Diagnostic and treatment preferences for cracked posterior teeth.

BACKGROUND: Longitudinal cracks in teeth are common and often present challenges in diagnosis and management. This study investigated the preferred diagnostic process and treatment modalities for these cracked teeth. METHODS: Dentists currently registered with Dental Board of Australia and practising within Australia were invited to complete an online Qualtrics-based survey on their perspectives on the presentations, diagnosis, and treatment preferences for cracked teeth. RESULTS: Of respondents, 56.8% chose to place an indirect cuspal-coverage restoration on an asymptomatic cracked vital tooth. When the tooth was mildly cold sensitive, direct cuspal-coverage restoration was favoured (64.9%), while 36.8% preferred placing an orthodontic band in a tooth with biting pain. Respondents had higher odds of recommending indirect restoration when CAD-CAM milling was available on-site or magnification was routinely used, regardless of presenting symptoms. Almost half (46.8%) preferred to extract if the tooth undergoing root canal treatment had a crack with a 5 mm probing pocket depth. Most (71.4%) demonstrated a poor understanding of cracked tooth biomechanics. CONCLUSION: Australian dentists varied in their diagnostic and treatment preferences for cracked teeth, reflecting a need for more well-controlled clinical studies in the diagnostic process, clinical biomechanics and treatment modalities for these teeth. © 2023 Australian Dental Association.

Global Cross-Sectional Study Evaluating the Attitudes towards a COVID-19 Vaccine in Pregnant and Postpartum Women.

Pregnant and postpartum women have an increased risk of severe complications from COVID-19. Many clinical guidelines recommend vaccination of these populations, and it is therefore critical to understand their attitudes toward COVID-19 vaccines. We conducted a cross-sectional online survey in November 2020 of currently pregnant and ≤1-year postpartum women in Brazil, India, the United Kingdom (UK), and the United States (US) that assessed their openness to COVID-19 vaccines and reasons for vaccine hesitancy. Logistic regression analyses were conducted to evaluate openness to receiving a vaccine. Out of 2010 respondents, 67% were open to receiving a COVID-19 vaccine themselves. Among pregnant and postpartum participants, 72% and 57% were willing to receive a vaccine, respectively. Vaccine openness varied significantly by country: India (87%), Brazil (71%), UK (59%), and US (52%). Across all participants, among the 33% who were unsure/not open to receiving a COVID-19 vaccine, the most common reason cited was safety/side effect concerns (51%). Participants were similarly open to their children/other family members receiving a COVID-19 vaccine. Presence of a comorbidity, a positive COVID-19 test result, and pregnancy were all significantly associated with positive vaccine acceptance. Targeted outreach to address pregnant and postpartum women's concerns about the COVID-19 vaccine is needed.

Interest in Home Birth During the COVID-19 Pandemic: Analysis of Google Trends Data.

INTRODUCTION: Nearly all (94%-99%) pregnant persons in developed countries search for pregnancy-related information online. The advent of the novel coronavirus disease 2019 (COVID-19) and the associated restrictions in hospital policies may have pushed pregnant persons in the United States to consider giving birth at home to achieve their desired birth experience. METHODS: Google Trends is an open, rich source of real-time, anonymized, relative data on disease patterns and population behavior that provides data in the form of search volume index (SVI): the search volume for a queried term relative to overall search volume for a given time frame and geographic location. The SVI is normalized to a scale of 0 to 100. After the World Health Organization declared COVID-19 a pandemic on March 11, 2020, Google Trends was queried on February 21, 2021, for the search term home birth with location set to the United States and the time frame March 11, 2019 to February 21, 2021. RESULTS: The median SVI for home birth during nominally pre-COVID-19 baseline (weeks of March 17, 2019 to March 8, 2020) was relatively constant at 43 (range, 25-56) and increased sharply to 77 during the week of March 15, to 86 during the week of March 22, and peaked at 100 during the week of March 29, 2020. The SVI declined substantially in the following weeks but remained significantly elevated compared with baseline levels. During the approximate 2-year period of query, the states with the highest SVI values (≥80) were Arkansas, Washington, Montana, and Georgia. DISCUSSION: Interest in home birth spiked in the United States immediately after COVID-19 was declared a pandemic and remained significantly elevated thereafter. These results have implications for caregivers and health systems to ensure safe pregnancies and childbirths through the resolution of the ongoing pandemic.

