Patient-Reported Outcomes in Autosomal Dominant Osteopetrosis: Findings from the Osteopetrosis Registry Study.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and skeletal fragility. The full phenotype and disease burden on patients' daily lives has not been systematically measured. OBJECTIVE: We developed an online registry to ascertain population-based data on the spectrum and rate of progression of disease and to identify relevant patient centered outcomes that could be used to measure treatment effects and guide the design of future clinical trials. DESIGN: Cross-sectional data from participants with osteopetrosis were collected using an online REDCap-based database. PARTICIPANTS: Thirty-four participants with a confirmed diagnosis of ADO, aged 4-84 years. MAIN OUTCOME MEASURES: Participants aged 18 years and older completed the PROMIS 57, participants aged 8 to 17 years completed the PROMIS Pediatric 49, and parents of participants aged <18 years completed the PROMIS Parent Proxy 49. RESULTS: Based on the PROMIS 57, relative to the general population, adults with ADO reported low physical function and low ability to participate in social roles and activities, and high levels of anxiety, fatigue, sleep problems, and pain interference. Daily pain medications were reported by 24% of the adult population. In contrast, neither pediatric participants, nor their parent proxy reported a negative impact on health-related quality of life. CONCLUSIONS: Data from this registry demonstrate the broad spectrum of ADO disease severity and high impact on health-related quality of life in adults with ADO.

Autosomal Dominant Osteopetrosis (ADO) caused by a Missense Variant in the TCIRG1 Gene.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder due to impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in one patient with ADO. CASE DESCRIPTION: Here we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of five protein prediction programs suggest this variant likely inhibits the function of TCIRG1. CONCLUSIONS: This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with two subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.

Hospital Care for Patients Uninsured due to Immigration Status during the COVID-19 Pandemic in Toronto: Lessons from Front-Line Knowledge Translation.

Before the COVID-19 pandemic, patients in Ontario who were uninsured due to immigration status faced barriers to hospital care that resulted in preventable illness and death. In March 2020, the Ontario Ministry of Health issued a memo indicating that it would pay for medically necessary hospital services for uninsured patients (Ontario Ministry of Health 2020). Front-line providers and research workers associated with the Health Network for Uninsured Clients (HNUC) set out to ensure that hospitals in Toronto implemented the ministry's memo. In this paper, we demonstrate a model of front-line worker-led knowledge translation informed by real-time data and anchored in clearly articulated values and goals. On April 1, 2023, the Ontario Ministry of Health cancelled this uninsured coverage (Ontario Ministry of Health 2023). Healthcare provider associations, grassroots groups and coalitions - including the HNUC - are mobilizing to see this uninsured coverage reinstated.

Assessment of adolescent decision-making capacity for pharmacy access to hormonal contraception.

OBJECTIVES: To examine adolescents' decision-making capacity for pharmacsist-prescribed hormonal contraception. STUDY DESIGN: A subset of 60 females, ages 14-21, were recruited to complete the MacArthur Competence Assessment Tool-Treatment. Overall scores were compared by age and demographic factors and variation examined. RESULTS: Participants scored high on the MacArthur Competence Assessment Tool-Treatment with little variation in the scores (18.8 [±1.9]/20 total points). Factors such as chronic illness, health literacy, and family affluence were not associated with of overall scores. CONCLUSIONS: Adolescents and young adults have the capacity to make decisions regarding contraception in the pharmacy access settings.

Adolescent Women with Congenital Heart Disease: Self-Reported Reproductive Health Discussions with Health Care Providers.

