Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy.

Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease.

The effect of levocarnitine supplementation on dialysis-related hypotension: A systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Dialysis patients have been shown to have low serum carnitine due to poor nutrition, deprivation of endogenous synthesis from kidneys, and removal by hemodialysis. Carnitine deficiency leads to impaired cardiac function and dialysis-related hypotension which are associated with increased mortality. Supplementing with levocarnitine among hemodialysis patients may diminish incidence of intradialytic hypotension. Data on this topic, however, lacks consensus. METHODS: We conducted electronic searches in PubMed, Embase and Cochrane Central Register of Controlled Trials from January 1960 to 19th November 2021 to identify randomized controlled studies (RCTs), which examined the effects of oral or intravenous levocarnitine (L-carnitine) on dialysis-related hypotension among hemodialysis patients. The secondary outcome was muscle cramps. Study results were pooled and analyzed utilizing the random-effects model. Trial sequential analysis (TSA) was performed to assess the strength of current evidence. RESULTS: Eight trials with 224 participants were included in our meta-analysis. Compared to control group, L-carnitine reduced the incidence of dialysis-related hypotension among hemodialysis patients (pooled OR = 0.26, 95% CI [0.10-0.72], p = 0.01, I2 = 76.0%). TSA demonstrated that the evidence was sufficient to conclude the finding. Five studies with 147 participants showed a reduction in the incidence of muscle cramps with L-carnitine group (pooled OR = 0.22, 95% CI [0.06-0.81], p = 0.02, I2 = 74.7%). However, TSA suggested that further high-quality studies were required. Subgroup analysis on the route of supplementation revealed that only oral but not intravenous L-carnitine significantly reduced dialysis-related hypotension. Regarding dose and duration of L-carnitine supplementation, the dose > 4,200 mg/week and duration of at least 12 weeks appeared to prevent dialysis-related hypotension. CONCLUSION: Supplementing oral L-carnitine for at least three months above 4,200 mg/week helps prevent dialysis-related hypotension. L-carnitine supplementation may ameliorate muscle cramps. Further well-powered studies are required to conclude this benefit.

Long QT and Hearing Loss in High-Risk Infants Prospective Study Registry.

The objective of this study is to determine the prevalence of an abnormal electrocardiogram showing a prolonged QTc greater than 450 ms in infants with unilateral or bilateral sensorineural hearing loss. We conducted a prospective study of healthy term infants (≥37 weeks gestational age) who failed their newborn auditory brainstem response hearing screen, were seen by an audiologist and diagnosed as having sensorineural hearing loss during follow-up to 1 year of age. In infants with a diagnosis of hearing loss, we collected a detailed family history and performed an ECG between 2 and 6 months of age. We obtained follow-up for 1 year by calling the parent requesting the hearing and cardiac status of their child. Two of the 40 infants with sensorineural hearing loss (5%) had a QTc greater than 450 ms. Both had mild bilateral hearing loss and genetic testing did not identify a known mutation for long QT syndrome. The remaining 38 infants had QTc intervals of ≤ 450 ms. One patient diagnosed with bilateral severe sensorineural hearing loss had a normal ECG (QTc = 417 ms). Several months after the ECG was performed, the infant's mother contacted the study cardiologist after she learned that the infant's maternal grandmother was diagnosed with a cardiomyopathy and arrhythmias. Genetic testing was recommended even though the child was asymptomatic and was positive for a pathogenic mutation in the KCNQ1 gene. We speculate that molecular genetic testing in infants with hearing loss may become the standard of care rather than targeted electrocardiograms.Clinical Trial Registration NCT02082431 https://www.clinicaltrials.gov/ct2/show/NCT02692521?cond=NCT02692521&rank=1 .

Unusual Suspects: The People Inside and Outside of School Who Matter in Whole School, Whole Community, Whole Child Efforts.

BACKGROUND: Individuals learn and develop across their lifespan in response to the people with whom they interact in settings, communities, cultures, and experiences. Collaborative research and policy efforts underscore the critical and reparative role of identity-safe, culturally driven, and relationship-rich environments-in classrooms, schools, and communities-for the healthy social, emotional, cognitive, and physical development of all learners. These themes align closely with the Whole School, Whole Community, Whole Child (WSCC) model. METHODS: Collaborative research and policy efforts, combined with the WSCC model make a strong case to elevate the unusual suspects, the settings and people outside of instructional classrooms who are key actors in creating the conditions and relationships that promote student health and well-being. RESULTS: We describe promising cases of efforts aimed at bolstering adult capacity to foster student health and well-being. We also discuss how these types of systemic efforts can move beyond system and program level actors to acknowledge the power of individual-level implementation. CONCLUSIONS: It is time to recognize the systemic efforts, programmatic opportunities, and individual roles adults have in implementing an ideal WSCC model that is aligned with the collaborative research and policy efforts.

Normative data for three tests of visuocognitive function in primary school children: cross-sectional study.

BACKGROUND/AIMS: There is an increasing recognition that visuocognitive difficulties occur in children with neurodevelopmental problems. We obtained normative data for the performance of primary school children using three tests of visuocognitive function that are practicable in a clinical setting. METHODS: We tested 214 children aged between 4 and 11 years without known developmental problems, using tests to assess (1) orientation recognition and adaptive movement (postbox task), (2) object recognition (rectangles task) and (3) spatial integration (contours task). RESULTS: 96% could do the postbox task with ease-only 4% (all aged <9 years) exhibited minor difficulties. Errors in the rectangles task decreased with age: 33% of children aged 4-5 years had major difficulties but >99% of children aged ≥6 years had no, or minor, difficulties. Median scores for the contours task improved with age, and after age 8 years, 99% could see the contour using long-range spatial integration rather than density. CONCLUSIONS: These different aspects of children's visuocognitive performance were testable in a field setting. The data provide a benchmark by which to judge performance of children with neurodevelopmental problems and may be useful in assessment with a view to providing effective supportive strategies for children whose visuocognitive skills are lower than the expectation for their age.

