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The characterization and synthesis of VOL1, VO2L1, and VOL2, where L1 and L2 are the schiff base condensation products of salicylaldehyde and 3-methoxysalicylaldehyde with 1,3-diaminohydroxypropane, respectively are explained.

Focuses on the development and validation of the Desire for Control on Examinations (DCE), a scale measuring desire for control on examinations. Acceptable levels of reliability and substantial construct validity evidence; Comparison of DCE with J.M. Burger's general desire for control scale.

Describes a method for the synthesis and kinetics of trans-dichlorotetraamminecobalt (III) chloride. Importance of temperature in the experiment; Conductivity measurements for the trans isomer.

This study evaluated the efficacy of five commercially available sanitizers to reduce Salmonella (sessile and biofilm forms) count on experimentally inoculated materials representative of harvesting bins and picking bags in the fresh produce industry. Sessile Salmonella cells were grown onto tryptic soy agar to create a bacterial lawn, while multistrain Salmonella biofilms were grown in a Centers for Disease Control and Prevention (CDC) reactor at 22 ± 2 °C for 96 h. Samples were exposed to 500 ppm free chlorine, 500 ppm peroxyacetic acid (PAA), 75 psi steam, and 5% silver dihydrogen citrate (SDC) for 30 sec, 1, or 2 min or 100 ppm chlorine dioxide gas for 24 h. Sanitizer, surface type, and application time significantly affected the viability of Salmonella in both sessile and biofilm forms (P < 0.05). All treatments resulted in a significant reduction of Salmonella when compared to the control (P < 0.05). Chlorine dioxide gas was the most effective treatment in both sessile and biofilm forms regardless of the type of surface, and it achieved a 5-log reduction. PAA at 500 ppm applied for 2 min was the only liquid sanitizer that resulted in a greater than 3-log reduction in all surfaces. Scanning electronic microscopy demonstrated the porous surface nature of nylon and wood, compared to HDPE, impacted sanitizer antimicrobial activity. Understanding the efficacy of sanitizers to control Salmonella on harvesting bins and picking bags may improve the safety of fresh produce by increasing available sanitizing treatment., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: JBJS convened a symposium to discuss the reporting of sex and gender in research studies as an imperative to improve research methods and results to benefit all patients. Barriers to improved reporting include a lack of societal and cultural acceptance of its need; a lack of education regarding appropriate terminology and appropriate statistical methods and efficient study designs; a need for increased research funding to support larger group sizes; unknown concordance of cell and animal models with humans to reflect biologic variables such as sex; and a lack of understanding of key considerations of gender, race, and other social determinants of health and how these factors intersect. Attention to developing and disseminating best-practice statistical methods and to educating investigators (at all career levels), reviewers, funders, editors, and staff in their proper implementation will aid reporting. Concomitantly, well-designed studies with sufficient rigor and adequate resources are essential to enable meaningful and reproducible research. Existing recommendations, such as the Sex and Gender Equity in Research (SAGER) guidelines, provide valuable guidance that can be applied across the research ecosystem. Academic institutions and private foundations are likely groups to assist in scientific and institutional review board guidance and study recruitment and pilot funding to generate meaningful power estimates, and to serve as sources for additional funding and presentation of workshops, educational events, and seminars. All of this needs to be conducted on an ongoing basis to ensure that sex and gender are considered in scientific analyses, where relevant., Competing Interests: Disclosure: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R13AR082710. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I228)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Abstract: Sex and gender are distinct terms that must be used correctly. Data regarding sex and gender may be collected using a 2-step method that separates biological sex and self-reported gender identity. The PhenX Toolkit, funded by the National Institutes of Health (NIH), is one tool that provides investigators with recommended standard data-collection protocols. Another tool is the Diversity Minimal Item Set questionnaire. Importantly, sex and gender interact: for example, pain has both biological aspects (sex differences in electrical, ischemic, thermal, pressure, and muscle pain sensitivity) and cultural aspects (gender factors in how people report pain and how physicians understand and treat pain in patients). Gender norms, identity, and relations all impact patient care. Gender norms, for instance, may influence how a person experiences pain, gender identity may influence a person's willingness to report pain, and gender relations may influence a physician's gendered expectations in relation to a patient's gendered behaviors. Clinicians may perceive women's pain to be psychological; as a result, women may receive more nonspecific diagnoses, wait longer for treatment, and receive more antidepressants and fewer analgesics than men. Research on gender-diverse people and pain is just now emerging. Resources for methods of reporting include The Lancet, Nature, and the Sex and Gender Equity in Research (SAGER) Guidelines. We must consider all relevant factors intersecting with sex and gender, including age, disabilities, educational background, ethnicity, family configuration, geographic location, race, sexuality, social and economic status, sustainability, and more., Competing Interests: Disclosure: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R13AR082710. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Disclosure of Potential Conflicts of Interest form is provided with the online version of the article ( http://links.lww.com/JBJS/I133 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures., Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis., Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively., Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective., Competing Interests: Potential conflicts of interest. The authors: Nothing to report., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

