Direct Methotrexate Injection into the Gestational Sac for Nontubal Ectopic Pregnancy: A Review of Efficacy and Outcomes from a Single Institution.

STUDY OBJECTIVE: To evaluate the efficacy of nontubal ectopic pregnancy (NTEP) management with direct methotrexate (MTX) injection into the gestational sac. DESIGN: A retrospective chart review. SETTING: A tertiary academic and teaching hospital. PATIENTS: All cases of confirmed NTEP were retrospectively identified from 2012 to 2017. INTERVENTIONS: Ultrasound-guided direct injection of MTX into the fetal pole and surrounding gestational sac and a single dose of systemic MTX with or without fetal intracardiac injection of potassium chloride. MEASUREMENTS AND MAIN RESULTS: Treatment failure, complications from treatment, operating time, and days to negative serum human chorionic gonadotropin (hCG) after treatment were measured. Fourteen women (age 34 ± 5.2 years) with NTEP underwent direct MTX injection (cesarean scar, n = 4; interstitial, n = 6; cervical, n = 4). The mean estimated gestational age was 49 ± 11, CI (43, 56 days). One patient required laparoscopic intervention with a failure rate of 1 of 14 (a double interstitial, heterotopic pregnancy). There were no other major complications. The time in the operating room was similar for all NTEP types. The average time to negative serum hCG was not different for cesarean scar (84.5 ± 36 days), cervical pregnancies (70.5 ± 19 days), or interstitial pregnancies (45.3 ± 38 days, p = .15). CONCLUSION: Direct MTX injection into the gestational sac for NTEP treatment is safe and effective. The failure rate of 7% is considerably lower than what was previously reported for a failure of systemic MTX in similar cases (25%). Resolution of serum hCG after treatment can be quite prolonged even in uncomplicated cases.

Evidence for disruption of normal circadian cortisol rhythm in women with obesity.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the pathogenesis of comorbidities encountered in obesity, including the relative hypogonadotropic hypogonadism that we and others have observed. We sought to examine serum cortisol profiles throughout the day and evening in a sample of normal weight women and women with obesity. In this cross-sectional study, regularly cycling obese (n = 12) and normal weight (n = 10) women were recruited. Mean serum cortisol was measured by frequent blood sampling for 16 h (8am-midnight) in the luteal phase of the menstrual cycle. Women with obesity had significantly higher overall cortisol levels when compared to normal weight women (6.2 [4.3, 6.6] vs. 4.7 [3.7, 5.5] ug/dl, p = .04). Over the two-hour postprandial period, obese women displayed an almost two-fold greater (7.2 [6.5, 8.6] ug/dl) rise in cortisol than normal weight controls (4.4 [3.7, 6.2] ug/dl, p < .01). In addition, obese women demonstrated a sustained evening cortisol elevation compared to normal weight women, who displayed the typical decline in cortisol (3.2 [2.3, 4] vs. 2 [1.5, 3.2] ug/dl, p < .05). Changes in the HPA axis in the setting of obesity may be related to risks of obesity-associated metabolic comorbidities and reproductive dysfunction often seen in these women.

Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women.

OBJECTIVES: Female obesity is a state of relative hypogonadotrophic hypogonadism. The aim of this study is to examine gonadotrophin secretion and response to gonadotrophin-releasing hormone (GnRH) in the luteal phase of the menstrual cycle and to investigate the pharmacodynamics and pharmacokinetics of endogenous and exogenous luteinizing hormone (LH) in obese women. DESIGN: Participants underwent a luteal phase frequent blood sampling study. Endogenous LH pulsatility was observed, gonadotrophin-releasing hormone (GnRH) was given in two weight-based doses, and GnRH antagonist was administered followed by recombinant LH. PATIENTS: Regularly menstruating obese (n = 10) and normal weight (n = 10) women. MEASUREMENTS: Endogenous hypothalamic-pituitary function (as measured by LH pulsatility), pituitary sensitivity (GnRH-induced LH secretion), pharmacodynamics of endogenous LH and pharmacokinetics of exogenous LH were compared between the obese and normal weight groups. RESULTS: There were no statistically significant differences in endogenous LH pulsatility or pituitary responses to two weight-based doses of GnRH between the obese and normal weight women. There were no differences in the pharmacodynamics of endogenous LH or the pharmacokinetics of exogenous LH between the groups. FSH dynamics did not differ between the groups throughout the study. CONCLUSIONS: The relative hypogonadotrophic hypogonadism of obesity cannot be explained by differences in LH and FSH luteal phase dynamics or differences in endogenous LH pharmacodynamics or exogenous LH pharmacokinetics.