New concept: "TARN friendly trauma reporting" (what radiologists say really does matter).

AIM: To establish if detailed review of trauma reports with reference to coding manual improved accuracy of ISS and to establish if demonstrated changes in coding affected performance and tariff payment. MATERIALS AND METHODS: A study was undertaken which gathered data from 6 months across the five trusts with information on imaging undertaken, mechanism of injury (MOI), Injury Severity Score (ISS), and injury descriptors was included. Patients with ISS near to a best practice tariff boundary of 9 and 16 (5-8 and 11-15) then had their imaging reviewed by the Radiology Department with direct reference to the ISS coding manual. Injuries were then re-coded and ISS recalculated. RESULTS: Over the 6-month period, 1,693 patients were admitted to the database from the five hospitals. One hundred and sixty-nine (9.9%) patients met the inclusion criteria for review. Thirty-five (20.7%) had a change in abbreviated (region specific) injury code, with 30 a change in the resultant ISS. Three had a decrease in ISS and 27 increased ISS with all 27 moving across an ISS best practice tariff and three moving across two payment tariff boundaries. With re-coding, there was a potential £15,000 of lost revenue from the major trauma centre (MTC) alone. CONCLUSION: Reporting with reference to ISS description improves the accuracy of ISS significantly. Radiologists improving the descriptions of specific injury patterns and adopting 'Trauma Audit and Research Network friendly' reporting strategies may improve data accuracy, performance, and payment of best practice tariffs to hospitals.

Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation.

The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

The effect of exercise on local and systemic adverse reactions after vaccinations - Outcomes of two randomized controlled trials.

INTRODUCTION: An adverse reaction associated with vaccination is considered to be a key barrier to vaccinate, yet little attention has been given to interventions to reduce their occurrence. Exercise is a behavioural adjuvant which may also influence adverse reactions. Here, two randomized controlled trials are reported, examining the effects of exercise on self-reported adverse reactions following vaccination in adolescents and young adults. METHODS: Study one; 116 adolescents receiving the HPV vaccine were randomly allocated to either Control (n = 56) or Pre-vaccine Exercise (n = 60) group (2015-2016). Exercise consisted of 15-minutes upper body exercise. Study two; 78 young adults receiving the influenza vaccine were randomly allocated to either Control (n = 19), or one of 3 exercise groups: Pre-vaccine Arm (n = 19), Pre-vaccine Leg (n = 20) or Post-vaccine Arm (n = 20) (2017). Exercise included 15-minutes of arm or leg exercises prior to or after vaccination. All participants in both studies completed an adverse events diary for seven-days post-vaccination. RESULTS: Study one; Reported days of tenderness in female adolescents that exercised were significantly lower than control (p = 0.032), with a similar trend in reported days of pain (p = 0.050). Furthermore, days of feeling ill (p = 0.070) and reduced appetite (p = 0.067) were found to be lower with exercise, although not significant. Overall, female adolescents reported significantly more days of pain (p = 0.003), tenderness (p < 0.001), swelling (p = 0.011), and feeling ill (p = 0.0040). Study two; Exercise groups reported reduced days of swelling (p = 0.018), fever (p = 0.013), and lowered appetite (p = 0.011) across both genders. Furthermore, females reported reduced days of medication use with exercise (p = 0.034), and a trend toward reduced days of swelling (p = 0.052). DISCUSSION: In two separate trials, a short bout of exercise reduced reported adverse reactions after vaccinations for local and systemic adverse reactions. Gender differences in reported local and systemic adverse reactions were more evident among adolescents than young adults. These findings support the need for further work to examine the potential benefit of exercise in improving vaccination procedures.

Understanding breast cancer screening--past, present, and future.