STUDY OBJECTIVE: This study evaluated self-reported discussions with health care providers (HCPs) among adolescent and young adult (AYA) women with congenital heart disease (CHD). DESIGN: Data were collected through a one-time survey of AYA women. SETTING: Participants were recruited from pediatric cardiology clinics. PARTICIPANTS: AYA women with CHD, ages 14-21 (N = 107) INTERVENTIONS: None MAIN OUTCOME MEASURES: Questionnaires assessed adolescent characteristics and specific HCP discussions regarding transmissibility of a cardiac condition to the infant, risk of pregnancy, and hormonal contraception. Outcome measures were self-reported discussions with HCPs about these reproductive health topics. RESULTS: Mean age was 16.8 years (SD = 2.1). Self-reported reproductive health discussions were infrequent, including discussions on transmissibility of a heart condition to their offspring (37%), risk of pregnancy to their offspring (34%), risks of pregnancy to their health (46%), and risks of hormonal contraception given their heart condition (21%). Reported discussions were most commonly with a cardiologist. CONCLUSIONS: AYA women with CHD reported limited discussions about reproductive health topics important to those with CHD. Lack of appropriate and timely counseling could lead to poor maternal and child health outcomes. Targeted interventions that improve reproductive health discussions between HCPs and AYA women with CHD are needed to close critical information and service gaps.

Adolescents' and Young Adults' Ability to Self-Screen for Contraindications to Hormonal Contraception and the Role of Chronic Illness.

PURPOSE: Multiple states allow pharmacists to prescribe hormonal contraception but can have age restrictions. The study objective was to examine how age influences adolescents' and young adults' (AYAs) ability to self-report potential contraindications to hormonal contraception compared with physician reports (our "gold standard"). METHODS: Between February 2017 and August 2018, girls aged 14-21 years and their physicians were recruited in outpatient adolescent primary and subspecialty care clinics. Screeners were completed separately for medical conditions that are potential contraindications to hormonal contraception as defined by the Centers for Disease Control Medical Eligibility Criteria. Overall, discordance was defined as differences between the patient's and provider's answers, and potential unsafe discordance was defined as AYAs underreporting of contraindications. Multivariable logistic regression was used to examine predictors of overall and unsafe discordance. RESULTS: Of 394 AYA/physician pairs, 45% were from subspecialty clinics, 35% identified as African American, the mean age was 16.7 ± 1.9 years, and 38% were sexually active. Fifty percent of patients reported potential contraindications to hormonal contraception. There was only an 18% rate of unsafe discordance, with no statistical difference by age but a higher rate in subspecialty clinics (28% vs. 10%). No variables were predictive of higher rates of unsafe discordance in general or subspecialty clinics. CONCLUSIONS: Potential overall and unsafe discordance between AYAs' and physicians' reports of medical contraindications to combined hormonal contraception were not related to younger age and thus support expansion of pharmacy access to adolescents. Pediatric subspecialists need to proactively address hormonal contraceptive needs and safety as pharmacy access expands.

Reproductive health conversations in adolescents with CHD.

BACKGROUND: Reproductive issues as related to CHD must be discussed in the clinic and at home. Providers can ensure that correct information is imparted to the adolescent and encourage mothers to provide support and guidance to the adolescent. The level to which these conversations occur is unknown. METHODS: A survey distributed to female adolescent/mother dyads assessed self-reported conversations with the healthcare provider and between each other about reproductive health topics. A clinician survey was completed to assess CHD diagnosis, risk of hormonal contraception, and pregnancy risk. RESULTS: Among 91 dyads, 33.0% of adolescents and 42.9% of mothers reported discussing recurrence risk of CHD with the provider. In regard to the cardiac lesion affecting a baby, 30.7% of adolescents and 28.7% of mothers reported discussing this with a provider. Significantly less adolescents and mothers reported discussing the risks of hormonal contraception and pregnancy with a provider. In assessing conversations between adolescents and mothers, only 44.2% of adolescents and 52.3% of mothers reported discussing with each other the safety of using birth control and 46.5% of adolescents and 64.0% of mothers reported discussing the safety of pregnancy. CONCLUSIONS: Adolescents with CHD and their mothers report low rates of reproductive health-related conversations with the healthcare provider, and mothers report low rates of having these conversations with their daughters. These topics should be discussed at each appointment with the cardiologist and must be encouraged to continue at home.

Measuring research mistrust in adolescents and adults: Validity and reliability of an adapted version of the Group-Based Medical Mistrust Scale.

