Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.

High dose genistein in Sanfilippo syndrome: A randomised controlled trial.

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P = .26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P = .0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

PURPOSE: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. RESULTS: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. CONCLUSION: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Perceived fatigue in children and young adults with neurofibromatosis type 1.

AIM: This study describes the prevalence and severity of perceived fatigue in a young neurofibromatosis type 1 (NF1) population. METHODS: Ethical approval was obtained and NF1 affected Individuals aged 2-18 years from the Manchester's NF1 clinic invited along with any unaffected siblings. The PedsQL Multidimensional Fatigue Scale Parental and child report was used. This validated measure explores cognitive, physical and sleep/rest domains on a 0-100 scale. Higher scores indicate less fatigue. Fatigue scores in affected children were compared to unaffected siblings after adjusting for age, sex and Index of Multiple Deprivation and with published population standards using z-scores. RESULTS: A total of 286 families were invited and 75 affected and 16 siblings participated. There were significant differences between NF1 and controls in the aggregated fatigue core (child report 55 ± 19 vs. 75 (14), P < 0.001; parent 54 ± 20 vs. 73 ± 18, P = 0.001) and the three sub-domains: cognitive (child 48 ± 27 vs. 75 ± 23, P < 0.001), physical (child 59 ± 19 vs. 82 ± 14, P < 0.001) and sleep/rest (child 59 ± 19 vs. 71 ± 15, P = 0.018). Similar differences were seen when compared with published controls (aggregated child z-score -1.9 ± 1.4, P < 0.001; parent -3.2 ± 1.8, P < 0.001). Prevalence of severe fatigue indicated by scores <2 standard deviation below published means for healthy controls were also higher for children with NF on both parent and child reports. Agreement between child and parent reports were limited as is frequently seen in the literature. CONCLUSION: This study suggests that children with NF1 are affected by perceived fatigue when compared with healthy children who do not have NF1.

Science in the service of patients: lessons from the past in the moral battle for the future of medical education.

Medical schools instill a classic moral standoff in which the responsibility for the betterment of the patient stands at odds with the responsibility for the betterment of society. In critical ways, the latter, in the form of a robust research and technology-driven enterprise, has taken precedence over the former, resulting in harm to patients and individual dignity. This tradeoff can be traced to Abraham Flexner, the father of American medical education. In the wake of the Flexner report, American medicine set out on a course of exponential scientific advancement, but the mistreatment of research subjects and the erosion of the doctor-patient relationship in a health care system that is increasingly unaffordable, complex, and impersonal suggest that such progress has come at a price. Recent efforts by medical schools to emphasize humanism in their curricula and admissions processes have shown promise in orienting the values of academic medicine toward the individual patient's well-being.

The development of children's regret and relief.

Previous research found that children first experience regret at 5 years and relief at 7. In two experiments, we explored three possibilities for this lag: (1) relief genuinely develops later than regret; (2) tests of relief have previously been artefactually difficult; or (3) evidence for regret resulted from false positives. In Experiment 1 (N=162 4- to 7-year-olds) children chose one of two cards that led to winning or losing tokens. Children rated their happiness then saw a better (regret) or worse (relief) alternative. Children re-rated their happiness. Regret after winning was first experienced at 4, regret after losing and relief after winning were experienced at 5 years and relief after losing at 7 years. Experiment 2 (N=297 5- to 8-year-olds) used a similar task but manipulated children's responsibility for the outcome. Greater responsibility for the outcome resulted in a greater likelihood of an experience of regret and relief. Results support that previous tests of relief were artefactually difficult and regret and relief are experienced earlier than previously thought.

Children's thinking about their own and others' regret and relief.

In two experiments using a decision-making game, we investigated children's thinking about regret and relief. In Experiment 1 (N=43, 31 children [5 years 4 months to 8 years 2 months of age] and 12 adults), participants chose between two boxes containing different numbers of stickers. They rated their happiness before learning that the other box contained more (regret) or fewer (relief) stickers. They rerated their chosen box with the counterfactual knowledge. The experience of regret was evident at 5 years of age, and the experience of relief was evident at 7 years of age. In Experiment 2 (N=69, 53 children [5 years 3 months to 6 years 11 months of age] and 16 adults), participants either played the game (self condition) or watched another play the game (other condition). Children in the self condition confirmed the results from Experiment 1. We found no evidence that children up to 7 years of age were able to predict others' regret and relief, a finding that suggests differing developmental trajectories between experiencing and understanding others' regret and relief.

Utilization, financial outcomes and stakeholder perspectives of a re-organized adult sickle cell program.

In 2011 Yale New Haven Hospital, in response to high utilization of acute care services and widespread patient and health care personnel dissatisfaction, set out to improve its care of adults living with sickle cell disease. Re-organization components included recruitment of additional personnel; re-locating inpatients to a single nursing unit; reducing the number of involved providers; personalized care plans for pain management; setting limits upon access to parenteral opioids; and an emphasis upon clinic visits focused upon home management of pain as well as specialty and primary care. Outcomes included dramatic reductions in inpatient days (79%), emergency department visits (63%), and hospitalizations (53%); an increase in outpatient visits (31%); and a decrease in costs (49%). Providers and nurses viewed the re-organization and outcomes positively. Most patients reported improvements in pain control and life style; many patients thought the re-organization process was unfair. Their primary complaint was a lack of shared decision-making. We attribute the contrast in these perspectives to the inherent difficulties of managing recurrent acute and chronic pain with opioids, especially within the context of the imbalance in wellness, power, and privilege between persons living with sickle cell disease, predominantly persons of color and poor socio-economic status, and health care organizations and their personnel.