Pregnancy in a woman with premature ovarian insufficiency associated with blepharophimosis, ptosis, epicanthus inversus syndrome type I. A case report.

BACKGROUND: Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) type I is a rare disorder that causes a recognizable pattern of eye abnormalities and is associated with premature ovarian insufficiency. There is no data to guide the treatment of these patients when presenting with infertility. CASE: A 30-year-old, nulligravid woman with premature ovarian insufficiency associated with BPES type I presented to care secondary to a desire to conceive. Ovarian stimulation with gonadotropins was performed, and the patient conceived and delivered viable twins. CONCLUSION: It is not known whether premature ovarian insufficiency associated with BPES type I follows the same clinical course as idiopathic premature ovarian insufficiency. In patients with BPES type I who present with infertility, ovarian stimulation with gonadotropins may be a reasonable therapeutic option.

Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome.

PURPOSE: To determine if microRNAs are differentially expressed in the follicular fluid of women with PCOS compared to fertile oocyte donors and identify associated altered gene expression. METHODS: Women undergoing IVF who met Rotterdam criteria for PCOS or who were fertile oocyte donors were recruited from a private IVF center. Individual follicle fluid was collected at the time of oocyte retrieval. MicroRNA analysis was performed using microarray and validated using real-time PCR on additional samples. Potential gene targets were identified and their expression analyzed by real time PCR. RESULTS: Microarray profiling of human follicular fluid revealed expression of 235 miRNAs, 29 were differentially expressed between the groups. Using PCR validation, 5 miRNAs (32, 34c, 135a, 18b, and 9) showed significantly increased expression in the PCOS group. Pathway analysis revealed genes involved in insulin regulation and inflammation. Three potential target genes were found to have significantly decreased expression in the PCOS group (interleukin 8, synaptogamin 1, and insulin receptor substrate 2). CONCLUSIONS: MicroRNAs are differentially expressed in the follicular fluid of women with PCOS when compared to fertile oocyte donors. There is also altered expression of potential target genes associated with the PCOS phenotype.

Ovarian Leydig Cell Tumor Associated with Recurrent Torsion and Virilization in an Adolescent Patient.

Ovarian tumors are rare in children; however, their incidence increases with age. Of these ovarian tumors, Leydig cell tumors are some of the rarest, accounting for less than 0.1% of all ovarian tumors across all ages. Leydig cell tumors predominantly occur in postmenopausal women and are characterized by nodular proliferation of Leydig cells in the ovarian hilum with intracytoplasmic Reinke crystals. These tumors secrete androgens, which can disrupt ovarian function, clinically presenting with abnormal uterine bleeding and virilization. Although they are generally benign, current recommendations are for treatment with a unilateral salpingo-oophorectomy. In adolescents, hyperandrogenism is most commonly caused by polycystic ovarian syndrome (PCOS); however, the differential for hyperandrogenism is broad. We present a case of a 15-year-old girl with a history of primary amenorrhea who presented with a Leydig cell tumor associated with recurrent ovarian torsion and virilization. This case reviews the challenges with diagnosis, management, and future implications of a rare androgen-secreting tumor in young patients.

Where Do We Go from here? Post-pandemic Planning and the Future of Graduate Medical Education.

