Cytochrome P450-catalyzed oxidation of halogen-containing substrates.

Cytochrome P450 (CYP) enzymes are heme-thiolate monooxygenases which catalyze the oxidation of aliphatic and aromatic C-H bonds and other reactions. The oxidation of halogens by cytochrome P450 enzymes has also been reported. Here we use CYP199A4, from the bacterium Rhodopseudomonas palustris strain HaA2, with a range of para-substituted benzoic acid ligands, which contain halogens, to assess if this enzyme can oxidize these species or if the presence of these electronegative atoms can alter the outcome of P450-catalyzed reactions. Despite binding to the enzyme, there was no detectable oxidation of any of the 4-halobenzoic acids. CYP199A4 was, however, able to efficiently catalyze the oxidation of both 4-chloromethyl- and 4-bromomethyl-benzoic acid to 4-formylbenzoic acid via hydroxylation of the α­carbon. The 4-chloromethyl substrate bound in the enzyme active site in a similar manner to 4-ethylbenzoic acid. This places the benzylic α­carbon hydrogens in an unfavorable position for abstraction indicating a degree of substrate mobility must be possible within the active site. CYP199A4 catalyzed oxidations of 4-(2'-haloethyl)benzoic acids yielding α-hydroxylation and desaturation metabolites. The α-hydroxylation product was the major metabolite. The desaturation pathway is significantly disfavored compared to 4-ethylbenzoic acid. This may be due to the electron-withdrawing halogen atom or a different positioning of the substrate within the active site. The latter was demonstrated by the X-ray crystal structures of CYP199A4 with these substrates. Overall, the presence of a halogen atom positioned close to the heme iron can alter the binding orientation and outcomes of enzyme-catalyzed oxidation.

Transnational Caregiving and Grief: An Autobiographical Case Study of Loss and Love During the COVID-19 Pandemic.

This article examines grief while providing transnational caregiving during the COVID-19 pandemic. There are an estimated 275 million migrants living in their destination homeland which is 3.5% of the global population. The transnational family strives to maintain solidarity, intergenerational ties, and cultural values while sustaining family structure across international borders. Transnational caregiving is the exchange of support and care across distance and international borders. The devastating assault of COVID-19 on older adults impacted caregiving significantly, especially transnational caregiving. A qualitative case study method was selected to examine a participant's understanding and experience of transnational caregiving during the COVID-19 pandemic. Through the interviews and writing of the narrative summary, five themes emerged related to transnational caregiving and COVID-related losses -exposure to sudden and unexpected death, isolation, guilt, loss and change of traditions, and lack of closure.

Transition Navigator Intervention Improves Transition Readiness to Adult Care for Youth With Sickle Cell Disease.

OBJECTIVE: Adolescents and young adults (AYA) with sickle cell disease (SCD) experience high rates of acute care utilization and increased morbidity. At this high-risk time, they also face the need to transition from pediatric to adult services, which, if poorly coordinated, adds to heightened morbidity and acute care utilization. The study objective was to characterize the feasibility, acceptability, and short-term efficacy of a protocolized transition navigator (TN) intervention in AYA with SCD. METHODS: We developed a protocolized TN intervention that used ecological assessment and motivational interviewing to assess transition readiness, identify goals, and remove barriers to transition, and to provide disease and pain management education and skills to AYAs with SCD. RESULTS: Ninety-three percent (56/60) of enrolled individuals completed the intervention. Participation in the TN program was associated with significant improvement in mean transition readiness scores (3.58-4.15, P < .0001), disease knowledge scale (8.91-10.13, P < .0001), Adolescent Medication Barriers Scale (40.05-35.39, P = .003) and confidence in both disease (22.5-23.96, P = .048) and pain management (25.07-26.61, P = .003) for youth with SCD. CONCLUSION: The TN intervention was acceptable to youth with SCD, feasible to implement at an urban academic medical center, and addressed barriers to transition identified by the youth. Longer-term assessment is needed to determine if the TN intervention improved successful transfer to and retention in adult care.

Health-care Transition: A Vital Part of Care, Growth, and Change for Pediatric Patients.

Preparing all youth for the transition to adult-oriented care, adulthood itself, and a greater responsibility for their own health and health-care is an essential part of pediatric care. This process, typically described as health-care transition, can occur throughout ongoing pediatric health-care to prepare patients for transfer to an adult clinician and integration into adult care. Gaps remain in practice and in outcomes research regarding health-care transition. This review discusses recent literature, details best practices, and recommends guidance and tools to assist pediatric clinicians in providing a smooth transition process and a successful transfer to adult care for youth with and without special health-care needs.

Long-term psychosocial outcomes of adults transplanted in childhood: A social work perspective.