CD47-SIRPa is a myeloid check point pathway that promotes phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in acute myeloid leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high affinity for CD47. Composed of the N-terminal D1 domain of SIRPα genetically linked to an inactive Fc domain from human immunoglobulin (Ig) G, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML, VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VENbased regimen can be augmented through CD47 inhibition (CD47i) in AML and how this triplet may be enhanced. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN plus azacitidin (VEN+AZA) regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that the loss of resident macrophages in the bone marrow in AML reduced efficiency of CD47i. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via polyinosinic:polycytidylic acid (poly(I:C)), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.

World Health Day underscores the scientific community's commitment to achieving health equity for all. It is paramount to eliminate bias in research that has traditionally focused on men, neglecting the specific needs of diverse populations. Innovative clinical trial designs are being developed with more inclusive enrollment. Ensuring equitable access to essential antibiotics, coupled with robust infection prevention and control measures, is vital to safeguarding public health. The pursuit of health equity extends beyond the realm of medicine. Investments in local food production and robust social safety nets are critical for mitigating the effects of climate change on access to healthy diets. Additionally, in times of polycrisis, prioritizing the unique needs of children and empowering community-led healthcare initiatives in conflict zones are essential steps. By taking these actions, we can move closer to realizing everyone's fundamental right to health., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment., Significance: Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950., (©2024 American Association for Cancer Research.)