Background: As the pandemic wanes, there is an opportunity to reevaluate resultant changes in graduate medical education (GME), particularly from the viewpoints of those affected most. We aimed to assess both trainee and faculty perceptions on the educational changes and innovations resulting from the pandemic to inform future educational planning. Methods: We surveyed trainees and core education faculty at three New York City children's hospitals. Surveys assessed perceived changes to educational activities, skills, scholarship, effectiveness of virtual teaching, future desirability, and qualitative themes. Results: The survey was completed by 194 participants, including 88 (45.4%) faculty and 106 (54.6%) trainees. Trainees were more likely to report a negative impact of the pandemic compared with faculty (75.5% vs. 50%, p < 0.01). Most respondents reported a decrease in formal educational activities (69.8%), inpatient (77.7%) and outpatient (77.8%) clinical teaching. Despite this, most perceived clinical and teaching skills to have stayed the same. Most (93.4%) participated in virtual education; however, only 36.5% of faculty taught virtually. Only 4.2% of faculty had extensive training in virtual teaching and 28.9% felt very comfortable teaching virtually. In the future, most (87.5%) prefer a hybrid approach, particularly virtual didactic conferences and virtual grand rounds. Faculty themes included challenges to workflows and increased empathy for trainees, while trainee themes included increased work/life balance and support, but increased burnout. Conclusion: Many changes and innovations resulted from the pandemic. Hospital systems and GME programs should consider this data and incorporate viewpoints from trainees and faculty when adapting educational strategies in the future. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01737-8.

Developing an Entrustable Professional Activity to Improve the Care of LGBTQ+ Youth.

Despite the multitude of health inequities often experienced by lesbian, gay, bisexual, transgender, and queer (LGBTQ)+ youth, few training programs consistently and comprehensively address these disparities through education and assessment of learners. Over the past decade, programs have begun to incrementally increase the number of hours dedicated to LGBTQ+ health training; however, the lack of standardization for curricula and assessment remains a significant barrier. As medical education shifts to a competency-based approach, focusing on patient outcomes and the competencies trainees must achieve to meet those outcomes, we must take this opportunity to develop curricula and assessment tools that emphasize inclusive, affirming, equitable, and culturally humble care for LGBTQ+ youth. Entrustable professional activities (EPA) are increasingly used to educate and assess trainees on their progression from full supervision to unsupervised practice. Given their multifaceted use to standardize curricula, assess learners, and highlight programmatic gaps in education, we believe an EPA is the ideal tool to systematically improve LGBTQ+ health training in graduate medical education. Our team of national experts in this field developed an LGBTQ+ health EPA. We describe our methods of development, the functions and curricular components of the EPA, and the many applications for widespread program use.

Meeting the demand for fertility services: the present and future of reproductive endocrinology and infertility in the United States.

The field of reproductive endocrinology and infertility (REI) is at a crossroads; there is a mismatch between demand for reproductive endocrinology, infertility and assisted reproductive technology (ART) services, and availability of care. This document's focus is to provide data justifying the critical need for increased provision of fertility services in the United States now and into the future, offer approaches to rectify the developing physician shortage problem, and suggest a framework for the discussion on how to meet that increase in demand. The Society of REI recommend the following: 1. Our field should aggressively explore and implement courses of action to increase the number of qualified, highly trained REI physicians trained annually. We recommend efforts to increase the number of REI fellowships and the size complement of existing fellowships be prioritized where possible. These courses of action include: a. Increase the number of REI fellowship training programs. b. Increase the number of fellows trained at current REI fellowship programs. c. The pros and cons of a 2-year focused clinical fellowship track for fellows interested primarily in ART practice were extensively explored. We do not recommend shortening the REI fellowship to 2 years at this time, because efforts should be focused on increasing the number of fellowship training slots (1a and b). 2. It is recommended that the field aggressively implements courses of action to increase the number of and appropriate usage of non-REI providers to increase clinical efficiency under appropriate board-certified REI physician supervision. 3. Automating processes through technologic improvements can free providers at all levels to practice at the top of their license.

ATP-uncoupled, six-electron photoreduction of hydrogen cyanide to methane by the molybdenum-iron protein.