Effect of keratometry on visual outcomes 1 month after hyperopic LASIK.

PURPOSE: To determine whether preoperative, postoperative, or change in keratometry can be used to predict visual outcomes in hyperopic LASIK. METHODS: A retrospective analysis was conducted on hyperopic eyes treated at Optical Express clinics. All eyes were targeted for emmetropia and treated using wavefront-guided LASIK (VISX S4, Abbott Medical Optics [AMO]), with flaps created using a femtosecond laser (IntraLase FS-60 [AMO]). A total of 1659 consecutive eyes of 895 patients met the study inclusion criteria: preoperative sphere > or = 1.00 diopter, complete 1-month follow-up data, and availability of pre- and postoperative keratometry measurements. Factors associated with 1-month visual results were evaluated with multivariate analysis. RESULTS: Preoperative sphere was strongly correlated with visual outcomes. Higher levels of correction were associated with a greater loss of best spectacle-corrected visual acuity (BSCVA), a lower percentage of eyes achieving 20/20 BSCVA, and a lower percentage of eyes achieving 20/20 uncorrected visual acuity. For a given level of preoperative sphere, however, no statistically significant correlation was observed between visual outcomes and either pre- or postoperative keratometry. CONCLUSIONS: Preoperative, calculated postoperative, or 1-month postoperative keratometry values do not correlate with visual acuity outcomes following hyperopic LASIK.

Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease.

BACKGROUND AND OBJECTIVES: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, reduces bioavailability of nitric oxide and induces endothelial dysfunction. This dimethylated amino acid accumulates in chronic kidney disease and may be involved in the pathophysiology of cardiovascular disease (CVD) in this population. DESIGN, SETTINGS, PARTICIPANTS, & METHODS: The Modification of Diet in Renal Disease Study was a randomized, controlled trial conducted between 1989 and 1993. We measured ADMA in frozen samples collected at baseline (n = 820) and obtained survival status, up to December 31, 2000, from the National Death Index. We examined the relationship of ADMA with prevalent CVD and performed multivariable Cox models to examine the relationship of ADMA with all-cause and CVD mortality. RESULTS: Mean (SD) age was 52 (12) yr, GFR was 32 +/- 12 ml/min per 1.73 m(2), and ADMA was 0.70 +/- 0.25 micromol/L. A 1-SD increase in ADMA was associated with a 31% increased odds of prevalent CVD in an adjusted logistic regression model. During the 10-yr follow-up period, 202 (25%) participants died of any cause, 122 (15%) from CVD, and 545 (66%) reached kidney failure. In multivariable Cox models, a 1-SD increase in ADMA was associated with a 9% increased risk for all-cause and 19% increased risk for CVD mortality. CONCLUSIONS: In this cohort of patients with predominantly nondiabetic, stages 3 to 4 chronic kidney disease, there was a strong association of ADMA with prevalent CVD and a modest association with all-cause and CVD mortality.

Association of visceral and subcutaneous adiposity with kidney function.

BACKGROUND AND OBJECTIVES: Obesity is a risk factor for incident chronic kidney disease (CKD). Visceral (VAT) and subcutaneous adipose tissue (SAT) may confer differential metabolic risk profiles. The relations of VAT and SAT were analyzed with CKD as estimated by creatinine- and cystatin-based estimating equations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants from the Framingham Offspring Study who underwent abdominal computed tomography for VAT and SAT quantification were included (n = 1299; 53% women; mean age 60 yr). CKD was defined as estimated GFR <60 ml/min per 1.73 m(2), as estimated using creatinine (n = 89) in the Modification of Diet in Renal Disease (MDRD) formula or by cystatin C (n = 136). Regression models evaluated the cross-sectional relations between VAT and SAT with CKD and cystatin C, with age and gender adjustment and cardiovascular risk factor adjustment. RESULTS: Neither VAT nor SAT was associated with CKD as estimated by the MDRD equation. In contrast, both VAT and SAT were associated with CKD when defined using cystatin-based equations. The estimated decrease in estimated GFR by cystatin C per 1-SD increase of VAT was 1.9 ml/min per 1.73 m(2) and for SAT was 2.6 ml/min per 1.73 m(2) in a multivariable-adjusted model. CONCLUSIONS: VAT and SAT were associated with CKD when defined using cystatin C estimating equations but not when using a creatinine-based estimating equation. Mechanisms linking adipose tissue to cystatin C warrant further research.

Using indirect questions to detect intimate partner violence: the SAFE-T questionnaire.

A screening instrument for detecting intimate partner violence (IPV) was developed using indirect questions. The authors identified 5 of 18 items studied that clearly distinguished victims of IPV from a random group of health conference attendees with a sensitivity of 85% and a specificity of 87%. This 5-item instrument (SAFE-T) was then tested on 435 women presenting to three emergency departments and the results compared to a direct question regarding current abuse. The SAFE-T questions detected only 54% of the women who admitted being abused and correctly classified 81% of the women who said they were not victims. The 1-year prevalence of IPV in this sample of women presenting to an emergency department was 11.6%. The authors conclude that indirect questioning of women appears to be more effective at ruling out IPV in an emergency department population and may be less useful for women "early" in an abusive relationship.