Reproductive Justice: A Case-Based, Interactive Curriculum.

Introduction: Reproductive injustices such as forced sterilization, preventable maternal morbidity and mortality, restricted access to family planning services, and policy-driven environmental violence undermine reproductive autonomy and health outcomes, with disproportionate impact on historically marginalized communities. However, curricula focused on reproductive justice (RJ) are lacking in medical education. Methods: We designed a novel, interactive, case-based RJ curriculum for postclerkship medical students. This curriculum was created using published guidelines on best practices for incorporating RJ in medical education. The session included a prerecorded video on the history of RJ, an article, and four interactive cases. Students engaged in a 2-hour small-group session, discussing key learning points of each case. We evaluated the curriculum's impact with a pre- and postsurvey and focus group. Results: Sixty-eight students participated in this RJ curriculum in October 2020 and March 2021. Forty-one percent of them completed the presurvey, and 46% completed the postsurvey. Twenty-two percent completed both surveys. Ninety percent of respondents agreed that RJ was relevant to their future practice, and 87% agreed that participating in this session would impact their clinical practice. Most respondents (81%) agreed that more RJ content is needed. Focus group participants appreciated the case-based, interactive format and the intersectionality within the cases. Discussion: This interactive curriculum is an innovative and effective way to teach medical students about RJ and its relevance to clinical practice. Walking alongside patients as they accessed reproductive health care in a case-based curriculum improved students' comfort and self-reported knowledge on several RJ topics.

School Readiness of Young Children Enrolled in Preschool in the United States.

OBJECTIVE: As preschool enrollment increases, it is important to know whether children enrolled in preschool are more likely to be "healthy and ready to learn (HRTL)." Our objective was to assess whether there are detectable school readiness differences between children enrolled in preschool and those who are not in a large, cross-sectional, nationally representative US sample. METHODS: Caregivers of 4931 3- to 4-year-old children in the 2016 National Survey of Children's Health indicated whether their child had started school and completed questions forming the "HRTL" School Readiness National Outcome Measure and its domains: early learning skills, self-regulation, social-emotional development, and physical health/motor development. Propensity score-matched logistic regression models estimated prevalence ratios (PRs) comparing children in versus not in preschool. RESULTS: 49.1% of children had started preschool. After matching, children in preschool did not differ from children not in preschool on the composite (PR = 1.21; 95% confidence interval [CI]: 0.92-1.58) or any domains. Children in preschool were more likely to be "on track" with rhyming words (PR = 1.48; 95% CI: 1.11-1.96), writing their name (PR = 2.36; 95% CI: 1.82-3.08), and holding a pencil (PR = 1.55; 95% CI: 1.12-2.14) but less likely with explaining things they have seen/done (PR = 0.59; 95% CI: 0.44-0.79) and overall health (PR = 0.57; 95% CI: 0.33-0.97). Some associations were sex specific. CONCLUSION: The largely null findings of this study underscore the need for further research that incorporates information regarding the extent and quality of preschool exposure when evaluating the developmental benefits of preschool on a national level.

The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity.

The mitochondrial thioredoxin/peroxiredoxin system encompasses NADPH, thioredoxin reductase 2 (TrxR2), thioredoxin 2, and peroxiredoxins 3 and 5 (Prx3 and Prx5) and is crucial to regulate cell redox homeostasis via the efficient catabolism of peroxides (TrxR2 and Trxrd2 refer to the mitochondrial thioredoxin reductase protein and gene, respectively). Here, we report that endothelial TrxR2 controls both the steady-state concentration of peroxynitrite, the product of the reaction of superoxide radical and nitric oxide, and the integrity of the vascular system. Mice with endothelial deletion of the Trxrd2 gene develop increased vascular stiffness and hypertrophy of the vascular wall. Furthermore, they suffer from renal abnormalities, including thickening of the Bowman's capsule, glomerulosclerosis, and functional alterations. Mechanistically, we show that loss of Trxrd2 results in enhanced peroxynitrite steady-state levels in both vascular endothelial cells and vessels by using a highly sensitive redox probe, fluorescein-boronate. High steady-state peroxynitrite levels were further found to coincide with elevated protein tyrosine nitration in renal tissue and a substantial change of the redox state of Prx3 toward the oxidized protein, even though glutaredoxin 2 (Grx2) expression increased in parallel. Additional studies using a mitochondria-specific fluorescence probe (MitoPY1) in vessels revealed that enhanced peroxynitrite levels are indeed generated in mitochondria. Treatment with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin [Mn(III)TMPyP], a peroxynitrite-decomposition catalyst, blunted intravascular formation of peroxynitrite. Our data provide compelling evidence for a yet-unrecognized role of TrxR2 in balancing the nitric oxide/peroxynitrite ratio in endothelial cells in vivo and thus establish a link between enhanced mitochondrial peroxynitrite and disruption of vascular integrity.

Pediatricians' knowledge, attitudes and practices surrounding menstruation and feminine products.

