Correlating the Bethesda System for Reporting Thyroid Cytopathology with Histology and Extent of Surgery: A Review of 21,746 Patients from Four Endocrine Surgery Registries Across Two Continents.

BACKGROUND: The Bethesda system for cytopathology (TBSRTC) is a 6-tier diagnostic framework developed to standardize thyroid cytopathology reporting. The aim of this study was to determine the risk of malignancy (ROM) for each Bethesda category. METHODS: Thyroidectomy-related data from 314 facilities in 22 countries were entered into the following outcome registries: CESQIP (North America), Eurocrine (Europe), SQRTPA (Sweden) and UKRETS (UK). Demographic, cytological, pathologic and extent of surgery data were mapped into one dataset and analyzed. RESULTS: Out of 41,294 thyroidectomy patient entries from January 1, 2015, to June 30, 2017, 21,746 patients underwent both thyroid FNA and surgery. A comparison of cytology and surgical pathology data demonstrated a ROM for Bethesda categories 1 to 6 of 19.2%, 12.7%, 31.9%, 31.4%, 77.8% and 96.0%, respectively. Male patients had a higher rate of malignancy for every Bethesda category. Secondary analysis demonstrated a high ROM in male patients with Bethesda 3 category aged 31-35 years (52.1%, 95% confidence interval (CI) 37.9-66.2%), aged 36-40 years (55.9%, 95% CI 39.2-72.6%) and aged 41-45 years (46.9%, 95% CI 33-60.9%). Patients with Bethesda 5 and 6 scores were more likely to undergo total thyroidectomy (65.9% and 84.6%); for patients with Bethesda scores 2 and 3, a higher percentage of females underwent total thyroidectomy compared to males in spite of a higher ROM for males. CONCLUSIONS: These data demonstrate that Bethesda categories 1-4 are associated with a higher ROM compared to the first edition of TBSRTC, especially in male patients, and validate findings from the second edition of TBSRTC.

Retrospective natural history of thymidine kinase 2 deficiency.

BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial.

STUDY OBJECTIVE: The optimal intranasal volume of administration for achieving timely and effective sedation in children is unclear. We aimed to compare clinical outcomes relevant to procedural sedation associated with using escalating volumes of administration to administer intranasal midazolam. METHODS: We conducted a randomized, single-blinded, 3-arm, superiority clinical trial. Children aged 1 to 7 years and undergoing laceration repair requiring 0.5 mg/kg intranasal midazolam (5 mg/mL) were block-randomized to receive midazolam using 1 of 3 volumes of administration: 0.2, 0.5, or 1 mL. Procedures were videotaped, with outcome assessors blinded to volume of administration. Primary outcome was time to onset of minimal sedation (ie, score of 1 on the University of Michigan Sedation Scale). Secondary outcomes included procedural distress, time to procedure start, deepest level of sedation achieved, adverse events, and clinician and caregiver satisfaction. RESULTS: Ninety-nine children were enrolled; 96 were analyzed for the primary outcome and secondary outcomes, except for the outcome of procedural distress, for which only 90 were analyzed. Time to onset of minimal sedation for each escalating volume of administration was 4.7 minutes (95% confidence interval [CI] 3.8 to 5.4 minutes), 4.3 minutes (95% CI 3.9 to 4.9 minutes), and 5.2 minutes (95% CI 4.6 to 7.0 minutes), respectively. There were no differences in secondary outcomes except for clinician satisfaction with ease of administration: fewer clinicians were satisfied when using a volume of administration of 0.2 mL. CONCLUSION: There was a slightly shorter time to onset of minimal sedation when a volume of administration of 0.5 mL was used compared with 1 mL, but all 3 volumes of administration produced comparable clinical outcomes. Fewer clinicians were satisfied with ease of administration with a volume of administration of 0.2 mL.

Mitochondrial disease patients' perception of dietary supplements' use.

Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertained each patient's mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health. Regardless of the specific underlying mitochondrial disease, the majority of the survey respondents stated they are or have been on dietary supplements. Most patients take more than four supplements primarily coenzyme Q10, l-carnitine, and riboflavin. The majority of patients taking supplements reported health benefits from the supplements. The onset of perceived benefits was between 2weeks to 3months of initiating intake. Supplements seem to be safe, with only 28% of patients experiencing mild side-effects and only 5.6% discontinuing their intake due to intolerance. Only 9% of patients had insurance coverage for their supplements and when paying out of pocket, 95% of them spend up to $500/month. Despite the use of concomitant therapies (prescribed medications, physical therapy, diet changes and other), 45.5% of patients think that dietary supplements are the only intervention improving their symptoms. Some limitations of this study include the retrospective collection of data probably associated with substantial recall bias, lack of longitudinal follow up to document pre- and post-supplement clinical status and second hand reports by parents for children which may reflect parents' subjective interpretation of symptoms severity and supplements effect rather than real patients' experience. More extensive prospective studies will help further elucidate this topic.

Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy.

STUDY QUESTION: Among women who carry pathogenic mitochondrial DNA (mtDNA) point mutations and healthy oocyte donors, what are the levels of support for developing oocyte mitochondrial replacement therapy (OMRT) to prevent transmission of mtDNA mutations? SUMMARY ANSWER: The majority of mtDNA carriers and oocyte donors support the development of OMRT techniques to prevent transmission of mtDNA diseases. WHAT IS KNOWN ALREADY: Point mutations of mtDNA cause a variety of maternally inherited human diseases that are frequently disabling and often fatal. Recent developments in (OMRT) as well as pronuclear transfer between embryos offer new potential options to prevent transmission of mtDNA disease. However, it is unclear whether the non-scientific community will approve of embryos that contain DNA from three people. STUDY DESIGN, SIZE, DURATION: Between 1 June 2012 through 12 February 2015, we administered surveys in cross-sectional studies of 92 female carriers of mtDNA point mutations and 112 healthy oocyte donors. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OMRT carrier survey was completed by 92 female carriers of an mtDNA point mutation. Carriers were recruited through the North American Mitochondrial Disease Consortium (NAMDC), the United Mitochondrial Disease Foundation (UMDF), patient support groups, research and private patients followed at the Columbia University Medical Center (CUMC) and patients' referrals of maternal relatives. The OMRT donor survey was completed by 112 women who had donated oocytes through a major ITALIC! in vitro fertilization clinic. MAIN RESULTS AND THE ROLE OF CHANCE: All carriers surveyed were aware that they could transmit the mutation to their offspring, with 78% (35/45) of women, who were of childbearing age, indicating that the risk was sufficient to consider not having children, and 95% (87/92) of all carriers designating that the development of this technique was important and worthwhile. Of the 21 surveyed female carriers considering childbearing, 20 (95%) considered having their own biological offspring somewhat or very important and 16 of the 21 respondents (76%) were willing to donate oocytes for research and development. Of 112 healthy oocyte donors who completed the OMRT donor survey, 97 (87%) indicated that they would donate oocytes for generating a viable embryo through OMRT. LIMITATIONS, REASONS FOR CAUTION: Many of the participants were either patients or relatives of patients who were already enrolled in a research-oriented database, or who sought care in a tertiary research university setting, indicating a potential sampling bias. The survey was administered to a select group of individuals, who carry, or are at risk for carrying, mtDNA point mutations. These individuals are more likely to have been affected by the mutation or have witnessed first-hand the devastating effects of these mutations. It has not been established whether the general public would be supportive of this work. This survey did not explicitly address alternatives to OMRT. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study indicating a high level of interest in the development of these methods among women affected by the diseases or who are at risk of carrying mtDNA mutations as well as willingness of most donors to provide oocytes for the development of OMRT. STUDY FUNDING/COMPETING INTERESTS: This work was conducted under the auspices of the NAMDC (Study Protocol 7404). NAMDC (U54NS078059) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS. NAMDC is funded through a collaboration between NCATS, NINDS, NICHD and NIH Office of Dietary Supplements. The work was also supported by the Bernard and Anne Spitzer Fund and the New York Stem Cell Foundation (NYSCF). Dr Hirano has received research support from Santhera Pharmaceuticals and Edison Pharmaceuticals for studies unrelated to this work. None of the other authors have conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Predictors of low weight and tube feedings in children with congenital diaphragmatic hernia at 1 year of age.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) survivors often have gastrointestinal disorders, and limited outcome data exist. This study reviewed risk factors for low weight and use of feeding tubes after CDH repair at 1 year of age. The hypothesis was that patients who required extracorporeal membrane oxygenation (ECMO) or with significant pulmonary arterial hypertension (PAH) would have lower weight percentiles and more often require tube feedings. METHODS: A retrospective chart review of 89 infants with CDH diagnosed in the neonatal period was conducted. Statistical analysis was performed using χ test, Fisher exact test, and logistic regression. RESULTS: Seventy-two patients (81%) survived to 1 year of age. Of these patients, 35% were <5th percentile for weight and 18% were receiving tube feedings. Both ECMO and PAH were associated with an increased risk for requiring tube feedings at 1 year of age, with respective odds ratios of 6.00 (P = 0.01) and 15.75 (P = 0.02); however, neither ECMO nor PAH was associated with low weight at 1 year of age. No statistical correlation was found between an abnormal pH probe and tube feedings at 1 year of age. CONCLUSIONS: Patients with CDH are at increased risk for having a weight <5th percentile at 1 year of age. A history of ECMO and PAH are independently associated with an increased requirement for tube feedings at 1 year of age. Close nutritional monitoring and counseling should be considered in all of the patients with CDH, particularly those with a history of ECMO or PAH.

