Identification of postpartum symptom informedness and preparedness typologies and their associations with psychological health: A latent class analysis.

BACKGROUND: Birthing parents, defined as postpartum women and people with various gender identities who give birth, commonly experience challenging postpartum symptoms. However, many report feeling uninformed and unprepared to navigate their postpartum health. OBJECTIVE: To identify typologies of postpartum symptom informedness and preparedness using latent class analysis (LCA) and to examine the associated patient and healthcare characteristics. METHODS: We used survey data from a large, multi-method, longitudinal research project Postnatal Safety Learning Lab. Participants were recruited using convenience sampling and enrolled between November 2020 and June 2021. LCA was used to identify subgroups of birthing parents with different symptom informedness and preparedness using 10 binary variables (N = 148). Bivariate analysis was conducted to examine the association between characteristics and each typology. FINDINGS: The 3-class models had better fit indices and interpretability for both informedness and preparedness typologies: High, High-moderate, and Moderate-low. The sample characteristics were different by typologies. In the modified discrimination in medical settings assessment, we found higher discrimination scores in the moderate-low informedness and preparedness typologies. The moderate-low preparedness typology had a higher percentage of birthing parents who did not have private insurance, underwent cesarean section, and planned for formula or mixed infant feeding. The median PHQ-4 scores at 4 weeks postpartum were lower among those in high informedness and preparedness typologies. CONCLUSION: In our sample, 18 to 21 % of birthing parents were in the moderate-low informedness or preparedness typologies. Future research and practice should consider providing tailored information and anticipatory guidance as a part of more equitable and supportive care.

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis.

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .

Lupus nephritis kidney biopsy characteristics and preterm birth.

Individuals with lupus nephritis (LN) are at high risk of adverse maternal and fetal outcomes in pregnancy. Outside of pregnancy, proliferative lesions on kidney biopsies are associated with disease progression, but these have not been consistently associated with increased risk in pregnancy. This retrospective, single-center study examines how histologic findings, the timing from kidney biopsy to pregnancy, and the clinical features in the first trimester are associated with preterm birth among individuals with LN. Among 35 deliveries in 31 women, the mean gestational age at delivery was 33.8 weeks. The presence of a urine protein-to-creatinine ratio >0.5 g/g in the first trimester was associated with preterm delivery (81% vs. 36%, p = 0.04). Preterm birth was more common in individuals with glomerular crescents on biopsy (89% in those with >20% crescents vs. 50% in those with <20%, p = 0.06). A pregnancy occurring within 2 years after a kidney biopsy was more likely to result in preterm birth than if the biopsy was performed more than 2 years prior to conception (82% vs. 23%, p = 0.01). The time from diagnostic biopsy may be a surrogate for disease activity, and a 2-year delay from biopsy might allow sufficient time to achieve disease remission. Overall, these data could aid family planning discussions and promote preconception disease optimization for patients and their providers.

Allopurinol: Clinical Considerations in the Development and Treatment of Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Other Associated Drug Reactions.

Allopurinol lowers urate production through the inhibition of xanthine oxidase. It is oxidatively hydroxylated to oxypurinol and is the most prescribed medication for gout treatment. Although it has a beneficial effect in the treatment of this common disease, like many medications, it is also known for having numerous adverse effects. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), diseases that exist on a spectrum, are two of the most dangerous adverse effects associated with allopurinol use. These immune-mediated disease processes involve almost every organ system. They are essential to recognize as early as possible, as they could potentially be deadly, requiring cessation of the medication with initial signs of rash or other early manifestations of SJS/TEN. One major consideration in the increased risk of allopurinol-mediated or modulated SJS/TEN is the need to have a lower dose in the setting of renal disease. The purpose of this review is not only to examine the involvement of allopurinol in SJS/TEN but also to provide detailed information about the drug, allopurinol, and general features and characteristics of SJS/TEN and other associated drug reactions.

MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction.

Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained ß-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho-Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/ß-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis.

Examining School Nurses' Knowledge and Confidence Related to Their Intention to Screen for and Report Child Sexual Abuse: A Descriptive Cross-Sectional Study.