Abstract: Sex and gender influence every aspect of human health; thus, sex- and gender-related topics should be incorporated in all aspects of health education curricula. Sex and gender health education (SGHE) is the rigorous, intersectional, data-driven integration of sex and gender into all elements of health education. A multisectoral group of thought leaders has collaborated to advance SGHE since 2012. This cross-sector collaboration to advance SGHE has been successful on several fronts, primarily developing robust interprofessional SGHE programs, hosting a series of international SGHE summits, developing sex- and gender-specific resources, and broadening the collaboration beyond medical education. However, other deeply entrenched challenges have proven more difficult to address, including accurate and consistent sex and gender reporting in research publications, broadening institutional support for SGHE, and the development and implementation of evaluation plans for assessing learner outcomes and the downstream effects of SGHE on patient care. This commentary reflects on progress made in SGHE over the first decade of the current collaboration (2012-2022), articulates a vision for next steps to advance SGHE, and proposes 4 benchmarks to guide the next decade of SGHE: (1) integrate sex, gender, and intersectionality across health curricula; (2) develop sex- and gender-specific resources for health professionals; (3) improve sex and gender reporting in research publications; and (4) develop evaluation plans to assess learner and patient outcomes., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Abstract: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Ultraviolet-C (UV-C) light-assisted water treatment systems are an increasingly investigated alternative to chemical sanitizers for agricultural surface water decontamination. However, the relatively high concentration of particulate matter in surface water is a major challenge to expanding its application in the production of fresh produce. The objective of this project was to test the efficacy of two commercial UV-C devices to reduce the microbial risk of agricultural water in order to develop a web application to assist growers in decision-making related to the on-farm implementation of UV-C technologies for agricultural water treatment. An on-farm study using three agricultural water sources was performed to determine the microbial reduction efficacy of a low power, low flow (LP/LF; 1-9 gallons per minute (GPM), 1.34-gallon capacity) and a high powered, high flow (HP/HF; 1-110 GPM, 4.75-gallon capacity) device at flow rates of 6, 7, and 9 GPM. A threshold of 30% UVT for the HP/HF device was observed, wherein lower water transmissibility significantly impacted microbial inactivation. Although less effective at lower %UVT, the LP/LF device costs less to install, maintain, and operate. The observations were used to design an online tool for growers to calculate the predicted reduction of generic Escherichia coli using either device based on the %UVT of their water source. However, because this study utilized an exploratory and proof-of-concept approach, the experimental flow rates were limited to reflect the capacities of the smaller unit (9 GPM) for direct comparison to the larger unit. Thus, the preliminary model and tool are largely limited to the experimental conditions. Yet, these results of this study demonstrate the utility of UV-C light in reducing the microbial risk of agricultural water, and future studies using different UV-C devices and higher flow rates will expand the use of the decision-making tool., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Delivery of acupuncture in the setting of a clinical trial is a unique practice that diverges significantly from the delivery of acupuncture in a real-world clinical setting. Research acupuncturists, particularly those trained in traditional Chinese medicine (TCM), are often required to set aside valued precepts of traditional care, including diagnosing imbalances, individualizing treatment, and forging a therapeutic relationship with patients. TCM-trained acupuncturists express mixed feelings about participating in clinical trials. Many are eager to play a vital role in the advancement of acupuncture science and appreciate the need for strict protocol adherence to minimize bias. However, the acupuncturist(s) may also have concerns about clinical trial methodology, including but not limited to the delivery of a control condition, e.g., sham acupuncture. Investigators should anticipate certain questions and even a level of resistance to the requirements of research among acupuncturists and be prepared to address them. This manuscript presents a brief review of the subjective experience of the research acupuncturist within the available scientific literature as it pertains to the delivery of active and sham clinical research protocols. Our goals are to better understand the perspectives of acupuncturists who may participate in clinical research, so that their concerns may be addressed in study design and methodology. To that end, we suggest the creation of a novel training program specifically for clinical trial acupuncturists, intended for qualified TCM- and Western-trained practitioners, that would help to standardize the research acupuncturist's role and help to strengthen the design and execution of acupuncture studies. Please cite this article as: Anastasi JK, Capili B, Neumaier J, Hackett L. Delivery of acupuncture in clinical trials: Research acupuncturists' perspectives. J Integr Med. 2023; 21(4):315-319., (Copyright © 2023. Published by Elsevier B.V.)