This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making--instead of giving just a 'yes' or 'no' answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice. Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with the goal of improving cancer detection, reducing mortality, and improving patient outcome.

Clinical audit training improves undergraduates' performance in root canal therapy.

AIM: To evaluate the effectiveness of clinical audit-feedback cycle as an educational tool in improving the technical quality of root canal therapy (RCT) and compliance with record keeping performed by dental undergraduates. METHODS: Clinical audit learning was introduced in Year 3 of a 5-year curriculum for dental undergraduates. During classroom activities, students were briefed on clinical audit, selected their audit topics in groups of 5 or 6 students, and prepared and presented their audit protocols. One chosen topic was RCT, in which 3 different cohorts of Year 3 students conducted retrospective audits of patients' records in 2012, 2014 and 2015 for their compliance with recommended record keeping criteria and their performance in RCT. Students were trained by and calibrated against an endodontist (κ ≥ 0.8). After each audit, the findings were reported in class, and recommendations were made for improvement in performance of RCT and record keeping. Students' compliance with published guidelines was presented and their RCT performances in each year were compared using the chi-square test. RESULTS: Overall compliance with of record keeping guidelines was 44.1% in 2012, 79.6% in 2014 and 94.6% in 2015 (P = .001). In the 2012 audit, acceptable extension, condensation and the absence of mishap were observed in 72.4, 75.7% and 91.5%; in the 2014 audit, 95.1%, 64.8% and 51.4%; and in 2015 audit, 96.4%, 82.1% and 92.8% of cases, respectively. In 2015, 76.8% of root canal fillings met all 3 technical quality criteria when compared to 48.6% in 2014 and 44.7% in 2012 (P = .001). CONCLUSION: Clinical audit-feedback cycle is an effective educational tool for improving dental undergraduates' compliance with record keeping and performance in the technical quality of RCT.

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10-4) compared with either PBF- (P=1.5 × 10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10-5) and disease-free survival (P=4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

An update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong.

OBJECTIVE: New information about antiepileptic drugs has arisen since the publication of the Hong Kong Epilepsy Guideline in 2009. This article set out to fill the knowledge gap between 2007 and 2016 on the use of antiepileptic drugs in Hong Kong. PARTICIPANTS: Between May 2014 and April 2016, four consensus meetings were held in Hong Kong, where a group comprising 15 professionals (neurologists, paediatricians, neurosurgeons, radiologists, and clinical psychologists) from both public and private sectors aimed to review the best available evidence and update all practising physicians on a range of clinical issues including drug-related matters. All participants were council members of The Hong Kong Epilepsy Society. EVIDENCE: A literature review of the clinical use of antiepileptic drugs as monotherapy suggested Level A evidence for levetiracetam and Level B evidence for lacosamide. No change in the level of evidence was found for oxcarbazepine (Level A evidence) or pregabalin (undesignated), and no evidence was found for perampanel. A literature review on the clinical use of antiepileptic drugs as adjunctive therapy suggested Level A evidence for both lacosamide and perampanel. No change to the level of evidence was found for levetiracetam (Level A evidence), oxcarbazepine (Level A evidence), or pregabalin (Level A evidence). A literature search on the use of generic antiepileptic drugs suggested Level A evidence for the use of lamotrigine in generic substitution. CONSENSUS PROCESS: Three lead authors of the Subcommittee drafted the manuscript that consisted of two parts-part A: evidence on new antiepileptic drugs, and part B: generic drugs. The recommendations on monotherapy/adjunctive therapy were presented during the meetings. The pros and cons for our health care system of generic substitution were discussed. The recommendations represent the 'general consensus' of the participants in keeping with the evidence found in the literature. CONCLUSIONS: Recommendations for the use of levetiracetam, lacosamide, oxcarbazepine, pregabalin, and perampanel were made. The consensus statements may provide a reference to physicians in their daily practice. Controversy exists over the use of generic products among patients who are currently taking brand medications. In this regard, approvals from prescriber and patient are pivotal. Good communication between doctors and patients is essential, as well as enlisting the assistance of doctors, nurses, and pharmacists, therapeutic blood monitoring if available, and the option of brand antiepileptic drug as a self-financed item. The physical appearance of generic drugs should be considered as it may hamper drug compliance. Support from medical services is recommended. In the longer term, the benefit of flexibility and the options to have a balance between the generic and brand drug market may need to be addressed by institutions and regulatory bodies.