Mistrust of health care providers among persons of color is a significant barrier to engaging them in research studies. Underrepresentation of persons of color is particularly problematic when the health problem under study disproportionately affects minoritized communities. The purpose of this study was to test the validity and reliability of an abbreviated and adapted version of the Group Based Medical Mistrust Scale. The GBMMS is a 12-item scale with three subscales that assess suspicion, experiences of discrimination, and lack of support in the health care setting. To adapt for use in the research setting, we shortened the scale to six items, and replaced "health care workers" and "health care" with "medical researchers" and "medical research," respectively. Using panelists from a market research firm, we recruited and enrolled a racially and ethnically diverse sample of American adults (N = 365) and adolescents aged 14-17 (N = 250). We administered the adapted scale in a web-based survey. We used Cronbach's alpha to evaluate measure internal reliability of the scale and external factor analysis to evaluate the relationships between the revised scale items. Five of the six items loaded onto a single factor, with (α = 0.917) for adolescents and (α = 0.912) for adults. Mean scores for each item ranged from 2.5-2.9, and the mean summary score (range 6-25) was 13.3 for adults and 13.1 for adolescents. Among adults, Black respondents had significantly higher mean summary scores compared to whites and those in other racia/ethnic groups (p<0.001). There was a trend toward significance for Black adolescents as compared to white respondents and those in other racial/ethnic groups (p = 0.09). This five-item modified version of the GBMMS is reliable and valid for measuring research mistrust with American adults and adolescents of diverse racial and ethnic identities.

Tapping into Community Resiliency in Rural Adolescent Pregnancy Prevention: An Implementation Sciences Approach.

Although rural youth experience marked inequities in adolescent pregnancy, there is little guidance for implementing evidence-based programs (EBPs) in rural settings. When implementation occurs in rural communities, it frequently focuses on deficits, rather than strengths or capacity for growth. Using the consolidated framework for implementation research (CFIR), we describe a resiliency-focused implementation of two middle school EBPs in rural Midwestern communities, including the intervention, outer and inner settings, individuals, implementation processes and preliminary outcomes. Data included program staff interviews, feedback from local partners, community meetings notes, and participant surveys. Using the CFIR, we describe the engagement of rural communities themselves in a resilience-based implementation of adolescent pregnancy prevention EPBs. Communities self-described as rural, traditional and religious. They identified adolescent pregnancy, substance use, and academic success as priorities. To address infrastructure needs and build on local strengths, funds were used to hire local partners to implement the program. As small communities, stakeholders were closely networked and wanted to address local needs. Local partners selected the EBP based upon community values and priorities. Champions, including local partner organizations and schools were locally based and were well connected. Intensive training of local staff and piloting with adaptation assured fidelity and sustainability, while increasing community implementation skills and comfort. In Clinton County, enrollment was 1946 with students receiving the program in 6th, 7th, and/or 8th grades. In Southern Indiana, 7275 students received the program once in either 6th, 7th, or 8th. We conclude that the CFIR can facilitate the implementation of a community resilience-focused adolescent pregnancy prevention intervention in rural communities.

Menstrual Dysfunction and Treatment Among Adolescents With Congenital Heart Disease.

STUDY OBJECTIVE: This study describes menstrual dysfunction and treatment among adolescent and young adult (AYA) females with congenital heart disease (CHD). DESIGN: Data collected from a 1-time survey completed by AYA females (and mothers if AYA unable). SETTING: Participants were recruited from pediatric cardiology clinics. PARTICIPANTS: Female AYA with CHD, aged 14-21 years (N = 114). INTERVENTIONS: None. MAIN OUTCOME MEASURES: The questionnaire assessed sexual and reproductive health (SRH) concerns, behaviors, and management. Outcome measures were self-reported menstrual complaints, use of over-the-counter (OTC) pain relief medications for dysmenorrhea, reported visits with a clinician for a menstrual problem, and reported use of hormones for menstrual problems or birth control. RESULTS: Mean age was 17.0 years (SD = 2.2). The majority of participants (83%) reported 1 or more menstrual complaints (67.5% cramping, 42.1% irregular menses, 46.5% heavy periods), and 88% reported any history of taking OTC medications for pain relief. Increased menstrual complaints were not associated with level of cardiac complexity, reported transplantation, or reported use of hormonal contraception. However, 32% of participants reported use of hormonal contraception for menstrual dysfunction. Combined oral contraceptive pills (COCs) were the most common; 2 of these women carried contraindications to estrogen. CONCLUSIONS: A large majority of AYA females with CHD reported menstrual dysfunction. Use of OTC medication for menstrual pain and inappropriate use of estrogen creates concerns that menstrual disorders may be unaddressed or addressed inappropriately. Thus, gynecological needs of adolescents with CHD may need to be specifically targeted by providers who feel comfortable with this population and their complex needs.