Cover crops are plants seeded before or after cash crops to improve soil health, reduce weed pressure, and prevent erosion. Cover crops also produce various antimicrobial secondary metabolites (i.e., glucosinolates, quercetin), yet the role of cover crops in moderating the population of human pathogens in the soil has rarely been investigated. This study aims to determine the antimicrobial capacity of three cover crop species to reduce the population of generic Escherichia coli (E. coli) in contaminated agricultural soil. Four-week-old mustard greens (Brassicajuncea), sunn hemp (Crotalaria juncea), and buckwheat (Fagopyrum esculentum) were mixed into autoclaved soil and inoculated with rifampicin-resistant generic E. coli to achieve a starting concentration of 5 log CFU/g. The surviving microbial populations on days 0, 4, 10, 15, 20, 30, and 40 were enumerated. All three cover crops significantly reduced the population of generic E. coli compared to the control (p < 0.0001), particularly between days 10 and to 30. Buckwheat resulted in the highest reduction (3.92 log CFU/g). An inhibitory effect (p < 0.0001) on microbial growth was also observed in soils containing mustard greens and sunn hemp. This study provides evidence for the bacteriostatic and bactericidal effect of particular cover crops. More research regarding the secondary metabolites produced by certain cover crops and their potential as a bio mitigation strategy to improve on-farm produce safety is warranted., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Ultraviolet-C (UV-C) irradiation is a well-recognized technology for improving blueberry postharvest quality, and previous literature indicates that it has the potential for dual-use as an antimicrobial intervention for this industry. However, the practicality and feasibility of deploying this technology in fresh blueberry fruit are significantly hindered by the shadowing effect occurring at the blossom-end scar of the fruit. The purpose of this study was to determine if treating the blueberry fruit within a chamber fitted with UV-Light Emitting Diodes (LEDs) emitting a peak UV-C at 275 nm could minimize this shadowing and result in improved treatment efficacy. Ten blueberry fruits were dip-inoculated with E. coli at a concentration of 10 5  CFU/mL and irradiated within the system at doses of 0, 1.617, 3.234, 9.702, and 16.17 mJ/cm 2 (0, 30, 60, 180, and 300 s). Statistical analysis was performed to characterize the extent of microbial survival as well as the UV-C inactivation kinetics. A maximum of 0.91-0.95 log reduction was observed, which attenuated after 60 s of treatment. The microbial inactivation and survival were thus modeled using the Geeraerd-tail model in Microsoft Excel with the GInaFIt add-in (RMSE = 0.2862). Temperatures fluctuated between 23 ± 0.5°C and 39.5°C ± 0.5°C during treatment but did not statistically impact the treatment efficacy (P = 0.0823). The data indicate that the design of a UV-LED system may improve the antimicrobial efficacy of UV-C technology for the surface decontamination of irregularly shaped fruits, and that further optimization could facilitate its use in the industry., Competing Interests: Declaration of Competing Interests 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Funding agencies have ample room to improve their policies.

Excellent research integrates sex, gender, and/or intersectional analysis-from the very beginning and throughout the research process. This article highlights techniques for analyzing sex, how sex and sex interact, how sex and gender interact, and the need for intersectional analysis. Designing sex, gender, and intersectional analysis into research is one crucial component contributing to world-class health and biomedicine., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In recent years, interest has grown in whether and to what extent demographic diversity sparks discovery and innovation in research. At the same time, topic modeling has been employed to discover differences in what women and men write about. This study engages these two strands of scholarship to explore associations between changing researcher demographics and research questions asked in the discipline of history. Specifically, we analyze developments in history as women entered the field., Methods: We focus on author gender in diachronic analysis of history dissertations from 1980 (when online data is first available) to 2015 and a select set of general history journals from 1950 to 2015. We use correlated topic modeling and network visualizations to map developments in research agendas over time and to examine how women and men have contributed to these developments., Results: Our summary snapshot of aggregate interests of women and men for the period 1950 to 2015 identifies new topics associated with women authors: gender and women's history, body history, family and households, consumption and consumerism, and sexuality. Diachronic analysis demonstrates that while women pioneered topics such as gender and women's history or the history of sexuality, these topics broaden over time to become methodological frameworks that historians widely embraced and that changed in interesting ways as men engaged with them. Our analysis of history dissertations surface correlations between advisor/advisee gender pairings and choice of dissertation topic., Conclusions: Overall, this quantitative longitudinal study suggests that the growth in women historians has coincided with the broadening of research agendas and an increased sensitivity to new topics and methodologies in the field., Competing Interests: The authors have declared that no competing interests exist.