Effects of desvenlafaxine on blood pressure in patients treated for major depressive disorder: a pooled analysis.

OBJECTIVE: To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term studies and in two longer-term, randomized withdrawal studies. RESEARCH DESIGN AND METHODS: Data from patients randomly assigned to desvenlafaxine 10 mg to 400 mg/day or placebo in 11 short-term (8-12 weeks), fixed-dose, double-blind, placebo-controlled studies of major depressive disorder (MDD) were pooled for analysis; two desvenlafaxine randomized withdrawal studies (36 and 46 weeks) were analyzed separately. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224. MAIN OUTCOME MEASURES: Outcomes included change from baseline in supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP), assessed using a mixed model repeated measures (MMRM) analysis, and incidence of hypertension (defined as three consecutive second SDBP measures ≥90 mm Hg AND increase of ≥10 mm Hg from baseline and/or SSBP ≥140 mm Hg AND increase of ≥10 mm Hg), analyzed using Cochran Mantel Hanzael tests. Potential predictors of change in SSBP and SDBP at LOCF were examined by including predictor variables in a regression model. RESULTS: In the pooled, short-term studies, mean changes from baseline over time in SSBP and SDBP were statistically significant compared with placebo for the desvenlafaxine doses of 10 mg/day or greater for SSBP (p ≤ 0.0004; MMRM) and 25 mg/day or greater for SDBP (p ≤ 0.0449; MMRM). The proportion of patients with new onset hypertension differed significantly from placebo for the 50, 200, and 400 mg/day doses (1.9%, 2.4%, 4.8%, respectively, vs 0.8%; all p ≤ 0.0244). Predictors of change in BP included baseline SDBP, baseline SSBP, dose, body mass index, gender, age, race, and history of hypertension. LIMITATIONS: Data were pooled from studies which differed somewhat in study design and patient demographics. None of the studies were originally designed to examine treatment effects on BP. Study entry criteria limit generalization of these results to medically stable patients with a primary diagnosis of MDD. CONCLUSIONS: Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.

Polymicrobial bacterial or fungal infections: incidence, spectrum of infection, risk factors, and clinical outcomes from a large hematopoietic stem cell transplant center.

BACKGROUND: Infections cause significant morbidity and mortality for patients who undergo hematopoietic stem cell transplantation (HSCT). Cancer patients who develop polymicrobial infection (PI) are at increased risk for poor clinical outcomes, yet very limited data have been published within the HSCT setting. METHODS: An observational study of 901 stem cell transplant recipients was conducted at Northwestern Memorial Hospital to identify the incidence, risk factors and outcomes for HSCT recipients who develop infection(s) with multiple bacterial or fungal organisms. RESULTS: Among 901 HSCT recipients reviewed (675 autografts and 226 allografts), 237 patients (27%) had microbiologically documented microorganisms isolated, including 179 patients (76%) with monomicrobial infection and 59 patients (24%) with multiple microorganisms, of which 34 (14%) were classified as PI, and 25 (10%) as multiple distinct episodes of infection. CONCLUSION: The results show co-infection with multiple organisms during HSCT is relatively rare; however, these patients are at an increased risk for the development of acute graft-versus-host disease, delayed engraftment, and overall mortality.

Amphotericin B deoxycholate nasal spray administered to hematopoietic stem cell recipients with prior fungal colonization of the upper airway passages is associated with low rates of invasive fungal infection.