A detailed study of the eight-electron/eight-proton catalytic reaction of nitrogenase has been hampered by the fact that electron and proton flow in this system is controlled by ATP-dependent protein-protein interactions. Recent studies have shown that it is possible to circumvent the dependence on ATP through the use of potent small-molecule reductants or light-driven electron injection, but success has been limited to two-electron reductions of hydrazine, acetylene, or protons. Here we show that a variant of the molybdenum-iron protein labeled with a Ru-photosensitizer can support the light-driven, six-electron catalytic reduction of hydrogen cyanide into methane and likely also ammonia. Our findings suggest that the efficiency of this light-driven system is limited by the initial one- or two-electron reduction of the catalytic cofactor (FeMoco) to enable substrate binding, but the subsequent electron-transfer steps into the FeMoco-bound substrate proceed efficiently.

Bridging the Gap in Graduate Medical Education: A Longitudinal Pediatric Lesbian, Gay, Bisexual, Transgender, Queer/Questioning Health Curriculum.

OBJECTIVE: Despite known health disparities, there is limited training in lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) health, particularly in pediatric graduate medical education (GME). We aimed to develop a longitudinal LGBTQ curriculum for a pediatrics residency program tailored to the needs and interests of our trainees. METHODS: We developed a year-long curriculum based on a formal needs assessment and evaluated changes in provider knowledge, comfort, and self-reported clinical impact through pre- and postsurveys. RESULTS: The needs assessment was completed by 78 out of 110 providers (70.9% response rate); 60 (54.5%) and 70 (63.6%) completed the pre- and postcurriculum surveys, respectively. Postcurriculum implementation, there was an increase in mean comfort level asking about sexual orientation (4.1-4.5, P < .01), gender identity (3.5-3.8, P = .02), and sexual practices (3.4-3.8, P < .01), psychosocial screening (3.2-4.2, P < .01), applying medical/preventive screening guidelines (2.4-3.6, P < .01), and medically managing transgender patients (1.9-3.1, P < .01). Knowledge-based assessments increased from 25.2% correct to 38.5% (P = .01). Faculty felt significantly more comfortable teaching this material to trainees (21.7-70.0%, P < .01). Providers reported high scores regarding impact on clinical practice (4.0 of 5), intent to change practice (4.5 of 5), importance of (4.8 of 5) and satisfaction with (4.5 of 5) the curriculum. CONCLUSIONS: There is a need to incorporate formal LGBTQ health training in GME. Our curriculum improved provider knowledge, comfort, self-reported clinical practice, and faculty preparedness to teach this material. It can serve as a framework for other pediatric programs to develop their own curricula.

An unmet need for paediatric LGBTQ training.

BACKGROUND: Lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) youth have increased health risks, exacerbated by discrimination and lack of provider training. Currently, no graduate medical education requirements address the need for LGBTQ health training, particularly for paediatric providers. We aimed to perform a needs assessment of provider knowledge, comfort and awareness of community resources regarding LGBTQ youth. METHODS: We administered two anonymous surveys from May to October 2017. The first survey of 73 residents assessed awareness of community resources and comfort providing referrals. A second survey of 110 trainees and faculty assessed comfort and knowledge regarding paediatric LGBTQ health. RESULTS: In the first survey of residents regarding community resources (n = 30, 41% response rate), most did not know where to refer LGBTQ patients for mental health care (67%), transgender care (73%), support groups (87%), emergency shelters (86%) or family resources (87%). Ninety-seven per cent would refer to the social worker. In the second survey of trainees and faculty (n = 78, 71% response rate), most had little or no knowledge regarding pre-exposure prophylaxis (60%), post-exposure prophylaxis (54%), strategies for coming out (68%), homelessness/environmental risks (59%), gender dysphoria (63%), puberty blockade (77%), hormonal (78%) and surgical (81%) transitioning, domestic violence (58%), EMR logistics (89%) and community resources (80%). Only 33% felt very comfortable eliciting a history about sexual orientation, 13% about gender identity and 14% about sexual practices. CONCLUSION: There is a clear need and desire for dedicated paediatric LGBTQ health training in graduate medical education. Residents and faculty need resources and training to better care for LGBTQ youth.