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with several of the authors IA, DLK, and AO., (Copyright © 2022 Barron, Aksentijevich, Deuitch, Stone, Hoffmann, Videgar-Laird, Soldatos, Bergerson, Toro, Cudrici, Nehrebecky, Romeo, Jones, Boehm, Kanakry, Dimitrova, Calvo, Alao, Kapuria, Ben-Yakov, Pichard, Hathaway, Brofferio, McRae, Moura, Schnappauf, Rosenzweig, Heller, Cowen, Kastner and Ombrello.)

To improve the outcomes of research and medicine, government-based international research funding agencies have implemented various types of policies and mechanisms with respect to sex as a biological variable and gender as a sociocultural factor. After the 1990s, the US National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR), and the European Commission (EC) began requesting that applicants address sex and gender considerations in grant proposals, and offering resources to help the scientific community integrate sex and gender into biomedical research. Although it is too early to analyze data on the success of all of the policies and mechanisms implemented, here we review the use both of carrots (incentives) and sticks (requirements) developed to motivate researchers and the entire scientific research enterprise to consider sex and gender influences on health and in science. The NIH focused on sex as a biological variable (SABV) aligned with an initiative to enhance reproducibility through rigor and transparency; CIHR instituted a sex- and gender-based analysis (SGBA) policy; and the EC required the integration of the "gender dimension," which incorporates sex, gender, and intersectional analysis into research and innovation. Other global efforts are briefly summarized. Although we are still learning what works, we share lessons learned to improve the integration of sex and gender considerations into research. In conjunction with refining and expanding the policies of funding agencies and mechanisms, private funders/philanthropic groups, editors of peer-reviewed journals, academic institutions, professional organizations, ethics boards, health care systems, and industry also need to make concerted efforts to integrate sex and gender into research, and we all must bridge across silos to promote systemwide solutions throughout the biomedical enterprise. For example, policies that encourage researchers to disaggregate data by sex and gender, the development of tools to better measure gender effects, or policies similar to SABV and/or SGBA adopted by private funders would accelerate progress. Uptake, accountability for, and a critical appraisal of sex and gender throughout the biomedical enterprise will be crucial to achieving the goal of relevant, reproducible, replicable, and responsible science that will lead to better evidence-based, personalized care for all, but especially for women., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis., Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML)., Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts., Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion., Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Artificial Intelligence (AI) can potentially impact many aspects of human health, from basic research discovery to individual health assessment. It is critical that these advances in technology broadly benefit diverse populations from around the world. This can be challenging because AI algorithms are often developed on non-representative samples and evaluated based on narrow metrics. Here we outline key challenges to biomedical AI in outcome design, data collection and technology evaluation, and use examples from precision health to illustrate how bias and health disparity may arise in each stage. We then suggest both short term approaches-more diverse data collection and AI monitoring-and longer term structural changes in funding, publications, and education to address these challenges., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Vegetables in Cambodia are commonly sold in informal markets lacking food safety standards and controls. Current data on microbial contamination of vegetables in Cambodian informal markets are limited. The purpose of this study was to investigate Salmonella enterica and indicator organisms (Escherichia coli and coliforms) on the surface of fresh vegetables sold in informal markets in Cambodia. Samples of loose-leaf lettuce, tomatoes, and cucumbers were collected from 104 vendors at four informal markets in Battambang and Siem Reap provinces during the rainy and dry seasons. Detection methods for S. enterica were adapted from the U.S. Food and Drug Administration's Bacteriological Analytical Manual. Coliform and E. coli populations were quantified by plating onto E. coli/coliform count plates. S. enterica was most prevalent on lettuce during the dry season (56.5%, 95% confidence interval [CI] [41.0, 70.8]) than during the rainy season (15.4%, 95% CI [7.5, 29.1]), whereas no significant seasonal differences were apparent for tomatoes and cucumbers. Regardless of season, levels of S. enterica were highest on lettuce (5.7 log CFU/g, 95% CI [5.5, 5.9]), relative to cucumbers (4.2 log CFU/g, 95% CI [3.8, 4.6]) and tomatoes (4.3 log CFU/g, 95% CI [4.1, 4.6]). For E. coli, prevalence was higher during the rainy season (34.0%, 95% CI [25.4, 43.8]) than during the dry season (9.1%, 95% CI [4.9, 16.5]), with the highest prevalence estimated on lettuce. Coliform levels on lettuce and tomatoes were greater during the rainy season (6.3 and 5.3 log CFU/g, 95% CI [5.7, 6.8] and [4.7, 5.8], respectively) than during the dry season (5.2 and 3.9 log CFU/g, 95% CI [4.7, 5.7] and [3.4, 4.4], respectively). These results indicate seasonal patterns for microbial prevalence in lettuce and an overall high level of bacterial contamination on raw vegetables sold in Cambodian informal markets., (Copyright ©, International Association for Food Protection.)