Mitochondrial diseases in North America: An analysis of the NAMDC Registry.

OBJECTIVE: To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. METHODS: This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists. RESULTS: One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with POLG1 and PDHA1 being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants. CONCLUSIONS: The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.

Preprocedural Ultrasound for Infant Lumbar Puncture: A Randomized Clinical Trial.

BACKGROUND: Our purpose was to determine the potential effect of preprocedural ultrasound (US) to increase lumbar puncture (LP) success compared with standard palpation method. Further, we assessed feasibility of and clinician satisfaction with a standardized US protocol. METHODS: This prospective, two-arm, parallel-group randomized trial was conducted in a single-center pediatric emergency department. We compared preprocedural US versus palpation method on success with infant LPs. Infants less than 3 months of age requiring LP were enrolled. Sixteen pediatric emergency medicine physicians with varied US experience were trained to conduct the USs to mark interspace locations. Primary outcome was successful LP, defined as obtaining a cerebrospinal fluid (CSF) sample on first attempt with < 1,000 red blood cells per high-powered field (clear CSF). Secondary outcomes included clear CSF on any attempt, any CSF on the first attempt, traumatic LP proportion, and LP attempt frequency. Feasibility was assessed by comparing provider number attempting the LP and procedure duration. Clinician satisfaction and sonographer perceptions of US acceptability and impact were assessed. RESULTS: Eighty-one patients consented and 80 were analyzed (99%): 40 per group. No statistical difference was seen for the primary outcome (p > 0.05) between intervention and control groups (difference 3%; 95% confidence interval = -19% to 24%). There were no statistical differences between intervention and controls groups for secondary outcomes including the rate of traumatic LPs, number of attempts, and the duration of LP procedure. Most sonographers (84%) strongly agreed or agreed that the US protocol was technically easy to perform, well tolerated by the patient (94%), well accepted by the family (100%), and well accepted by the LP procedural clinicians (99%). In the US group, the majority of clinicians who performed the LPs (68.4%) noted that the preprocedural US influenced their behavior, most commonly helping with overall visualization at the selected interspace (28.9%) or prompting a change in interspace (26.3% higher, 5.3% lower). Seventy-seven percent agreed or strongly agreed that they would like to use the technique again for their next LP. The mean US duration was 4.6 minutes. CONCLUSIONS: Preprocedural US by did not improve the rates of first-attempt success when compared with palpation method. Our results suggest that US is feasible and well accepted, with a perceptible impact on care.