Self-Report Measures of Parental Self-Efficacy: A Systematic Review of the Current Literature.

Parenting self-efficacy (PSE) describes a parent's belief in their ability to perform the parenting role successfully. Higher levels of PSE have consistently been shown to be correlated with a wide range of parenting and child outcomes. Consequently, many parenting interventions aim to improve PSE. PSE measurement has typically been via self-report measures. However, the wide range of available measures has resulted in their limited use, inconsistent terminology and ambiguous theoretical grounding. The purpose of this systematic review was to examine the psychometric and administrative qualities of the available PSE measures and offer clarity to the terminology and the theory underpinning their use so that the future use of PSE measures can be appropriate. Eleven electronic databases were searched. Articles were included if they introduced a new measure or were psychometric evaluations of an available measure of PSE for parents of children (from infancy until 18 years of age). Thirty-four measures were identified and their psychometric and administrative qualities were examined. Overall, the quality of the available measures was varied. Whilst this review makes recommendations regarding PSE measures for parents of infants through to adolescents, some caution should be applied when choosing the most appropriate measure. The theoretical grounding of each measure was clarified so that appropriate measures can be chosen under the relevant circumstances. The implications of refinement of the available measures are discussed and further research into improving PSE measurement is identified.

Family caregiving for adults with sickle cell disease and extremely high hospital use.

This study investigated coping with chronic illness in the adult patient-caregiver relationship for sickle cell disease, marked by debilitating acute and chronic pain. One-on-one interviews (N = 16) were conducted with eight primary caregivers of eight adults with extremely high hospital use, severe sickle cell disease with hospital admissions several times monthly over successive years. Caregivers were predominantly parents; two were romantic partners. Caregivers attributed disruptions to the disease's variability, tensions in how much support to give, and adults' inability to fulfill parental obligations. Both groups expressed fears of patients' increasing age, declining health, and early death. Targeted counseling and resilience training is recommended.

Sickle cell disease patients with and without extremely high hospital use: pain, opioids, and coping.

CONTEXT: Patients with sickle cell disease (SCD) and extremely high hospital use (EHHU) encounter significant challenges in pain management because of opioid medication use for pain and providers' concerns about addiction. OBJECTIVES: To characterize engagement with the health care system surrounding opioid pain management among SCD patients with EHHU by comparing their experiences with low-hospital-using (LHU) patients and their medical providers' perspectives. METHODS: One-on-one, semistructured qualitative interviews with patients and medical providers were audiotaped and transcribed. Participants were eight SCD patients with EHHU; matched by age, gender, and hemoglobinopathy type with eight SCD patients with low hospital use; and five providers identified by patients with EHHU as important to their care. A multidisciplinary team conducted chart review, created narrative summaries from the interviews, and used qualitative software to code transcripts based on themes. RESULTS: High-hospital-using patients and LHU patients had similar descriptions of their experience of pain and pain management with opioids. Patients and medical providers shared concerns about addiction. LHU patients described themselves as allies using specific interpersonal and symptom-related strategies, whereas high-hospital-using patients took a defensive and reactive stance toward their providers, who were similarly defensive about their care. CONCLUSION: The prescription of opioid medications for SCD pain management exacerbates issues of distrust in the patient-provider relationship. Such issues dominate patient care in patients with EHHU. Patients with EHHU and providers may learn from the proactive nature of LHU patients' engagement with the health care system as further research and interventions are designed for EHHU.

Long-term Prescription of Opioids and/or Benzodiazepines and Mortality Among HIV-Infected and Uninfected Patients.

BACKGROUND: Increased long-term prescription of opioids and/or benzodiazepines necessitates evaluating risks associated with their receipt. We sought to evaluate the association between long-term opioids and/or benzodiazepines and mortality in HIV-infected patients receiving antiretroviral therapy and uninfected patients. METHODS: Prospective analysis of all-cause mortality using multivariable methods and propensity score matching among HIV-infected patients receiving antiretroviral therapy and uninfected patients. RESULTS: Of 64,602 available patients (16,989 HIV-infected and 47,613 uninfected), 27,128 (exposed and unexposed to long-term opioids and/or benzodiazepines) were 1:1 matched by propensity score. The hazard ratio for death was 1.40 [95% confidence interval (CI): 1.22 to 1.61] for long-term opioid receipt, 1.26 (95% CI: 1.08 to 1.48) for long-term benzodiazepine receipt, and 1.56 (95% CI: 1.26 to 1.92) for long-term opioid and benzodiazepine receipt. There was an interaction (P = 0.01) between long-term opioid receipt and HIV status with mortality. For long-term opioid receipt, the hazard ratio was 1.46 (95% CI: 1.15 to 1.87) among HIV-infected patients, and 1.25 (95% CI: 1.05 to 1.49) among uninfected patients. Mortality risk was increased for patients receiving both long-term opioids and benzodiazepines when opioid doses were ≥ 20 mg morphine-equivalent daily dose and for patients receiving long-term opioids alone when doses were ≥ 50 mg morphine-equivalent daily dose. CONCLUSIONS: Long-term opioid receipt was associated with an increased risk of death; especially with long-term benzodiazepine receipt, higher opioid doses, and among HIV-infected patients. Long-term benzodiazepine receipt was associated with an increased risk of death regardless of opioid receipt. Strategies to mitigate risks associated with these medications, and caution when they are coprescribed, are needed particularly in HIV-infected populations.