While much research exists regarding medical outcomes for pediatric end stage renal disease (ESRD) populations and for adults receiving dialysis or kidney transplant, the understanding of long-term psychosocial outcomes for individuals diagnosed with ESRD or transplanted in childhood remains limited. A literature review was undertaken by two social work researchers to identify relationship, education, employment, and quality of life (QOL) outcomes for this population utilizing PUBMED and PsycInfo databases. Inconsistencies in the MeSH terms and keywords used across the relevant articles were noted. The impact of transplantation in childhood is significant across multiple facets of social development including but not limited to peer/intimate relationships, education and employment and QOL, and overall well-being. When compared to healthy peers, those with ESRD were delayed in all areas of social development. While improvements in psychosocial outcomes have occurred alongside improved graft and patient survival, more focused longitudinal and qualitative inquiry is needed. Partnerships are needed across disciplines and across those caring for different age cohorts in pediatric, adult nephrology, and transplant practices.

Clinical trial readiness study of distal myopathy and dysphagia in nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is a lysosomal storage disorder with late-onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. METHODS: We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. RESULTS: There were significant differences in the Timed Up and Go Test (TUG) and Timed 25-Foot Walk (25-FW) between baseline and 1-y follow-up (P < .05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P < .05). CONCLUSIONS: Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and well-being.

Giving Credence to the Experience of X-Linked Hypophosphatemia in Adulthood: An Interprofessional Mixed-Methods Study.

PURPOSE: X-linked hypophosphatemia (XLH) is a rare X-linked dominant metabolic bone disease, often diagnosed in childhood but causing increasing physical debilitation and pain in adulthood. Physical comorbidities of XLH in adulthood include pervasive and early-onset degenerative arthritis, mineralizing enthesophytes and osteophytes, osteomalacia and pseudofracture, dental abscesses, and hearing loss. METHODS: This mixed-methods analysis included physical findings, diagnostic imaging, occupational and physical therapy assessments, and semi-structured interviews by social work to understand the functional outcomes and lived experience of XLH in adulthood, through connections between qualitative data obtained by social work and occupational therapy with the quantitative findings from other disciplines. RESULTS: Three primary themes of chronic pain, fear of falling, and lack of credence given by health care providers emerged from qualitative data and could be correlated with physical findings from functional outcome assessments These concerns contrasted with resilience, adaption, and compensation demonstrated by participants. CONCLUSIONS: While new treatments may ease the burden of disease for adults with XLH, further research, increased provider awareness and education, and further development of standards of care are needed to promote accurate and adequate assessment and intervention for adults with XLH.

Clinical myopathy in patients with nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is a lysosomal storage disorder. Patient survival years after renal transplantation has revealed systemic complications including distal myopathy and dysphagia. METHODS: We evaluated 20 adult patients with nephropathic cystinosis using patient-reported and clinical outcome measures. Standard motor measures, video fluoroscopy swallow studies, and tests of respiratory function were performed. We also used Rasch analysis of an initial survey to design a 16-item survey focused on upper and lower extremity function, which was completed by 31 additional patients. RESULTS: Distal myopathy and dysphagia were common in patients with nephropathic cystinosis. Muscle weakness ranges from mild involvement of intrinsic hand muscles to prominent distal greater than proximal weakness and contractures. CONCLUSIONS: In addition to further characterization of underlying dysphagia and muscle weakness, we propose a new psychometrically devised, disease specific, functional outcome measures for distal myopathy in patients with nephropathic cystinosis.

Discussing Future Goals and Legal Aspects of Health Care: Essential Steps in Transitioning Youth to Adult-Oriented Care.

Discussing realistic future goals with the adolescent alone and with family, and reviewing legal aspects of health care transition (HCT), are essential steps in the transition from pediatric to adult-oriented care. Secondary analysis of datasets from 2 studies related to HCT assessed differences in provider practice for youth with and without special health care needs (SHCNs). Across both datasets, between 57% and 68.6% of providers reported some discussion of future goals with adolescent or with family. However, only 28.6% to 31% of providers reported discussing future goals with youth with SHCNs alone. It was rare for providers to report discussing legal aspects of HCT with any youth. Findings identify a gap in discussing future goals and legal aspects of HCT, as part of routine care for adolescents. Additional research to understand barriers and improve likelihood of these steps within HCT is needed.

Leadership, Literacy, and Translational Expertise in Genomics: Challenges and Opportunities for Social Work.

The transdisciplinary field of genomics is revolutionizing conceptualizations of health, mental health, family formation, and public policy. Many professions must rapidly acquire genomic expertise to maintain state-of-the-art knowledge in their practice. Calls for social workers to build genomic capacity come regularly, yet social work education has not prepared practitioners to join the genomics workforce in providing socially just, ethically informed care to all clients, particularly those from vulnerable and marginalized groups. The authors suggest a set of action steps for bringing social work skills and practice into the 21st century. They propose that good genomic practice entails bringing social work values, skills, and behaviors to genomics. With education and training, social workers may facilitate socially just dissemination of genomic knowledge and services across practice domains. Increased genomic literacy will support the profession's mission to address disparities in health, health care access, and mortality.