BACKGROUND: Child sexual abuse (CSA) is a preventable national public health problem that results in adverse health consequences. Research suggests youth experiencing CSA are often of school age. Screening for early detection of health issues is integral to school nurse (SN) practice. Still, there is little evidence that routine screening when CSA is suspected is occurring in schools, despite recommendations that it should be. Lack of confidence and knowledge related to screening and reporting for CSA contribute to a SN's missed opportunity for early intervention. PURPOSE: The aim of this study was to describe SNs' knowledge and self-efficacy associated with screening for and reporting suspected CSA in school settings. METHODS: A descriptive cross-sectional survey design was employed. The Child Abuse Report Intention Scale was sent to over 2,000 members of the National Association of School Nurses. RESULTS: Among SN respondents (N = 123), the main findings showed almost half reported being concerned a youth was experiencing CSA but may have missed identifying it. Self-efficacy and professional responsibility were predictors of SNs' intention to screen as well as knowledge about obvious and serious signs of abuse were predictors of SNs' intention to report in this sample. IMPLICATIONS: An educational partnership between forensic nurse examiners and SNs can facilitate improving SNs' knowledge about nonspecific physical and behavioral indicators of abuse that are not overtly obvious. The development of a screening tool specific for use by SNs can empower their confidence to screen by providing a resource for them to use as a guide when they are uncertain about the evidence.

Birthing Parent Experiences of Postpartum at-Home Blood Pressure Monitoring Versus Office-Based Follow up After Diagnosis of Hypertensive Disorders of Pregnancy.

Hypertensive disorders of pregnancy are a leading cause of pregnancy-related morbidity and mortality. The primary objective of this study was to compare the frequency of documentation of postpartum blood pressure through remote blood pressure monitoring with text-message delivered reminders versus office-based follow-up 7-10 days postpartum. The secondary objective was to examine barriers and facilitators of both care strategies from the perspectives of individuals who experienced a hypertensive disorder of pregnancy. We conducted a randomized controlled trial at a tertiary care academic medical center in the southeastern US with 100 postpartum individuals (50 per arm) from 2018 to 2019. Among 100 trial participants, blood pressure follow-up within 7-10 days postpartum was higher albeit not statistically significant between postpartum individuals randomized to the remote assessment intervention versus office-based standard care (absolute risk difference 18.0%, 95% CI -0.1 to 36.1%, p = 0.06). Patient-reported facilitators for remote blood pressure monitoring were maternal convenience, clarity of instructions, and reassurance from the health assessments. These positive aspects occurred alongside barriers, which included constraints due to newborn needs and the realities of daily postpartum life.

Inherited phosphate and pyrophosphate disorders: New insights and novel therapies changing the oral health landscape.

BACKGROUND: Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes the following 4 mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, although manifestations are distinct from those in the skeleton. TYPES OF STUDIES REVIEWED: The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may affect oral health and dental treatments of affected patients. RESULTS: Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia and hyperphosphatemic familial tumoral calcinosis and disruptions in pyrophosphate levels in hypophosphatasia and generalized arterial calcification of infancy contribute to dental mineralization defects. Traditionally, there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected patients. PRACTICAL IMPLICATIONS: Research over the past 2 decades has exponentially expanded the understanding of mineral metabolism, and has led to novel treatments for mineralization disorders. Newly implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral health care that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams.

Does maternity care in Australia align with the national maternity Strategy? Findings from a national survey of women's experiences.

BACKGROUND: Women Centred Care: Strategic directions for Australian maternity services (the Strategy), released in November 2019, provides national guidance on effective maternity care provision. The Strategy is structured around four core values (safety, respect, choice, and access) underpinning twelve woman-centred care principles. AIM: To explore whether the experiences of women who accessed Australian maternity services were aligned with the Strategy's values and principles. METHODS: Women who had completed an entire maternity care episode in Australia between January 2020 and June 2023 were invited to participate in an online survey. Women's experiences according to the Strategy's values and principles and their association with model of care, age, place of residence, educational attainment, and household income are reported. FINDINGS: The survey was completed by 1750 women. A proportion of women perceived the Strategy's values were not reflected in the care they experienced. At its lowest, only 50.3 % of women received an aspect of care that mostly or always aligned with the values, and 85.9 % at its highest. Women in private models of care were more likely to experience care according to the Strategy. Women in standard and high-risk public hospital care, rural/remote dwelling women, and younger women were less likely to experience care accordingly. Care was universally perceived to be worse in the postnatal period. CONCLUSION: Despite articulating how Australian maternity care should be provided, the intent of the Strategy has not been fully realised. Inequities exist in women's access to and experiences of care across the entire maternity episode.

