 112.3, P ≤ .01). Men were more likely to post about health policy and research (P < .001). Men were more likely to post statements compared with women (39% vs 21%, P < .001). Style: Men's posts were more likely to be coded adversarial (12.3% vs 5.5%, P < .001) authoritative (12.2% vs 6.5%, P < .001) or self-amplifying (6.5% vs 3.6%, P < .001)., Conclusions: Women contribute disproportionately fewer posts to the American Academy of Pediatrics SOHM listserv compared with their percentage in the subspecialty. We noted significant gender differences in language style and content, which may impact career development and online community inclusion., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: To describe the clinical course of children with positive urine cultures without pyuria who were not given antibiotics initially, identify predictors of subsequent antibiotic treatment, and evaluate the association between subsequent treatment and urinary tract infection (UTI) within 30 days., Methods: We conducted a multicenter retrospective cohort study of children 1 to 24 months old who had positive urine cultures without pyuria and who were not started on antibiotics upon presentation to 3 health care systems from 2010 to 2021. Outcomes included clinical status at the time urine cultures resulted, escalation of care (emergency department visit or hospitalization) and subsequent antibiotic treatment within 7 days, and subsequent UTI within 30 days of presentation., Results: Of 202 included children, 61% were female and median age was 9 months. Of 151 patients with clinical status information when cultures resulted, 107 (70.8%, 95% confidence interval [CI] 62.9-77.9%) were improved. Two of 202 children (1.0%, 95% CI 0.2-4.0%) experienced care escalation. Antibiotics were started in 142 (82.2%) children, and treatment was associated with prior UTI (risk ratio [RR] 1.20, 95% CI 1.15-1.26) and lack of improvement (RR 1.22, 95% CI 1.13-1.33). Subsequent UTI was diagnosed in 2 of 164 (1.2%, 95% CI 0.1-4.3%) treated and 0 of 36 (0%, 95% CI 0-9.7%) untreated children., Conclusions: Seventy percent of children with positive urine cultures without pyuria improved before starting antibiotics; however, >80% were ultimately treated. Future research should study the impact of diagnostic stewardship interventions and various urine testing strategies to optimize the management of children evaluated for UTI.retain-->., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Abundant disparities for women in medicine contribute to many women physicians considering leaving medicine. There is a strong financial and ethical case for leaders in academic medicine to focus on strategies to improve retention. This article focuses on five immediate actions that leaders can take to enhance gender equity and improve career satisfaction for all members of the workplace., (©Jessica M Allan, Amber K Brooks, Cindy Crusto, Lauren D Feld, Amy S Oxentenko, Nancy D Spector, Monica Verduzco-Gutierrez, Julie K Silver. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.06.2023.)

Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients. Germline whole-exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR-CPS patients compared to 0 of 9 low-risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t-MN patients most likely to benefit from genetic testing for inherited CPS., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukemia (AML), by tracking several features ionizing from only 2500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screen showed that the BCR-ABL inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses. In order to identify the cellular (off-)targets of nilotinib, we performed thermal proteome profiling (TPP). Unlike imatinib, nilotinib and other later-generation BCR-ABL inhibitors bind to p38α and inhibit the p38α-MK2/3 signaling axis, which suppressed pro-inflammatory cytokine expression, cell adhesion, and innate immunity markers in activated monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Our specific aim was to assess the gender distribution of aspects of scholarly productivity and professional standing for pediatric hospital medicine over a 5-year period. We also evaluated for correlation between the makeup of editorial boards, conference planning committees, and chosen content., Methods: We reviewed scholarly publications, presentations, editorial boards, planning committees, awardees, and society leadership in pediatric hospital medicine from 2015 to 2019 and determined gender using published methods to assess for differences between observed proportions of women authors and presenters and the proportion of women in the field., Results: The field of pediatric hospital medicine at large is 69% women (95% confidence internal [CI] 68%-71%), and an estimated 57% of senior members are women (95% CI 54%-60%). We evaluated 570 original science manuscripts and found 67% (95% CI 63%-71%) women first authors and 49% (95% CI 44%-53%) women senior authors. We evaluated 1093 presentations at national conferences and found 69% (95% CI 65%-72%) women presenters of submitted content and 44% (95% CI 37%-51%) women presenters of invited content. Senior authorship and invited speaking engagements demonstrated disproportionately low representation of women when compared with senior members of the field (senior authorship, P = .002; invited presenters, P < .001). Strong positive correlation between gender composition of conference planning committees and selected content was also noted (r = 0.94)., Conclusion: Our study demonstrated representative gender distribution for some aspects of scholarly productivity in pediatric hospital medicine; however, a lack of gender parity exists in senior roles., Competing Interests: CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., (© 2021. The Author(s).)

