SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot-Marie-Tooth disease Type 1A mouse model.

Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1-/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, genetic deletion of SARM1 conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in C3-PMP CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

Contact Engineering High-Performance n-Type MoTe2 Transistors.

Semiconducting MoTe2 is one of the few two-dimensional (2D) materials with a moderate band gap, similar to silicon. However, this material remains underexplored for 2D electronics due to ambient instability and predominantly p-type Fermi level pinning at contacts. Here, we demonstrate unipolar n-type MoTe2 transistors with the highest performance to date, including high saturation current (>400 µA/µm at 80 K and >200 µA/µm at 300 K) and relatively low contact resistance (1.2 to 2 kΩ·µm from 80 to 300 K), achieved with Ag contacts and AlOx encapsulation. We also investigate other contact metals (Sc, Ti, Cr, Au, Ni, Pt), extracting their Schottky barrier heights using an analytic subthreshold model. High-resolution X-ray photoelectron spectroscopy reveals that interfacial metal-Te compounds dominate the contact resistance. Among the metals studied, Sc has the lowest work function but is the most reactive, which we counter by inserting monolayer hexagonal boron nitride between MoTe2 and Sc. These metal-insulator-semiconductor (MIS) contacts partly depin the metal Fermi level and lead to the smallest Schottky barrier for electron injection. Overall, this work improves our understanding of n-type contacts to 2D materials, an important advance for low-power electronics.

Unipolar n-Type Black Phosphorus Transistors with Low Work Function Contacts.

Black phosphorus (BP) is a promising two-dimensional (2D) material for nanoscale transistors, due to its expected higher mobility than other 2D semiconductors. While most studies have reported ambipolar BP with a stronger p-type transport, it is important to fabricate both unipolar p- and n-type transistors for low-power digital circuits. Here, we report unipolar n-type BP transistors with low work function Sc and Er contacts, demonstrating a record high n-type current of 200 µA/µm in 6.5 nm thick BP. Intriguingly, the electrical transport of the as-fabricated, capped devices changes from ambipolar to n-type unipolar behavior after a month at room temperature. Transmission electron microscopy analysis of the contact cross-section reveals an intermixing layer consisting of partly oxidized metal at the interface. This intermixing layer results in a low n-type Schottky barrier between Sc and BP, leading to the unipolar behavior of the BP transistor. This unipolar transport with a suppressed p-type current is favorable for digital logic circuits to ensure a lower off-power consumption.

Clinicopathologic features and pathogenesis of melanocytic colonization in atypical meningioma.

Only two prior cases of benign dendritic melanocytes colonizing a meningioma have been reported. We add a third case, describe clinicopathologic features shared by the three, and elucidate the risk factors for this very rare phenomenon. A 29 year-old Hispanic woman presented with headache and hydrocephalus. MRI showed a lobulated enhancing pineal region mass measuring 41 mm in greatest dimension. Subtotal resection of the mass demonstrated an atypical meningioma, WHO grade II, and the patient subsequently underwent radiotherapy. She presented 4 years later with diplopia, and MRI showed an enhancing extra-axial mass measuring 47 mm in greatest dimension and centered on the tentorial incisura. Subtotal resection showed a brain-invasive atypical meningioma with melanocytic colonization. The previous two cases in the literature were atypical meningiomas, one of which was also brain invasive. Atypical meningiomas may be at particular risk for melanocytic colonization as they upregulate molecules known to be chemoattractants for melanocytes. We detected c-Kit expression in a minority of the melanocytes as well as stem cell factor and basic fibroblast growth factor in the meningioma cells, suggesting that mechanisms implicated in normal melanocyte migration may be involved. In some cases, brain invasion with disruption of the leptomeningeal barrier may also facilitate migration from the subarachnoid space into the tumor. Whether there is low-level proliferation of the dendritic melanocytes is unclear. Given that all three patients were non-Caucasian, meningiomas in persons and/or brain regions with increased dendritic melanocytes may predispose to colonization. The age range spanned from 6 years old to 70 years old. All three patients were female. The role of gender and estrogen in the pathogenesis of this entity remains to be clarified. Whether melanocytic colonization may also occur in the more common Grade I meningiomas awaits identification of additional cases.

Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study.