ATP- and iron-protein-independent activation of nitrogenase catalysis by light.

We report here the light-driven activation of the molybdenum-iron-protein (MoFeP) of nitrogenase for substrate reduction independent of ATP hydrolysis and the iron-protein (FeP), which have been believed to be essential for catalytic turnover. A MoFeP variant labeled on its surface with a Ru-photosensitizer is shown to photocatalytically reduce protons and acetylene, most likely at its active site, FeMoco. The uncoupling of nitrogenase catalysis from ATP hydrolysis should enable the study of redox dynamics within MoFeP and the population of discrete reaction intermediates for structural investigations.

A Curriculum to Improve Pediatric Residents' Telephone Triage Skills.

Introduction: Telephone triage systems are frequently used due to their success in decreasing emergency department utilization, reduction of health care costs, and high levels of satisfaction among patients and providers. Despite phone triage's prevalence, few residency programs have designated curricula for residents to learn this vital skill. Methods: We designed a phone triage curriculum initially piloted with senior residents at one of our continuity clinics. The curriculum consisted of a didactic session, a just-in-time simulation training session, and an experiential component of being on call during the ambulatory rotation. Retrospective pre-post self-assessments evaluated resident perceptions of their skills in taking histories and triaging care over the phone in addition to obtaining qualitative feedback from faculty and residents immediately after the curriculum and 1-2 years postgraduation. Results: Of 11 eligible residents, 10 (91%) chose to participate in the pilot curriculum. Residents reported that their skills in history taking over the phone improved from 20% to 90% and their ability to triage patients over the phone improved from 0% to 80%. This led to a quality improvement initiative to increase patient calls and has continued for 5 years, with continued positive feedback from residents and attendings. Discussion: Phone triage skills are a necessity for pediatric providers, but few residency programs have training curricula in place. Through an experience-based phone triage program, residents significantly improved their self-reported skills at history taking and triaging. Similar curricula could easily be adopted at other institutions.

Rainbows and "Ready for Residency": Integrating LGBTQ Health Into Medical Education.

Introduction: To provide appropriate and sensitive care for lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) youth, providers must learn specific skills and guidelines. Most medical schools lack formal education on LGBTQ health, particularly for adolescent patients. Methods: We developed an Introduction to LGBTQ Health course for fourth-year medical students as part of a monthlong Ready for Residency curriculum in March and April of their graduating year. The course addressed guidelines recommended in the care of LGBTQ individuals utilizing problem-based learning methodology. Through learner-led discussion, students worked in small groups to research case-based scenarios and reported their findings to the larger group, followed by teaching points from a facilitator. The course was evaluated on curricular perception using a 5-point Likert scale and open-ended feedback. Results: One hundred forty-six students participated in the curriculum; 103 completed the session evaluation. Mean total scores were 4.6 out of 5 in March and 4.7 out of 5 in April after changes were made based on student feedback, namely, increasing the session from 50 to 80 minutes and decreasing session size from 72 students to 36. Students felt the session was well planned and run, engaging, and relevant; appropriately integrated evidence-based medicine; and taught them what they hoped to learn. Discussion: Many medical schools lack curricula dedicated to LGBTQ health care. Implementing this mandatory LGBTQ health course was well received and highly rated by almost all students regardless of anticipated specialty. The session could be easily replicated at medical schools across the country.

A Resident-Led QI Project to Improve Dental Health at a Primary Care Pediatric Practice.