The effects of fasting compared to eating a meal or snack during simulated night shift on changes in metabolism associated with circadian misalignment: a protocol and methods paper.

Study Objectives: This protocol paper outlines the methods that will be used to examine the impact of altering meal timing on metabolism, cognitive performance, and mood during the simulated night shift. Methods: Participants (male and female) will be recruited according to an a priori selected sample size to complete a 7-day within and between participant's laboratory protocol. Participants will be randomly assigned to one of the three conditions: meal at night or snack at night or no meal at night. This protocol includes an 8-hour nighttime baseline sleep, followed by 4 consecutive nights of simulated nightshift (7 hours day sleep; 10:00-17:00 hours), and an 8-hour nighttime sleep (return to dayshift). During the simulated night shift, meals will be provided at ~06:30, 09:30, 14:10, and 19:00 hours (no eating at night); ~06:30, 19:00, and 00:30 hours (meal at night); or ~06:30, 14:10, 19:00, and 00:30 hours (snack at night). Meal composition will be strictly controlled throughout the study (45%-65% carbohydrates, 15%-25% protein, and 20%-35% fat per day) with daily energy provided to meet individual needs using the Harris-Benedict equation (light/sedentary activity). The primary outcome measures are serum concentrations of blood glucose, insulin, and free fatty acids area under the curve in response to the oral glucose tolerance test. Mixed-effect ANOVAs will be conducted. Conclusions: This protocol paper describes a methodology to describe an innovative approach to reduce the metabolic disease impact associated with shift work.

Carer Perspectives About the Acceptability and Usability of the TRANSITION Tool to Support Preparation for Older Adult Care Transitions: A Qualitative Study.

INTRODUCTION: Transitional care of older adults can be highly stressful for informal carers (carers) particularly when they are not involved in preparation and planning with health practitioners. This study aimed to ascertain carer perspectives about the potential acceptability and usability of a tool entitled the TRANSITION tool to support preparation and planning for the transition of an older adult from hospital to home. DESIGN: Exploratory qualitative. METHODS: Semi-structured interviews were undertaken between March 2020 and October 2021. A focus group was conducted in July 2022 to seek additional information and support data saturation. A total of 23 participants took part. Data were thematically analysed. FINDINGS: Participants explained their perspectives about the tool in four themes: (1) the TRANSITION tool has value, but health practitioners ask the questions; (2) the TRANSITION tool would be useful and acceptable, but not for all carers; (3) interacting with health practitioners is a barrier to using the tool and to communication; and (4) recognising us as part of the care team. CONCLUSIONS: While the tool was found to have potential value and utility, it would only be expected to support carers when they are valued and respected by health practitioners. Leadership is required in healthcare organisations to support genuine care for older adults and their carers, and to enable health practitioners to have time for transitional care communication. IMPLICATIONS FOR PRACTICE: The findings from the study suggest that the TRANSITION tool could support carers by prompting them about important areas of care to include in communication with health practitioners during discharge preparation.

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides.

The ability to investigate hypervalent iodine(V) fluorides has been limited primarily by their difficult preparation traditionally using harsh fluorinating reagents such as trifluoromethyl hypofluorite and bromine trifluoride. Here, we report a mild and efficient route using Selectfluor to deliver hypervalent iodine(V) fluorides in good isolated yields (72-90%). Stability studies revealed that bicyclic difluoro(aryl)-λ5-iodane 6 was much more stable in acetonitrile-d 3 than in chloroform-d 1, presumably due to acetonitrile coordinating to the iodine(V) centre and stabilising it via halogen bonding.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

INTRODUCTION: We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. METHODS: We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS: Higher sOB-R was associated with lower fractional anisotropy (FA, ß = -0.114 ± 0.02, p < 0.001), and higher free water (FW, ß = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, ß = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (ß = 0.115 ± 0.027, p < 0.001) and lower FW (ß = -0.096 ± 0.029, p = 0.001) and PSMD (ß = -0.085 ± 0.028, p = 0.002). DISCUSSION: Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. HIGHLIGHTS: Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma.

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Genetic counselors outside of the genetics clinic: Roles, practices, and ethico-legal implications in light of lagging legal recognition across Canada.