Use of High-Sensitivity Troponin T to Identify Patients With Acute Heart Failure at Lower Risk for Adverse Outcomes: An Exploratory Analysis From the RELAX-AHF Trial.

OBJECTIVES: The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 µg/l ["low hsTnT"]) identifies patients at low risk for adverse outcomes. BACKGROUND: Approximately 85% of patients who present to emergency departments with acute heart failure are admitted. Identification of patients at low risk might decrease unnecessary admissions. METHODS: A post-hoc analysis was conducted from the RELAX-AHF (Serelaxin, Recombinant Human Relaxin-2, for Treatment of Acute Heart Failure) trial, which randomized patients within 16 h of presentation who had systolic blood pressure >125 mm Hg, mild to moderate renal impairment, and N-terminal pro-brain natriuretic peptide ≥1,600 ng/l to serelaxin versus placebo. Linear regression models for continuous endpoints and Cox models for time-to-event endpoints were used. RESULTS: Of the 1,076 patients with available baseline hsTnT values, 107 (9.9%) had low hsTnT. No cardiovascular (CV) deaths through day 180 were observed in the low-hsTnT group compared with 79 CV deaths (7.3%) in patients with higher hsTnT. By univariate analyses, low hsTnT was associated with lower risk for all 5 primary outcomes: 1) days alive and out of the hospital by day 60; 2) CV death or rehospitalization for heart failure or renal failure by day 60; 3) length of stay; 4) worsening heart failure through day 5; and 5) CV death through day 180. After multivariate adjustment, only 180-day CV mortality remained significant (hazard ratio: 0.0; 95% confidence interval: 0.0 to 0.736; p = 0.0234; C-index = 0.838 [95% confidence interval: 0.798 to 0.878]). CONCLUSIONS: No CV deaths through day 180 were observed in patients with hsTnT levels ≤0.014 µg/l despite high N-terminal pro-brain natriuretic peptide levels. Low baseline hsTnT may identify patients with acute heart failure at very low risk for CV mortality.

Prevalence of and Risk Factors for Intracranial Abnormalities in Unprovoked Seizures.

BACKGROUND AND OBJECTIVES: Prospective data are lacking to determine which children might benefit from prompt neuroimaging after unprovoked seizures. We aimed to determine the prevalence of, and risk factors for, relevant intracranial abnormalities in children with first, unprovoked seizures. METHODS: We conducted a 6-center prospective study in children aged >28 days to 18 years with seemingly unprovoked seizures. Emergency department (ED) clinicians documented clinical findings on a standardized form. Our main outcome was the presence of a clinically relevant intracranial abnormality on computed tomography (CT) or MRI, defined as those that might change management, either emergently, urgently, or nonurgently. RESULTS: We enrolled 475 of 625 (76%) eligible patients. Of 354 patients for whom cranial MRI or CT scans were obtained in the ED or within 4 months of the ED visit, 40 (11.3%; 95% confidence interval [CI]: 8.0-14.6%) had clinically relevant intracranial abnormalities, with 3 (0.8%; 95% CI: 0.1-1.8%) having emergent/urgent abnormalities. On logistic regression analysis, a high-risk past medical history (adjusted odds ratio: 9.2; 95% CI: 2.4-35.7) and any focal aspect to the seizure (odds ratio: 2.5; 95% CI: 1.2-5.3) were independently associated with clinically relevant abnormalities. CONCLUSIONS: Clinically relevant intracranial abnormalities occur in 11% of children with first, unprovoked seizures. Emergent/urgent abnormalities, however, occur in <1%, suggesting that most children do not require neuroimaging in the ED. Findings on patient history and physical examination identify patients at higher risk of relevant abnormalities.