BACKGROUND: Dental caries are the most common chronic condition of childhood and have significant medical, psychological, and financial consequences. The American Academy of Pediatrics (AAP) recommends primary care physicians apply fluoride varnish (FV) every 3 to 6 months from tooth emergence through age 5. OBJECTIVE: Through a resident-led quality improvement (QI) project, we aimed to provide FV to 50% of patients ages 1 through 5 who did not have a dental visit in the preceding 6 months or receive FV elsewhere in the past month. METHODS: From May 2017 through April 2018, we conducted 7 monthly plan-do-study-act cycles to improve our primary outcome measure (FV application), secondary outcome measure (percentage of patients who had routine dental care), and process measure (percentage of dental referrals). Balancing measures included time taken away from other clinical priorities and reimbursement rates. RESULTS: Fluoride varnish application improved from 3.6% to 44% with a 54% peak. The percentage of patients under 6 who had seen a dentist in the past 6 months increased from 30% to 47%. The percentage of dental referrals increased from 17% to 33%. CONCLUSIONS: Application of FV is a quick, cost-effective way for primary care providers to improve dental health. This resident-led QI project increased rates of FV application, dental referrals, and dental visits while meeting ACGME guidelines for experiential learning in QI. By adapting to state-specific guidelines and workflows of each clinic, this QI project could be nationally reproduced to improve adherence to AAP and United States Preventive Services Task Force guidelines.

A single mutation in the active site swaps the substrate specificity of N-acetyl-L-ornithine transcarbamylase and N-succinyl-L-ornithine transcarbamylase.

Transcarbamylases catalyze the transfer of the carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate such as aspartate, ornithine, or putrescine. Previously, structural determination of a transcarbamylase from Xanthomonas campestris led to the discovery of a novel N-acetylornithine transcarbamylase (AOTCase) that catalyzes the carbamylation of N-acetylornithine. Recently, a novel N-succinylornithine transcarbamylase (SOTCase) from Bacteroides fragilis was identified. Structural comparisons of AOTCase from X. campestris and SOTCase from B. fragilis revealed that residue Glu92 (X. campestris numbering) plays a critical role in distinguishing AOTCase from SOTCase. Enzymatic assays of E92P, E92S, E92V, and E92A mutants of AOTCase demonstrate that each of these mutations converts the AOTCase to an SOTCase. Similarly, the P90E mutation in B. fragilis SOTCase (equivalent to E92 in X. campestris AOTCase) converts the SOTCase to AOTCase. Hence, a single amino acid substitution is sufficient to swap the substrate specificities of AOTCase and SOTCase. X-ray crystal structures of these mutants in complexes with CP and N-acetyl-L-norvaline (an analog of N-acetyl-L-ornithine) or N-succinyl-L-norvaline (an analog of N-succinyl-L-ornithine) substantiate this conversion. In addition to Glu92 (X. campestris numbering), other residues such as Asn185 and Lys30 in AOTCase, which are involved in binding substrates through bridging water molecules, help to define the substrate specificity of AOTCase. These results provide the correct annotation (AOTCase or SOTCase) for a set of the transcarbamylase-like proteins that have been erroneously annotated as ornithine transcarbamylase (OTCase, EC 2.1.3.3).

Structure of a novel N-acetyl-L-citrulline deacetylase from Xanthomonas campestris.

The structure of a novel acetylcitrulline deacetylase from the plant pathogen Xanthomonas campestris has been solved by multiple-wavelength anomalous dispersion (MAD) using crystals grown from selenomethionine-substituted protein and refined at 1.75 A resolution. The asymmetric unit of the crystal contains one monomer consisting of two domains, a catalytic domain and a dimerization domain. The catalytic domain is able to bind a single Co(II) ion at the active site with no change in conformation. The dimerization domain forms an interface between two monomers related by a crystallographic two-fold symmetry axis. The interface is maintained by hydrophobic interactions between helices and hydrogen bonding between two beta strands that form a continuous beta sheet across the dimer interface. Because the dimers are also related by two-fold crystallographic axes, they pack together across the crystal via the dimerization domain, suggesting that higher order oligomers may form in solution. The polypeptide fold of the monomer is similar to the fold of Pseudomonas sp. carboxypeptidase G2 and Neisseria meningitidis succinyl diaminopimelate desuccinylase. Structural comparison among these enzymes allowed modeling of substrate binding and suggests a possible catalytic mechanism, in which Glu130 functions as a bifunctional general acid-base catalyst and the metal ion polarizes the carbonyl of the acetyl group.