Multidisciplinary Support for Healthcare Transitioning Across an Urban Healthcare Network.

BACKGROUND: A successful transition from pediatric to adult oriented health care is a vital process in maintaining a patient-centered medical home for youth with special health care needs (YSHCNs). We assessed practices of pediatric providers who transition YSCHNs to adult-oriented medical care in a large urban academic healthcare network. METHODS: A cross-sectional Web-based survey was distributed to 376 generalist and subspecialist pediatric providers. Survey assessed provider-reported utilization of 11 Essential Steps adapted from the 2002 Consensus Statement on Health Care Transitions for YSHCNs, and recent transitioning literature. Compliance score (CS11) was calculated as a sum of steps completed. Additional items assessed knowledge of transitioning literature and respondent demographics. RESULTS: Survey achieved a 28% response rate (n=105), of whom 84 reported assisting transitioning YSHCNs. Only 16.7% of these respondents were compliant with 7 or more of the 11 Essential Steps. Respondents who identified social work or nursing were more likely to have CS11 scores ≥7 compared to those without and were more likely to be compliant with specific steps. CONCLUSION: We found limited and incomplete utilization of recommended transitioning steps for YSHCNs by pediatric providers within a large urban healthcare network. Access to support from social work and nursing was associated with greater utilization of specific recommended steps, and with more optimal compliance. Further research needs to assess the transitioning practices of all members of the multidisciplinary team and whether operationalizing healthcare transition for YSHCNs as a multidisciplinary activity impacts the transitioning process and patient outcomes.

Peer Support and Mentorship in a US Rare Disease Community: Findings from the Cystinosis in Emerging Adulthood Study.

PURPOSE: Medical advances have transformed the rare disease cystinosis from fatal in childhood to chronic and manageable into adulthood. Disease-specific advocacy groups and interaction via the Internet create opportunities for peer support, part of the changing experience and outcomes of the illness. METHODS: This study utilized a qualitative grounded theory approach to explore the experience of emerging adults and adults with cystinosis, and their parents. Individuals (n = 49) from 21 families were recruited online and in person for focus groups and/or individual interviews. RESULTS: Individuals participate in the disease community through comfortability, comparing notes, witnessing/scaling, modeling/mentoring, and going/being public. Participants valued connection to others who shared their diagnosis, and seek to provide support and mentorship to younger patients and their families. Adults with cystinosis perceived themselves as role models but also as examples of potential progression and disability. Going/being public about one's health condition carried emotional and social risks. IMPLICATIONS: Individuals and families benefit from peer support and mentorship from others who share their illness experience. Participation in the disease community helps individuals (and caregivers) negotiate living with illness and the transition to adulthood. Further research regarding these processes within other disease communities is needed.

That eagle covering me: transitioning and connected autonomy for emerging adults with cystinosis.

BACKGROUND: Rare diseases pose transitioning challenges owing to limited provider expertise and changing healthcare systems. The timeframe and developmental changes of emerging adulthood overlap with the transition of patients with cystinosis from pediatric to adult-oriented healthcare. METHODS: This study utilized techniques of qualitative grounded theory to explore the experiences of adults aged 18-47 with cystinosis, and their parents, with a focus on the transition to adulthood and adult-oriented care. Forty-six individuals from 21 families were recruited online and at cystinosis conferences to participate in focus groups and/or individual interviews. The constant comparative method was used to conduct both line-by-line and focused coding of verbatim transcripts. RESULTS: The following elements were reported to be critical to the transition to adulthood and adult-oriented care: gaining skills and responsibility for disease management, progressing toward autonomy while remaining connected to caregivers, and having strong communication with and between providers. CONCLUSIONS: Data analysis identified behaviors and relationships that support and/or threaten autonomy and treatment adherence. Participants described institutional, relational, and practical barriers to transition. Suggestions for improving transitioning include: identifying patient/family strengths and improving pediatric-adult provider partnerships and communication. Further research is needed into the experience of patients before and after transition to adult-oriented care.

"My funky genetics": BRCA1/2 mutation carriers' understanding of genetic inheritance and reproductive merger in the context of new reprogenetic technologies.

