The interplay of psychosis and non-compliance with fatal outcome in an adult with MSUD.

Significant progress has been achieved in enhancing early outcomes for individuals with maple syrup urine disease (MSUD), a rare metabolic disorder that leads to the accumulation of branched-chain amino acids leucine, isoleucine, and valine, where leucine is known as the primary neurotoxic metabolite. Newborn screening is helpful in early diagnosis and implementation of dietary treatment, thus reducing neurological deterioration and complications in young children. However, patients face the life-long challenge of maintaining metabolic control through adherence to a strict low-leucine diet to avoid long-term consequences of chronic hyperleucinemia, which include cognitive deficits, mood disorders, and movement disorders. This case report exemplifies the complex involvement of MSUD in adult survivors. Despite presenting early in life, the patient thrived until the onset of psychiatric symptoms. The subject of this case is a 25-year-old woman with MSUD, who remained in her usual state of health until presentation to the emergency department (ED) with psychosis and altered mental status. However, due to a lack of medical records and poor communication, there was a delay in considering MSUD as a primary cause of her psychiatric symptoms. Although a genetics consultation was later arranged and efforts were made to decrease plasma leucine to the therapeutic range, these interventions proved inadequate in halting her deterioration in health. Her condition worsened within 72 h, culminating in her untimely death. This case emphasizes the comorbidity of psychiatric involvement in MSUD, which contributes to metabolic decompensation that can lead to cerebral edema and death. This case also highlights the pressing need for enhanced strategies for the acute management and long-term care of MSUD patients with psychiatric involvement, particularly in scenarios where mental disturbance could lead to noncompliance.

A pilot study of home-based genetic testing completion rate in telegenetics cancer clinics in West Virginia Appalachia.

Telegenetics has shifted some genetic testing performance to the patient's own home, with the patient collecting his/her own sample. Little is known regarding the rate of test completion of such home-based genetic testing. This study compared the completion rate of home-based genetic tests before and after a reminder system was implemented. In the pre-reminder group, we reviewed medical records for patients who were seen via telegenetics and agreed to complete genetic testing using an at-home test kit. In the reminder group, a prospective analysis of the genetic test completion rate was performed taking a clinical quality improvement approach where three reminders were provided for patients who had not submitted their at-home genetic testing. Our study included 94 patients' records: 46 pre-reminders and 48 reminders. The lab received 24 patient samples (52.2%) in the pre-reminder group. In the reminder group, 30 patients returned their kits (62.5%). Despite a higher percentage of patients completing their test in the reminder group, there was no statistically significant difference between the pre-reminder and reminder groups. The rate of test completion in our pilot test was statistically similar between the two groups, but the reminder group was trending toward a higher percent of completion which may be clinically meaningful.

Genetics education in primary care residency training: satisfaction and current barriers.

BACKGROUND: Genetics education can be integrated into general care medicine through primary care residency programs. A study of primary care residents was done to evaluate quality, satisfaction, and barriers in genetics education in residency training programs. Thus, providing more evidence for the necessity for its development and progress. METHODS: A cross-sectional descriptive self-administered questionnaire survey was delivered to four primary care West Virginia University (WVU) residency training programs in 2020-2021. The anonymous 14-item survey included the following questionnaire domains: general data, genetics training satisfaction, and genetics education barriers. RESULTS: The survey response rate was 52% (70/123) and 59 participants completed the survey. Overall, respondents viewed genetic education as critical to their chosen specialty (90%). Trainees at all educational levels obtained their education mostly from class based educational curricula (77% from lectures, 65% from didactic and 49% from grand rounds). The majority of survey respondents indicated insufficient experience with genetic patient care (34% ward genetic consultation, 5% clinic experience, 0% genetic department rotation). The percentage of residents who were satisfied with genetic topics were as follows: basic genetics (57%), capturing family history (82%), initiating basic genetic workup (15%), a basic understanding of the genetic report (23%), basic management surveillance in the genetic patient (18%), understanding the genetic referral and explaining it to a patient (47%). Residents reported barriers to genetic interest included complexity of the field (87%), followed by limited utility of genetics testing (41%). The most common suggestions for improving the genetic education component were to provide more lectures (61%), followed by enhanced advertisement of genetic education resources specifically rotations in the genetics department (22%). Other suggestions include the integration of genetic education in inpatient learning (20%) and providing research experience (7%). CONCLUSION: Primary care residents were satisfied with their genetic knowledge in the classroom and stated a clear need for enhanced hands-on clinical skills and research experience in their current residency training. The survey suggestions for improvement can enhance primary care residents' genetic training that can lead to advances in rare disease recognition, precision medicine, and improve access to genetics testing.

Violence against health-care workers in a conflict affected city.

The problem of aggression towards health care staff is global. It negatively impacts on their psychological and physical well-being, and on their performance. This study was set to explore the exposure of healthcare personnel to different forms of violence and the influence of this violence on their work and life. A sample of 700 healthcare workers was collected from six major hospitals and 20 primary health care centers in Baghdad. The questionnaire inquired about exposure to any sort of violence including insult, assaults, and displacement, being arrested, kidnapped, and intentionally injured or threatened at the workplace. More than 85% of respondents reported exposure to violence. The most important reason for violence was the poor medical services and lack of hospital supplies (22.1%). Young doctors were significantly more exposed to violence, especially verbal, mostly during the day. A significant association was seen between exposure to physical violence, male gender and short duration of experience. The most significant source of violence was the patient's relatives.  There is an overwhelming surge of violence against health workers that may adversely reflect on their performance. Passing legislation that protects health workers against violence is an urgent need at this time of unrest.

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome.

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.

22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.

Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock.

Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.

Antenatal corticosteroid therapy: current strategies and identifying mediators and markers for response.

Landmark early work has led to the nearly universal use of antenatal corticosteroids to accelerate fetal lung maturity with pregnancies complicated by impending preterm birth. Antenatal corticosteroids clearly reduce respiratory morbidity, death, and other adverse neonatal outcomes. Limited pregnant human pharmacokinetic data and some animal data give clinicians some information as to the behavior of the drug in the body. However, there is controversy about the type, amount, and frequency of steroid to use for this therapy. This review article summarizes the history, clinical use, and pharmacology of antenatal steroids. In addition, the review highlights some potential mediators of steroid response and current research strategies aimed at possible optimization of this therapy.

Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P < 0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10(-219)). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.