Redefining "Medical Care."

President Donald J. Trump has said he will repeal the Affordable Care Act (ACA) and replace it with health savings accounts (HSAs). Conservatives have long preferred individual accounts to meet social welfare needs instead of more traditional entitlement programs. The types of "medical care" that can be reimbursed through an HSA are listed in section 213(d) of the Internal Revenue Code (Code) and include expenses "for the diagnosis, cure, mitigation, treatment, or prevention of disease, or for the purpose of affecting any structure or function of the body." In spite of the broad language, regulations and court interpretations have narrowed this definition substantially. It does not include the many social factors that determine health outcomes. Though the United States spends over seventeen percent of gross domestic product (GDP) on "healthcare", the country's focus on the traditional medicalized model of health results in overall population health that is far beneath the results of other countries that spend significantly less. Precision medicine is one exceptional way in which American healthcare has focused more on individuals instead of providing broad, one-size-fits-all medical care. The precision medicine movement calls for using the genetic code of individuals to both predict future illness and to target treatments for current illnesses. Yet the definition of "medical care" under the Code remains the same for all. My proposal for precision healthcare accounts involves two steps-- the first of which requires permitting physicians to write prescriptions for a broader range of goods and services. The social determinants of health are as important to health outcomes as are surgical procedures and drugs--or perhaps more so according to many population health studies. The second step requires agencies and courts to interpret what constitutes "medical care" under the Code differently depending on the taxpayer's income level. Childhood sports programs and payments for fruits and vegetables may be covered for those in the lower income brackets who could not otherwise afford these items and would not choose to spend scarce resources on them if they could. This all assumes that the government takes funds previously used to subsidize the purchase of health insurance under the ACA (or allocates new funds) and puts the funds in individual accounts so the poor or near poor have money to pay for these expenses. Section I of this Article will explore the current definition of medical care, which excludes the social determinants of health from "healthcare" spending. I then address how precision medicine has changed the types of services and treatments that it makes sense to reimburse for each individual. If efficacy can vary from person to person based on genetic code, then it also can vary depending on environment. There is an opportunity to not only vary the types of "medical care" that can be reimbursed or deducted within the traditional range of services and drugs, but also outside of that range. Section II addresses the historical shift towards health financing through individual accounts, and specifically through HSAs. If this is the only avenue for health reform in the next few years, I advocate using it to engage in the type of experiments that are typically only possible under the cover of tax expenditures. My proposal for precision healthcare accounts moves the government to experiment with individual social spending that can lead to improved overall health outcomes. Finally, in Section III, I address two dichotomies that affect any healthcare proposal: (1) entitlement programs v. grants-in-aid, and (2) pooled insurance v. consumer-driven health plans (CDHPs). In the end, I argue that an entitlement method of funding precision HSAs along with pooled insurance subsidized by the government is the most realistic resolution to these dichotomies. Only a broad-based entitlement to funding for all healthcare expenses (medical and social) allows for significant improvements in overall population health.

Structures of N-acetylornithine transcarbamoylase from Xanthomonas campestris complexed with substrates and substrate analogs imply mechanisms for substrate binding and catalysis.

N-acetyl-L-ornithine transcarbamoylase (AOTCase) is a new member of the transcarbamoylase superfamily that is essential for arginine biosynthesis in several eubacteria. We report here crystal structures of the binary complexes of AOTCase with its substrates, carbamoyl phosphate (CP) or N-acetyl-L-ornithine (AORN), and the ternary complex with CP and N-acetyl-L-norvaline. Comparison of these structures demonstrates that the substrate-binding mechanism of this novel transcarbamoylase is different from those of aspartate and ornithine transcarbamoylases, both of which show ordered substrate binding with large domain movements. CP and AORN bind to AOTCase independently, and the main conformational change upon substrate binding is ordering of the 80's loop, with a small domain closure around the active site and little movement of the 240's loop. The structures of the complexes provide insight into the mode of substrate binding and the mechanism of the transcarbamoylation reaction.