The liver plays a central role that influences cardiovascular disease outcomes through regulation of glucose and lipid metabolism. It is recognized that the local liver molecular clock regulates some liver-derived metabolites. However, it is unknown whether the liver clock may impact cardiovascular function. Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue surrounding blood vessels. Importantly, cross talk between the endothelium and PVAT via vasoactive factors is critical for vascular function. Therefore, we designed studies to test the hypothesis that cardiovascular function, including PVAT function, is impaired in mice with liver-specific circadian clock disruption. Bmal1 is a core circadian clock gene, thus studies were undertaken in male hepatocyte-specific Bmal1 knockout (HBK) mice and littermate controls (i.e., flox mice). HBK mice showed significantly elevated plasma levels of β-hydroxybutyrate, nonesterified fatty acids/free fatty acids, triglycerides, and insulin-like growth factor 1 compared with flox mice. Thoracic aorta PVAT in HBK mice had increased mRNA expression of several key regulatory and metabolic genes, Ppargc1a , Pparg , Adipoq , Lpl , and Ucp1 , suggesting altered PVAT energy metabolism and thermogenesis. Sensitivity to acetylcholine-induced vasorelaxation was significantly decreased in the aortae of HBK mice with PVAT attached compared with aortae of HBK mice with PVAT removed, however, aortic vasorelaxation in flox mice showed no differences with or without attached PVAT. HBK mice had a significantly lower systolic blood pressure during the inactive period of the day. These new findings establish a novel role of the liver circadian clock in regulating PVAT metabolic gene expression and PVAT-mediated aortic vascular function.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10 -9 ) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10 -8 ), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.

Pediatric Hospital Medicine (PHM), a field early in its development and with a robust pipeline of women, is in a unique position to lead the way in gender equity. We describe the proportion of women in divisional and fellowship leadership positions at university-based PHM programs (n = 142). When compared with the PHM field at large, women appear to be underrepresented as PHM division/program leaders (70% vs 55%; P< .001) but not as fellowship directors (70% vs 66%; P > .05). Women appear proportionally represented in associate/assistant leadership roles when compared with the distribution of the PHM field at large. Tracking these trends overtime is essential to advancing the field.

We demonstrated the sustained impact over a 5-year period of a clinical examination-based approach to identification of early-onset sepsis in late preterm and term neonates at our hospital. To date, more than 20 000 neonates have been safely managed using this approach, resulting in a 63% reduction in antibiotic use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.

Background The novel estrogen receptor, G-protein-coupled estrogen receptor (GPER), is responsible for rapid estrogen signaling. GPER activation elicits cardiovascular and nephroprotective effects against salt-induced complications, yet there is no direct evidence for GPER control of renal Na + handling. We hypothesized that GPER activation in the renal medulla facilitates Na + excretion. Methods and Results Herein, we show that infusion of the GPER agonist, G1, to the renal medulla increased Na + excretion in female Sprague Dawley rats, but not male rats. We found that GPER mRNA expression and protein abundance were markedly higher in outer medullary tissues from females relative to males. Blockade of GPER in the renal medulla attenuated Na + excretion in females. Given that medullary endothelin 1 is a well-established natriuretic factor that is regulated by sex and sex steroids, we hypothesized that GPER activation promotes natriuresis via an endothelin 1-dependent pathway. To test this mechanism, we determined the effect of medullary infusion of G1 after blockade of endothelin receptors. Dual endothelin receptor subtype A and endothelin receptor subtype B antagonism attenuated G1-induced natriuresis in females. Unlike males, female mice with genetic deletion of GPER had reduced endothelin 1, endothelin receptor subtype A, and endothelin receptor subtype B mRNA expression compared with wild-type controls. More important, we found that systemic GPER activation ameliorates the increase in mean arterial pressure induced by ovariectomy. Conclusions Our data uncover a novel role for renal medullary GPER in promoting Na + excretion via an endothelin 1-dependent pathway in female rats, but not in males. These results highlight GPER as a potential therapeutic target for salt-sensitive hypertension in postmenopausal women.

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1 . A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ET B ) receptors. Furthermore, ET B receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ET B receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ET B receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ET B blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.