Only Yes Means Yes: Sexual Coercion in Rural Adolescent Relationships.

PURPOSE: Sexual consent is important to healthy relationships; however, sexual coercion is common. We examine modifiable risk and protective factors for sexual coercion among high school students in a rural community. METHODS: We surveyed 10th graders (N = 442) in a rural, Midwestern, low-to-middle income county before receiving an evidence-based sex education program. Sexual coercion was a single item, "has anyone you were dating or going out with forced you to do sexual things that you did not want to do?" We examined associations between sexual coercion and demographics, risk behaviors, sexual self-efficacy, controlling relationship behaviors, parent communication, and adverse childhood experiences. RESULTS: Approximately 22% of females and 8% of males reported experiencing sexual coercion at least once in their lifetime. Gender differences emerged in associated risk and protective factors, including sexual sex efficacy, controlling relationship behaviors, parent-adolescent communication about sex, and adverse childhood experiences. CONCLUSIONS: Sexual coercion is common among adolescents in rural communities. Prevention interventions should target modifiable risk and protective factors.

Social Impact Bonds as a Funding Method for Health and Social Programs: Potential Areas of Concern.

Social Impact Bonds (SIBs) represent a new way to finance social service and health promotion programs whereby different types of investors provide an upfront investment of capital. If a given program meets predetermined criteria for a successful outcome, the government pays back investors with interest. Introduced in the United Kingdom in 2010, SIBs have since been implemented in the United States and across Europe, with some uptake in other jurisdictions. We identify and explore selected areas of concern related to SIBs, drawing from literature examining market-based reforms to health and social services and the evolution of the SIB funding mechanism. These areas of concern include increased costs to governments, restricted program scope, fragmented policymaking, undermining of public-sector service provision, mischaracterization of the root causes of social problems, and entrenchment of systemically produced vulnerabilities. We argue that it is essential to consider the long-term, aggregate, and contextualized effects of SIBs in order to evaluate their potential to contribute to public health. We conclude that such evaluations must explore the assumptions underlying the "common sense" arguments often used in support of SIBs.

Bringing stakeholders together for urban health equity: hallmarks of a compromised process.

There is a global trend towards the use of ad hoc participation processes that seek to engage grassroots stakeholders in decisions related to municipal infrastructure, land use and services. We present the results of a scholarly literature review examining 14 articles detailing specific cases of these processes to contribute to the discussion regarding their utility in advancing health equity. We explore hallmarks of compromised processes, potential harms to grassroots stakeholders, and potential mitigating factors. We conclude that participation processes often cut off participation following the planning phase at the point of implementation, limiting convener accountability to grassroots stakeholders, and, further, that where participation processes yield gains, these are often due to independent grassroots action. Given the emphasis on participation in health equity discourse, this study seeks to provide a real world exploration of the pitfalls and potential harms of participation processes that is relevant to health equity theory and practice.

Metal ion roles and the movement of hydrogen during reaction catalyzed by D-xylose isomerase: a joint x-ray and neutron diffraction study.

Conversion of aldo to keto sugars by the metalloenzyme D-xylose isomerase (XI) is a multistep reaction that involves hydrogen transfer. We have determined the structure of this enzyme by neutron diffraction in order to locate H atoms (or their isotope D). Two studies are presented, one of XI containing cadmium and cyclic D-glucose (before sugar ring opening has occurred), and the other containing nickel and linear D-glucose (after ring opening has occurred but before isomerization). Previously we reported the neutron structures of ligand-free enzyme and enzyme with bound product. The data show that His54 is doubly protonated on the ring N in all four structures. Lys289 is neutral before ring opening and gains a proton after this; the catalytic metal-bound water is deprotonated to hydroxyl during isomerization and O5 is deprotonated. These results lead to new suggestions as to how changes might take place over the course of the reaction.