Deleterious mutations in the BRCA1/BRCA2 genes elevate lifetime risk of breast and ovarian cancer. Each child of a mutation-positive parent has a 50% chance of inheriting it. Preimplantation genetic diagnosis (PGD) permits prospective parents to avoid the birth of a BRCA-mutation-positive child, introducing predictability into a process historically defined by chance. This investigation explored how BRCA1/2 mutation carriers understand genetic inheritance and consider a child's inheritance of a BRCA1/2 mutation, given the opportunities that exist to pursue PGD. Thirty-nine female and male BRCA1/2 mutation carriers of reproductive age were recruited from urban cancer and reproductive medical centers. Participants completed a standardized educational presentation on PGD and prenatal diagnosis, with pre- and posttest assessments. An interdisciplinary team of qualitative researchers analyzed data using grounded theory techniques. Participants expressed the belief that reproduction yields children with unique genetic strengths and challenges, including the BRCA1/2 mutation, family traits for which predictive tests do not exist, and hypothetical genetic risks. Participants expressed preference for biologically related children, yet stated their genetically "well" partner's lineage would be marred through reproductive merger, requiring the well partner to assume the burden of the BRCA1/2 mutation via their children. Participants expressed diverse views of genetically "well" partners' participation in family planning and risk management decisions. Pressure to use reprogenetic technology may grow as genetic susceptibility testing becomes more widely available. Work with individuals and couples across the disease spectrum must be attuned to the ways beliefs about genetic inheritance play into reproductive decision-making.

'Cancer doesn't have an age': genetic testing and cancer risk management in BRCA1/2 mutation-positive women aged 18-24.

Increasingly, 18-24-year-old women from hereditary breast/ovarian cancer (HBOC) families are pursuing genetic testing, despite their low absolute risks of breast and ovarian cancer and the fact that evidence-based management options used with older high-risk women are not generally available. Difficult clinical decisions in older carriers take on substantially more complexity and value-laden import in very young carriers. As a result, many of the latter receive highly personal and emotionally charged cancer risk information in a life context where management strategies are not well defined. We analyzed 32 in-depth interviews with BRCA1/2 mutation-positive women aged 18-24 using techniques of grounded theory and interpretive description. Participants described feeling vulnerable to a cancer diagnosis but in a quandary regarding their care because evidence-based approaches to management have not been developed and clinical trials have not been undertaken. Our participants demonstrated a wide range of genetic and health literacy. Inconsistent recommendations, surveillance fatigue, and the unpredictability of their having health insurance coverage for surgical risk-reducing procedures led several to contemplate risk-reducing mastectomy before age 25. Parents remained a primary source of emotional and financial support, slowing age-appropriate independence and complicating patient privacy. Our findings suggest that, for 18-24-year-olds, readiness to autonomously elect genetic testing, to fully understand and act on genetic information, and to confidently make decisions with life-long implications are all evolving processes. We comment on the tensions between informed consent, privacy, and the unique developmental needs of BRCA1/2 mutation-positive women just emerging into their adult years.

Nutrition assessment and hormonal influences on body composition in children with chronic kidney disease.

Malnutrition is a serious complication of chronic kidney disease (CKD) in the pediatric population. Management of the nutritional status of children presents the challenge of ensuring sufficient energy to promote linear growth, development of brain and organs, and maintenance of appropriate fat and muscle stores, while preventing excess protein intake and controlling electrolytes. Aggressive nutrition intervention in the early stages of CKD may be critical in the prevention of more serious complications further in the disease process. Nutrition assessment involves analysis of dietary intake, anthropometric parameters, and laboratory data. Currently, no guidelines are available for nutritional management of pediatric patients with CKD before the onset of dialysis. The content and algorithms in this article are intended to serve as a guide in the management of the nutritional status of children with CKD. Although adequate calorie and protein intake is critical in prevention of malnutrition, it is only part of a complex mechanism in the development of cachexia in CKD. Research suggests that the effects of inflammatory cytokines and hormones such as leptin and ghrelin play a role in the development of malnutrition in CKD. As a more thorough understanding of this mechanism emerges, new treatments aimed at inhibiting cachexia can be developed.

Stages of change and transitioning for adolescent patients with obesity and hypertension.

When exploring an adolescent patient's readiness to transition his/her health care to adult practice, it is important to understand the processes that allow for change and which promote self-efficacy and self-care. The large numbers of adolescents with hypertension and obesity, possible antecedents to adult kidney disease, require attention be paid to promoting lifestyle changes and adherence to treatment regimens as these patients enter adulthood. Transitioning to adult care is in many cases an externally imposed change, but a young patient's readiness for this change may be amenable to intervention based on the Stages of Change Model. This article reviews the impact of adolescent obesity and hypertension on future health, the application of the Stages of Change Model in health care and specifically with adolescents, and the concept of transitioning for young patients with special health care needs. The authors suggest that the application of the Stages of Change Model, including the use of motivation interviewing and cognitive-behavioral techniques, may encourage lifestyle change and treatment adherence and assist in preparing patients for transition to the adult health care setting.