OBJECTIVE: This study investigates whether primary care pediatricians adhere to the American Academy of Pediatrics (AAP) recommendations by routinely evaluating patients' menstrual cycles and educating patients about menstruation and feminine products. Additionally, this study examines pediatricians' knowledge and attitudes surrounding menstrual health topics. METHODS: A 53-item online questionnaire was developed to evaluate pediatricians' knowledge, attitudes and clinical practices regarding menstruation-related topics. The questionnaire was emailed to 2500 AAP members using a geographically-stratified sampling approach, with pediatricians in each state selected randomly. Mann-Whitney U tests, t-tests, and logistic regressions were used to assess associations between correlates and pediatricians' knowledge, attitudes and practices. RESULTS: Five hundred and eighteen out of 2500 pediatricians participated (response rate = 20.7%), 462 met inclusion criteria; 78.8% were female, 79.2% were Caucasian. The majority of the pediatricians (58.2%) were "not at all" or only "slightly" familiar with the AAP guidelines on anticipatory guidance surrounding menarche. Many reported they do not routinely provide anticipatory guidance regarding menstruation to pre-menarchal patients (24.7%), discuss menstruation with post-menarchal patients (33.1%) or ask patients the date of their last period (28.4%). The majority were unlikely to discuss feminine products with patients. Gaps in menstruation-related knowledge were noted. Male pediatricians were significantly less likely to evaluate patients' menstrual cycles and provide patient-education regarding menstruation-related topics, and had significantly lower self-rated and measured knowledge of these topics. CONCLUSIONS: A concerning number of pediatricians in a national sample do not abide by AAP recommendations surrounding menstruation and exhibit knowledge gaps in this area. To effectively address the health needs of female patients, pediatricians should better incorporate menstrual health care into their clinical practice.

Availability of Naloxone in Pharmacies and Knowledge of Pharmacy Staff Regarding Dispensing Naloxone to Younger Adolescents.

PURPOSE: This study assessed the immediate availability of naloxone in pharmacies and the knowledge of pharmacy staff regarding naloxone dispensing protocols, especially as it relates to younger adolescents. METHODS: The primary sample included pharmacies in the 10 states with the highest number of opioid-related overdose deaths in 2016; in addition, pharmacies in the 2 states with the highest prevalence of opioid-related overdose deaths in 2016 were also contacted. Researchers simulated a routine conversation between pharmacy staff and a potential customer about the immediate availability of and requirements to purchase naloxone. RESULTS: The primary sample included 120 pharmacies (82.5% chain pharmacies; 50.8% rural). The majority (80.3%) had at least one form of naloxone in stock. Pharmacy staff were knowledgeable about prescription and third-party purchasing requirements. However, almost half incorrectly responded that there was a minimum age requirement to purchase naloxone. CONCLUSION: This study reveals barriers to obtaining naloxone, including a lack of immediate in-store availability and a common misperception that naloxone cannot be dispensed to minors.

Targeting Pim Kinases and DAPK3 to Control Hypertension.

Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications.

Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium.

OBJECTIVE: Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell-specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control. APPROACH AND RESULTS: We analyzed the impact of an inducible, endothelial cell-specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation. Laser Doppler analysis and histology revealed impaired angiogenesis and arteriogenesis. In addition, endothelial loss of Txnrd2 resulted in a prothrombotic, proinflammatory vascular phenotype, manifested as intravascular cellular deposits, as well as microthrombi. This phenotype was confirmed by an increased leukocyte response toward interleukin-1 in the mouse cremaster model. In vitro, we could confirm the attenuated angiogenesis measured in vivo, which was accompanied by increased ROS and an impaired mitochondrial membrane potential. Ex vivo analysis of femoral arteries revealed reduced flow-dependent vasodilation in endothelial cell Txnrd2-deficient mice. This endothelial dysfunction could be, at least partly, ascribed to inadequate nitric oxide signaling. CONCLUSIONS: We conclude that the maintenance of mitochondrial ROS via Txnrd2 in endothelial cells is necessary for an intact vascular homeostasis and remodeling and that Txnrd2 plays a vitally important role in balancing mitochondrial ROS production in the endothelium.

The role of phosphorylatable serine residues in the DNA-binding domain of Arabidopsis bZIP transcription factors.

Reversible phosphorylation plays a crucial role in regulating the activity of enzymes and other proteins in all living organisms. Particularly, the phosphorylation of transcription factors can modulate their capability to regulate downstream target genes. In plants, basic domain-containing leucine-zipper (bZIP) transcription factors have an important function in the regulation of many developmental processes and adaptive responses to the environment. By a comprehensive sequence analysis, we identified a set of highly conserved, potentially phospho-accepting serines within the DNA-binding domain of plant bZIPs. Structural modelling revealed that these serines are in physical contact with the DNA and predicts that their phosphorylation will have a major influence on the DNA-binding activity of plant bZIPs. In support of this, we show, by means of a quantitative in vitro binding assay, that phosphorylation-mimicking substitutions of some of these serines strongly interfere with the DNA binding of two prototypical Arabidopsis bZIPs, namely AtZIP63 and HY5. Our data suggest that the identified serines could serve as in vivo targets for kinases and phosphatases, allowing the fine-tuning of bZIP factor activity at the DNA-protein interaction level.