Hydrogen location in stages of an enzyme-catalyzed reaction: time-of-flight neutron structure of D-xylose isomerase with bound D-xylulose.

The time-of-flight neutron Laue technique has been used to determine the location of hydrogen atoms in the enzyme d-xylose isomerase (XI). The neutron structure of crystalline XI with bound product, d-xylulose, shows, unexpectedly, that O5 of d-xylulose is not protonated but is hydrogen-bonded to doubly protonated His54. Also, Lys289, which is neutral in native XI, is protonated (positively charged), while the catalytic water in native XI has become activated to a hydroxyl anion which is in the proximity of C1 and C2, the molecular site of isomerization of xylose. These findings impact our understanding of the reaction mechanism.

Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites.

1,4-Difluorobenzo[c]phenanthrene (1,4-DFBcPh) and its putative metabolites, the dihydrodiol and diol epoxides, have been synthesized and structurally characterized, and the extent of DNA binding by the metabolites has been assessed. 1,4-DFBcPh and 1,4-difluoro-10-methoxybenzo[c]phenanthrene were prepared by photochemical cyclization of appropriate naphthylphenylethylenes. The dihydrodiol was synthesized from 1,4-difluoro-10-methoxybenzo[c]phenanthrene, and the diol epoxides were diastereoselectively synthesized from the dihydrodiol. Interesting differences were noted in 1H NMR spectra of the series 1 (syn) diol epoxides of benzo[c]phenanthrene (BcPh) and 1,4-DFBcPh; the BcPh diol epoxide displays a quasi-diequatorial orientation of the hydroxyl groups, but in the 1,4-DFBcPh case these are diaxially disposed. This difference probably stems from the presence of the fjord-region fluorine atom in 1,4-DFBcPh. A through-space, fjord-region H-F coupling has also been observed for 1,4-DFBcPh and its derivatives. Comparative X-ray crystallographic analyses of BcPh and 1,4-DFBcPh and their dihydrodiols show that introduction of fluorine increases the molecular distortion by about 6-7 degrees . As a guide to estimating the molecular distortion and its effects, and for comparison with the X-ray structures in known cases, optimized structures of BcPh, 1,4-DFBcPh, and 1,4-DMBcPh (the dimethyl analogue) as well as their dihydrodiols and diol epoxides were computed. Relative aromaticities of these compounds were assessed by nucleus-independent chemical shift calculations, and 13C NMR chemical shifts were computed by gauge-inducing atomic orbital calculations. 1,4-DFBcPh and its dihydrodiol were subjected to metabolism, and the amount of DNA binding in human breast cancer MCF-7 cells was assessed. The extent of DNA binding was then compared with that for BcPh and its dihydrodiol and the potent carcinogen benzo[a]pyrene. The 1,4-DFBcPh series 2 (anti) diol epoxide-derived DNA adducts were also compared with those arising from intracellular oxidation of the dihydrodiol with subsequent DNA binding. These experiments showed that increased molecular distortion decreased metabolic activation to the terminal metabolites but that diol epoxide metabolites that are formed are the DNA-damaging species.

Locating active-site hydrogen atoms in D-xylose isomerase: time-of-flight neutron diffraction.

Time-of-flight neutron diffraction has been used to locate hydrogen atoms that define the ionization states of amino acids in crystals of D-xylose isomerase. This enzyme, from Streptomyces rubiginosus, is one of the largest enzymes studied to date at high resolution (1.8 A) by this method. We have determined the position and orientation of a metal ion-bound water molecule that is located in the active site of the enzyme; this water has been thought to be involved in the isomerization step in which D-xylose is converted to D-xylulose or D-glucose to D-fructose. It is shown to be water (rather than a hydroxyl group) under the conditions of measurement (pH 8.0). Our analyses also reveal that one lysine probably has an -NH(2)-terminal group (rather than NH(3)(+)). The ionization state of each histidine residue also was determined. High-resolution x-ray studies (at 0.94 A) indicate disorder in some side chains when a truncated substrate is bound and suggest how some side chains might move during catalysis. This combination of time-of-flight neutron diffraction and x-ray diffraction can contribute greatly to the elucidation of enzyme mechanisms.