Background: In this paper, we argue for Gender as a Sociocultural Variable (GASV) as a complement to Sex as a Biological Variable (SABV). Sex (biology) and gender (sociocultural behaviors and attitudes) interact to influence health and disease processes across the lifespan-which is currently playing out in the COVID-19 pandemic. This study develops a gender assessment tool-the Stanford Gender-Related Variables for Health Research-for use in clinical and population research, including large-scale health surveys involving diverse Western populations. While analyzing sex as a biological variable is widely mandated, gender as a sociocultural variable is not, largely because the field lacks quantitative tools for analyzing the influence of gender on health outcomes., Methods: We conducted a comprehensive review of English-language measures of gender from 1975 to 2015 to identify variables across three domains: gender norms, gender-related traits, and gender relations. This yielded 11 variables tested with 44 items in three US cross-sectional survey populations: two internet-based (N = 2051; N = 2135) and a patient-research registry (N = 489), conducted between May 2017 and January 2018., Results: Exploratory and confirmatory factor analyses reduced 11 constructs to 7 gender-related variables: caregiver strain, work strain, independence, risk-taking, emotional intelligence, social support, and discrimination. Regression analyses, adjusted for age, ethnicity, income, education, sex assigned at birth, and self-reported gender identity, identified associations between these gender-related variables and self-rated general health, physical and mental health, and health-risk behaviors., Conclusion: Our new instrument represents an important step toward developing more comprehensive and precise survey-based measures of gender in relation to health. Our questionnaire is designed to shed light on how specific gender-related behaviors and attitudes contribute to health and disease processes, irrespective of-or in addition to-biological sex and self-reported gender identity. Use of these gender-related variables in experimental studies, such as clinical trials, may also help us understand if gender factors play an important role as treatment-effect modifiers and would thus need to be further considered in treatment decision-making.

Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity., Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models., Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2 , and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity., Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen., (©2020 American Association for Cancer Research.)

Strawberries are a highly perishable crop with postharvest losses than reach up to 40%. Cost-effective and sustainable technologies in the form of active packing films can provide a solution. Antimicrobial packaging films were produced from pullulan polymer and Solid Lipid Nanoparticles (SLN) containing 1% w/w cinnamaldehyde. Strawberries were stored at 3 °C for 10 days and 12 °C for 6 days. Microbial and physical quality parameters were evaluated during storage. A reduction of approximately 2 Log CFU/g in yeast and mold population was observed for treated strawberries stored at 3 °C as compared to the control ( p < 0.05). Yeast and molds counts were significantly lower on day 2 and 4 at 12 °C for treated samples. Strawberries packaged with the active films demonstrated lower respiration rates and the retention of bright red color at both storage temperatures. Active pullulan films were effective in maintaining the desired strawberry quality and reducing fungal decay during refrigerated storage.

Background: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5-7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients., Objective: To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model., Methods: Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model., Results: Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models., Conclusions: We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases.