Background: Antibiotic use in well-appearing late preterm and term chorioamnionitis-exposed (CE) infants was reduced by 88% after the adoption of a care approach that was focused on clinical monitoring in the intensive care nursery to determine the need for antibiotics. However, this approach continued to separate mothers and infants. We aimed to reduce maternal-infant separation while continuing to use a clinical examination-based approach to identify early-onset sepsis (EOS) in CE infants., Methods: Within a quality improvement framework, well-appearing CE infants ≥35 weeks' gestation were monitored clinically while in couplet care in the postpartum unit without laboratory testing or empirical antibiotics. Clinical monitoring included physician examination at birth and nurse examinations every 30 minutes for 2 hours and then every 4 hours until 24 hours of life. Infants who developed clinical signs of illness were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, and clinical outcomes were collected., Results: Among 319 initially well-appearing CE infants, 15 (4.7%) received antibiotics, 23 (7.2%) underwent laboratory testing, and 295 (92.5%) remained with their mothers in couplet care throughout the birth hospitalization. One infant had group B Streptococcus EOS identified and treated at 24 hours of age based on new-onset tachypnea and had an uncomplicated course., Conclusions: Management of well-appearing CE infants by using a clinical examination-based approach during couplet care in the postpartum unit maintained low rates of laboratory testing and antibiotic use and markedly reduced mother-infant separation without adverse events. A framework for repeated clinical assessments is an essential component of identifying infants with EOS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g  = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies., (© 2018 by The American Society of Hematology.)

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10 -9 , odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10 -8 , OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

Background: The risk of early-onset sepsis is low in well-appearing late-preterm and term infants even in the setting of chorioamnionitis. The empirical antibiotic strategies for chorioamnionitis-exposed infants that are recommended by national guidelines result in antibiotic exposure for numerous well-appearing, uninfected infants. We aimed to reduce unnecessary antibiotic use in chorioamnionitis-exposed infants through the implementation of a treatment approach that focused on clinical presentation to determine the need for antibiotics., Methods: Within a quality-improvement framework, a new treatment approach was implemented in March 2015. Well-appearing late-preterm and term infants who were exposed to chorioamnionitis were clinically monitored for at least 24 hours in a level II nursery; those who remained well appearing received no laboratory testing or antibiotics and were transferred to the level I nursery or discharged from the hospital. Newborns who became symptomatic were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, culture results, and clinical outcomes were collected., Results: Among 277 well-appearing, chorioamnionitis-exposed infants, 32 (11.6%) received antibiotics during the first 15 months of the quality-improvement initiative. No cases of culture result-positive early-onset sepsis occurred. No infant required intubation or inotropic support. Only 48 of 277 (17%) patients had sepsis laboratory testing. The implementation of the new approach was associated with a 55% reduction (95% confidence interval 40%-65%) in antibiotic exposure across all infants ≥34 weeks' gestation born at our hospital., Conclusions: A management approach using clinical presentation to determine the need for antibiotics in chorioamnionitis-exposed infants was successful in reducing antibiotic exposure and was not associated with any clinically relevant delays in care or adverse outcomes., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Introduction and Aims: Health and community service workers frequently encounter people with alcohol and other drug (AOD) problems in the course of their work, yet few have had training on how to respond effectively. A Drug and Alcohol First Aid workshop was developed by Lyndon, a non-government organisation treatment provider, and delivered to community and health sector workers and the general public. It presented evidence-based information regarding AOD use and harm reduction and treatment options. A pilot evaluation of the workshop was conducted to assess changes in participants' knowledge about AOD, methods of responding to use and attitudes towards individuals who use AOD, over a 3 month period., Design and Methods: A self-report evaluation survey was developed and administered to workshop participants at three time points: before (T1), immediately after (T2) and 3 months after the workshop (T3). Paired samples t-tests examined changes in knowledge, role adequacy, motivation and personal views., Results: A total of 142 participants completed the T1 survey, 184 completed the T2 survey and 98 completed the T3 survey. Between T1 and T2, there were significant increases in scores for knowledge and role adequacy, indicating significant improvements in these areas. No significant differences were found for motivation and personal views. At T3, knowledge and role adequacy scores remained significantly higher than at baseline., Discussion and Conclusions: Drug and Alcohol First Aid appears to be a viable initiative to improve AOD-related knowledge and role adequacy. However, alternative strategies may be required to shift negative attitudes towards individuals who use AOD. [Kostadinov VR, Roche AM, McEntee A, Allan JM, Meumann NR, McLaughlin LL. Brief workshops to teach drug and alcohol first aid: A pilot evaluation study. Drug Alcohol Rev 2018;37:23-27]., (© 2017 Australasian Professional Society on Alcohol and other Drugs.)

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high-resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk-stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS., (© 2017 John Wiley & Sons Ltd.)

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10 -11 ) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10 -9 ). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.