Advances in medical genetics have led to a significant increase in demand for genetic services and expertise across almost all medical specialties. Genetic counselors (GCs) in Canada play key roles in genetic services both within and outside of the Genetics Clinic, while not being regulated or legally recognized as healthcare professionals (HCPs) in most provinces. Understanding whether GCs outside of the "traditional" Genetics Clinic influence patient care, their level of professional autonomy and supervisory structure is, therefore, important. In this study, we explore the current landscape of GC practice outside of the Genetics Clinic by describing positions, determining the professional scope of practice, as defined by the Canadian Association of Genetic Counselors (CAGC) and Canadian Board of Genetic Counseling (CBGC) core competencies, and by elucidating associated ethico-legal implications. An online survey was developed and distributed to GCs working with patient-related data in Canada in positions outside of the Genetics Clinic through the CAGC ListServ and accessed between March 5 and April 9, 2021. Thirty GCs were included in the study, with 16/30 in public healthcare system positions. Most respondents held roles with direct (11/30) and indirect (14/30) impact on patient care and management, and the majority reported performing their primary roles with minimal supervision (56%) or complete independence (36%). Most roles (22/25) elicited by respondents were considered to be within the GC scope of practice, except for administrative tasks and special projects. GCs were the only genetics-trained professional(s) in 8/30 of respondents' workplaces. The results of the current study support the value of GCs translatable skillset in positions beyond the Genetics Clinic, and outline ethico-legal implications for GCs, regulated HCPs, patients, and health institutions in the absence of legal recognition, including medical-legal liability and title protection. This study provides evidence in support of regulation of GCs as HCPs.

One mechanism of sudden sensorineural hearing loss after sildenafil and sexual activity.

OBJECTIVES: A case of sudden sensorineural hearing loss following use of sildenafil was examined in detail over a period of three days from first report to recovery. DESIGN: Case study. The subject presented with sudden sensorineural hearing loss and diplacusis a day after onset. Testing involved detailed interview, standard audiometry, detailed inter-octave audiometry, and measurement of detailed psychophysical frequency tuning curves during a two day recovery period. STUDY SAMPLE: One male aged in his thirties with otherwise normal hearing. RESULTS: Although standard audiometry was within normal limits, detailed inter-octave audiometry and psychophysical frequency tuning curves were consistent with a punctate unilateral intra-cochlear lesion that resolved over a period of three days. CONCLUSIONS: This is the first report of such a frequency-specific audiometric shift and diplacusis after sildenafil, and is not consistent with previous reports of direct ototoxic pharmacological effects. We propose that the lesion was most likely caused by a cochlear bleed, and may have been due to physical exertion rather than a direct pharmaceutical effect. The study highlights the important role of additional diagnostic testing that can be easily achieved in a clinical setting with minimal equipment.

A microRNA focus on acne.

Acne (syn. acne vulgaris) is a common inflammatory skin disorder associated with puberty and adolescence. The disease is characterized by comedoneous lesions, papules, pustules, and nodules that are mostly found on the face. These lesions are caused by intricate interactions between the pilosebaceous unit and the Cutibacterium acnes (C. acnes) bacteria. Unhealthy acne and its aftereffects, like pigment changes and scarring, have a detrimental impact on one's quality of life. Recent years have seen a sharp increase in the approval of nucleic acid therapies (NATs), such as antisense oligonucleotides and short-interfering RNA medications, for rare diseases for which there are few or no effective treatments. These developments suggest that NATs may be useful in acne treatment plans down the road, as do clinical trials for microRNA (miRNA) modulation in skin contexts. We highlight promising miRNA targets for anti-acne therapy in this review. We outline the pathophysiology of acne in brief and emphasize the functions of C. acnes. Next, we concentrate on the distinct impacts of biofilm and planktonic C. acnes on a Toll-like receptor 2 axis that spans miR-146a-5p, which was recently discovered. Before discussing the potential contributions of miR-21-5p, miR-233-3p, and miR-150-5p to inflammatory axes in acne, we evaluate miR-146a-5p in sebocytes. Finally, we address patient involvement in miRNA-related acne research and translational perspectives.

Aquatic processing enhances the loss of aged carbon from drained and burned peatlands.