BACKGROUND: Invasive fungal infections cause major problems during hematopoietic stem cell transplantation (HSCT). Fungal colonization of the upper airway passages occurs frequently, and may serve as a portal of entry for potentially life-threatening fungal infections, especially in immunocompromised patients. METHODS: A clinical practice was instituted at Northwestern Memorial Hospital in Chicago in 2005, to administer amphotericin B deoxycholate nasal spray (ABNS) 0.5% to all HSCT recipients with fungal colonization of their nasal passages, in addition to standard oral antifungal prophylaxis. RESULTS: Among 1945 HSCT patients treated during the study period, 109 patients were identified with positive fungal surveillance cultures. CONCLUSION: Breakthrough fungal infections occurred in only 2 patients (2%), thus in this select group of HSCT recipients, ABNS administration is associated with a very low rate of breakthrough infection.

Desvenlafaxine 50 and 100 mg/d versus placebo for the treatment of major depressive disorder: a phase 4, randomized controlled trial.

OBJECTIVE: To assess short-term efficacy and safety of desvenlafaxine 50 and 100 mg/d versus placebo for treating major depressive disorder (MDD). Assessment of sexual function was a secondary objective. METHOD: Outpatients (≥ 18 years) who met criteria for MDD from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision and had screening and baseline 17-item Hamilton Depression Rating Scale (HDRS17) total scores ≥ 20 were randomly assigned to placebo or desvenlafaxine 50 or 100 mg/d in an 8-week study conducted from October 2011 to August 2012. The primary efficacy end point was change from baseline in HDRS17 total score at week 8, analyzed using a mixed-effects model for repeated measures. Sexual function was assessed using the Arizona Sexual Experiences Scale (ASEX). RESULTS: The safety population included 909 patients (intent-to-treat population, n = 886). Significantly greater improvement in adjusted mean HDRS17 total score from baseline to week 8 was observed for desvenlafaxine 50 mg (-11.28; P = .006) and desvenlafaxine 100 mg (-11.67; P < .001) compared with placebo (-9.71), with adjustment for multiplicity. In the ASEX total score analysis (n = 422), the treatment by gender interaction was not significant; thus, genders were combined for subsequent analyses. Comparisons for desvenlafaxine versus placebo for change from baseline in ASEX total and all item scores found P > .05, with no adjustment for multiplicity. Rates of sexual dysfunction based on ASEX were comparable among treatment groups. CONCLUSIONS: These results support previous findings demonstrating antidepressant efficacy, safety, and tolerability of desvenlafaxine 50 and 100 mg/d versus placebo. Sexual function was comparable between desvenlafaxine and placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01432457.

Prolonged altered mental status and bradycardia following pediatric donepezil ingestion.

CONTEXT: Donepezil is a centrally-acting, reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer disease. Altered mental status, nausea, vomiting, and bradycardia have been reported in therapeutic and supratherapeutic ingestions of donepezil, though pediatric exposures have not been well-described. We report a case of prolonged altered mental status and recurrent bradycardia in a child with a single-pill ingestion of donepezil. CASE DETAILS: A 14-month-old boy was brought to the Emergency Department 3 hours after ingesting one of his grandfather's donepezil tablets (10 mg). Upon arrival, he was somnolent and drooling, with multiple episodes of vomiting and diarrhea. Pupils were normal. Initial vitals: temperature, 36.8°C; blood pressure, 103/56 mmHg; heart rate, 140/min; respiratory rate, 36/min; oxygen saturation, 97%. His drooling, vomiting, and diarrhea resolved, but he remained intermittently agitated. Over the course of the following four days, he had intermittent, episodes of asymptomatic bradycardia to a low of 55/min, primarily when sleeping. A transient episode of junctional rhythm was observed. Serum donepezil level 97 hours post-ingestion was 10 ng/ml. He did not require atropine treatment, and was discharged in stable condition on hospital day 5. DISCUSSION: Donepezil has a prolonged elimination of half-life in adults of approximately 70 hours. Despite its relative specificity for central AChEs, peripheral cholinergic symptoms have been described. We report a case of a symptomatic ingestion of donepezil in a child. CONCLUSIONS: Even after a single-tablet ingestion, donepezil may cause prolonged altered mental status and bradycardia in young children.

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.