Prescription opioid misuse in the United States and the United Kingdom: cautionary lessons.

In the United States, opioid analgesics have increasingly been prescribed in the treatment of chronic pain, and this trend has accompanied increasing rates of misuse and overdose. Lawmakers have responded with myriad policies to curb the growing epidemic of opioid misuse, and a global alarm has been sounded among countries wishing to avoid this path. In the United Kingdom, a similar trend of increasing opioid consumption, albeit at lower levels, has been observed without an increase in reported misuse or drug-related deaths. The comparison between these two countries in opioid prescribing and opioid overdose mortality underscores important features of prescribing, culture, and health systems that may be permissive or protective in the development of a public health crisis. As access to opioid medications increases around the world, it becomes vitally important to understand the forces impacting opioid use and misuse. Trends in benzodiazepine and methadone use in the UK as well as structural elements of the National Health Service may serve to buffer opioid-related harms in the face of increasing prescriptions. In addition, the availability and price of heroin, as well as the ease of access to opioid agonist treatment in the UK may limit the growth of the illicit market for prescription opioids. The comparison between the US and the UK in opioid consumption and overdose rates should serve as a call to action for UK physicians and policymakers. Basic, proactive steps in the form of surveillance - of overdoses, marketing practices, prescribers, and patients - and education programs may help avert a public health crisis as opioid prescriptions increase.

Guideline-concordant management of opioid therapy among human immunodeficiency virus (HIV)-infected and uninfected veterans.

UNLABELLED: Whether patients receive guideline-concordant opioid therapy (OT) is largely unknown and may vary based on provider and patient characteristics. We assessed the extent to which human immunodeficiency virus (HIV)-infected and uninfected patients initiating long-term (≥ 90 days) OT received care concordant with American Pain Society/American Academy of Pain Medicine and Department of Veterans Affairs/Department of Defense guidelines by measuring receipt of 17 indicators during the first 6 months of OT. Of 20,753 patients, HIV-infected patients (n = 6,604) were more likely than uninfected patients to receive a primary care provider visit within 1 month (52.0% vs 30.9%) and 6 months (90.7% vs 73.7%) and urine drug tests within 1 month (14.8% vs 11.5%) and 6 months (19.5% vs 15.4%; all P < .001). HIV-infected patients were also more likely to receive OT concurrent with sedatives (24.6% vs 19.6%) and a current substance use disorder (21.6% vs 17.2%). Among both patient groups, only modest changes in guideline concordance were observed over time: urine drug tests and OT concurrent with current substance use disorders increased, whereas sedative coprescriptions decreased (all Ps for trend < .001). Over a 10-year period, on average, patients received no more than 40% of recommended care. OT guideline-concordant care is rare in primary care, varies by patient/provider characteristics, and has undergone few changes over time. PERSPECTIVE: The promulgation of OT clinical guidelines has not resulted in substantive changes over time in OT management, which falls well short of the standard recommended by leading medical societies. Strategies are needed to increase the provision of OT guideline-concordant care for all patients.

"I'm talking about pain": sickle cell disease patients with extremely high hospital use.

BACKGROUND: A small minority of sickle cell disease patients accounts for the majority of inpatient hospital days. Admitted as often as several times a month, over successive years, this cohort of patients has not been studied in depth despite their disproportionate contribution to inpatient hospital costs in sickle cell disease. OBJECTIVE: To characterize the subjective experience of extremely high hospital use in patients with sickle cell disease, and generate hypotheses about the antecedents and consequences of this phenomenon. DESIGN: Qualitative study involving in-depth, open-ended interviews using a standardized interview guide. SETTING: A single urban academic medical center. PARTICIPANTS: Eight individuals, of varying age and gender, identified as the sickle cell disease patients who are among the highest hospital use patients over a 3-year period. RESULTS: A common narrative emerged from the interview transcripts. Participants were exposed to the hospital environment and intravenous (IV) opioids at a young age, and this exposure was associated with extremely high hospital use in adulthood, evident in descriptions of multiple dimensions of their lives: pain and opioid medication use, interpersonal relationships, and personal development. CONCLUSIONS: Our results suggest a systematic, self-reinforcing process of isolation from mainstream society, support structures, and caregivers, based on increasing hospitalization, growing dependency on opioid medications, as well as missed developmental milestones. Further study and interventions should be geared towards breaking this spiraling cycle with long-term strategies in disease management and social integration.