Water-logged peatlands store tremendous amounts of soil carbon (C) globally, accumulating C over millennia. As peatlands become disturbed by human activity, these long-term C stores are getting destabilized and ultimately released as greenhouse gases that may exacerbate climate change. Oxidation of the dissolved organic carbon (DOC) mobilized from disturbed soils to streams and canals may be one avenue for the transfer of previously stored, millennia-aged C to the atmosphere. However, it remains unknown whether aged peat-derived DOC undergoes oxidation to carbon dioxide (CO2) following disturbance. Here, we use a new approach to measure the radiocarbon content of CO2 produced from the oxidation of DOC in canals overlying peatland soils that have undergone widespread disturbance in Indonesia. This work shows for the first time that aged DOC mobilized from drained and burned peatland soils is susceptible to oxidation by both microbial respiration and photomineralization over aquatic travel times for DOC. The bulk radiocarbon age of CO2 produced during canal oxidation ranged from modern to ~1300 years before present. These ages for CO2 were most strongly influenced by canal water depth, which was proportional to the water table level where DOC is mobilized from disturbed soils to canals. Canal microbes preferentially respired older or younger organic C pools to CO2, and this may have been facilitated by the use of a small particulate organic C pool over the dissolved pool. Given that high densities of canals are generally associated with lower water tables and higher fire risk, our findings suggest that peatland areas with high canal density may be a hotspot for the loss of aged C on the landscape. Taken together, the results of this study show how and why aquatic processing of organic C on the landscape can enhance the transfer of long-term peat C stores to the atmosphere following disturbance.

Health Care Costs After Genome-Wide Sequencing for Children With Rare Diseases in England and Canada.

Importance: Etiologic diagnoses for rare diseases can involve a diagnostic odyssey, with repeated health care interactions and inconclusive diagnostics. Prior studies reported cost savings associated with genome-wide sequencing (GWS) compared with cytogenetic or molecular testing through rapid genetic diagnosis, but there is limited evidence on whether diagnosis from GWS is associated with reduced health care costs. Objective: To measure changes in health care costs after diagnosis from GWS for Canadian and English children with suspected rare diseases. Design, Setting, and Participants: This cohort study was a quasiexperimental retrospective analysis across 3 distinct English and Canadian cohorts, completed in 2023. Mixed-effects generalized linear regression was used to estimate associations between GWS and costs in the 2 years before and after GWS. Difference-in-differences regression was used to estimate associations of genetic diagnosis and costs. Costs are in 2019 US dollars. GWS was conducted in a research setting (Genomics England 100 000 Genomes Project [100KGP] and Clinical Assessment of the Utility of Sequencing and Evaluation as a Service [CAUSES] Research Clinic) or clinical outpatient setting (publicly reimbursed GWS in British Columbia [BC], Canada). Participants were children with developmental disorders, seizure disorders, or both undergoing GWS between 2014 and 2019. Data were analyzed from April 2021 to September 2023. Exposures: GWS and genetic diagnosis. Main Outcomes and Measures: Annual health care costs and diagnostic costs per child. Results: Study cohorts included 7775 patients in 100KGP, among whom 788 children had epilepsy (mean [SD] age at GWS, 11.6 [11.1] years; 400 female [50.8%]) and 6987 children had an intellectual disability (mean [SD] age at GWS, 8.2 [8.4] years; 2750 female [39.4%]); 77 patients in CAUSES (mean [SD] age at GWS, 8.5 [4.4] years; 33 female [42.9%]); and 118 publicly reimbursed GWS recipients from BC (mean [SD] age at GWS, 5.5 [5.2] years; 58 female [49.2%]). GWS diagnostic yield was 143 children (18.1%) for those with epilepsy and 1323 children (18.9%) for those with an intellectual disability in 100KGP, 47 children (39.8%) in the BC publicly reimbursed setting, and 42 children (54.5%) in CAUSES. Mean annual per-patient spending over the study period was $5283 (95% CI, $5121-$5427) for epilepsy and $3373 (95% CI, $3322-$3424) for intellectual disability in the 100KGP, $724 (95% CI, $563-$886) in CAUSES, and $1573 (95% CI, $1372-$1773) in the BC reimbursed setting. Receiving a genetic diagnosis from GWS was not associated with changed costs in any cohort. Conclusions and Relevance: In this study, receiving a genetic diagnosis was not associated with cost savings. This finding suggests that patient benefit and cost-effectiveness should instead drive GWS implementation.