The goal of sex and gender analysis is to promote rigorous, reproducible and responsible science. Incorporating sex and gender analysis into experimental design has enabled advancements across many disciplines, such as improved treatment of heart disease and insights into the societal impact of algorithmic bias. Here we discuss the potential for sex and gender analysis to foster scientific discovery, improve experimental efficiency and enable social equality. We provide a roadmap for sex and gender analysis across scientific disciplines and call on researchers, funding agencies, peer-reviewed journals and universities to coordinate efforts to implement robust methods of sex and gender analysis.

The combination of a macrolide and rifampicin has been the mainstay of therapy in foals with Rhodococcus equi pneumonia for decades. Recent studies suggest that mass antimicrobial treatment of subclinically affected foals over time has selected for antimicrobial resistance. Our objective was to estimate the prevalence of R. equi strains resistant to macrolides and rifampicin at horse breeding farms in Kentucky. A hundred breeding farms in Kentucky were surveyed and R. equi were cultured from soil samples. Data were analyzed with logistic regression and generalized linear modeling (P < 0.05). Seventy-six percent (76%) of farms yielded resistant R. equi, and resistance to macrolides and rifampicin was associated with their use at farms. The present study is the first to report the prevalence and distribution of resistant isolates in the environment of farms in Kentucky, USA. Collectively, previous reports and the data presented herein provide irrefutable evidence of emerging antimicrobial resistance in R. equi with alarming prevalence. Widespread dissemination and maintenance of resistance genes in the environment where many other pathogenic bacteria exist is a concern for both animal and human health., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Given the disparities across regional cervical cancer screening programs implemented in Portugal, understanding the patterns of cervical cytology use is essential to improve cervical cancer control. We aimed to describe the use of cervical cytology and identify factors associated with its non- and underuse., Methods: A total of 5884 women aged 25-64 years were evaluated as part of the National Health Survey 2014. Previous use of cervical cytology was classified as never or ever, and ever-users having undergone the latest testing more than 5 years before were considered under-users. We computed age- and education-adjusted prevalence ratios and corresponding 95% confidence intervals for non- and underuse., Results: Overall, 13.2 and 12.0% of women reported nonuse and underuse of cervical cytology, respectively. The Norte region presented the lowest prevalence of nonuse and R.A. Açores the highest. Low socioeconomic status and unhealthy lifestyles were significantly associated with low cervical cytology use, whereas greater use was observed in those having more recent contact with health services., Conclusions: Cervical cytology use was shown to differ according to sociodemographic characteristics and access to/use of healthcare services. Large regional variations persist in Portugal despite organized screening programs that cover most of the country., (© 2019 Japan Society of Obstetrics and Gynecology.)

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

Gender diversity has the potential to drive scientific discovery and innovation. Here, we distinguish three approaches to gender diversity: diversity in research teams, diversity in research methods and diversity in research questions. While gender diversity is commonly understood to refer only to the gender composition of research teams, fully realizing the potential of diversity for science and innovation also requires attention to the methods employed and questions raised in scientific knowledge-making. We provide a framework for understanding the best ways to support the three approaches to gender diversity across four interdependent domains - from research teams to the broader disciplines in which they are embedded to research organizations and ultimately to the different societies that shape them through specific gender norms and policies. Our analysis demonstrates that realizing the benefits of diversity for science requires careful management of these four interdependent domains.

Word embeddings are a powerful machine-learning framework that represents each English word by a vector. The geometric relationship between these vectors captures meaningful semantic relationships between the corresponding words. In this paper, we develop a framework to demonstrate how the temporal dynamics of the embedding helps to quantify changes in stereotypes and attitudes toward women and ethnic minorities in the 20th and 21st centuries in the United States. We integrate word embeddings trained on 100 y of text data with the US Census to show that changes in the embedding track closely with demographic and occupation shifts over time. The embedding captures societal shifts-e.g., the women's movement in the 1960s and Asian immigration into the United States-and also illuminates how specific adjectives and occupations became more closely associated with certain populations over time. Our framework for temporal analysis of word embedding opens up a fruitful intersection between machine learning and quantitative social science., Competing Interests: The authors declare no conflict of interest.