Epidermal growth factor receptor (EGFR) mutations are commonly observed in Glioblastoma (GBM) and have long posed as a target for new therapies. Trials involving erlotinib have shown mixed results, likely owing to a mechanism of the mutation that may instead favor other EGFR inhibitors, such as lapatinib. We aimed to determine whether or not pulse high-dose lapatinib was a safe and tolerable regimen in addition to standard therapy. We recruited adult patients with newly-diagnosed GBM who had Karnofsky Performance Status ≥60, normal baseline hematological, hepatic, and renal function tests, and no prior history of radiation or treatment with EGFR inhibitor. Lapatinib was administered at 2500 mg twice daily for two consecutive days per week on a weekly basis throughout concomitant and adjuvant standard therapy. The primary endpoints were tolerability and safety. 12 patients were enrolled in this study over 2 years. Of the non-hematological adverse events, there were 2 grade 3 events, fatigue and post-radiation cystic brain necrosis. The most common adverse events in general were fatigue, rashes, and diarrhea. Of the hematological adverse events, there were 13 grade 3 events, all of which were due to lymphopenia and affected 6 of 12 patients. Pulse high-dose lapatinib in addition to standard therapy for newly-diagnosed GBM is a tolerable and safe regimen, but higher rates of lymphopenia should be noted. However, further investigations will be required to evaluate the efficacy of this combination for the treatments of GBM. Trial registration ClinicalTrials.gov Identifier: NCT01591577.

Fast phasic release properties of dopamine studied with a channel biosensor.

Few other neurotransmitters are of as intense interest to neuropsychiatry and neurology as dopamine, yet existing techniques to monitor dopamine release leave an important spatiotemporal gap in our understanding. Electrochemistry and fluorescence imaging tools have been developed to fill the gap, but these methods have important limitations. We circumvent these limitations by introducing a dopamine-gated chloride channel into rat dorsal striatal medium spiny neurons, targets of strong dopamine innervation, thereby transforming dopamine from a slow transmitter into a fast transmitter and revealing new opportunities for studying moment-to-moment regulation of dopamine release. We demonstrate pharmacological and biophysical properties of the channel that make it suitable for fast, local dopamine measurements, and we demonstrate for the first time spontaneous and evoked responses to vesicular dopamine release in the dorsal striatum. Evoked dopamine currents were separated into a fast, monosynaptic component and a slower-rising and decaying disynaptic component mediated by nicotinic receptor activation. In summary, LGC-53 represents a dopamine biosensor with properties suitable for temporal separation of distinct dopamine signals in targets of dopamine innervation.

Pharmacologic Restraint Use During Mental Health Admissions to Children's Hospitals.

OBJECTIVES: Primary mental health admissions are increasing across US children's hospitals. These patients may experience agitation requiring pharmacologic restraint. This study characterized pharmacologic restraint use in medical inpatient units by primary mental health diagnosis. METHODS: This retrospective, cross-sectional study used the Pediatric Health Information System database. The study included children aged 5 to 17 years admitted with a primary mental health diagnosis between 2016 and 2021. Rates of pharmacologic restraint use per 1000 patient days were determined for 13 mental health diagnoses and trended over time with Poisson regression. RESULTS: Of 91 898 hospitalizations across 43 hospitals, 3% of admissions and 1.3% of patient days involved pharmacologic restraint. Trends in the rate of pharmacologic restraint use remained stable (95% confidence interval [CI], 0.7-2.1), whereas the incidence increased by 141%. Diagnoses with the highest rates of pharmacologic restraint days per 1000 patient days included autism (79.4; 95% CI, 56.2-112.3), substance-related disorders (45.0; 95% CI, 35.9-56.4), and disruptive disorders (44.8; 95% CI, 25.1-79.8). The restraint rate significantly increased in disruptive disorders (rate ratio [RR], 1.4; 95% CI, 1.1-1.6), bipolar disorders (RR, 2.0; 95% CI, 1.4-3.0), eating disorders (RR, 2.4; 95% CI, 1.5-3.9), and somatic disorders (RR, 4.2; 95% CI, 1.9-9.1). The rate significantly decreased for autism (RR, 0.8; 95% CI, 0.6-1.0) and anxiety disorders (RR, 0.3; 95% CI, 0.2-0.6). CONCLUSIONS: Pharmacologic restraint use among children hospitalized with a primary mental health diagnosis increased in incidence and varied by diagnosis. Characterizing restraint rates and trends by diagnosis may help identify at-risk patients and guide targeted interventions to improve pharmacologic restraint utilization.

Lower opportunity ZIP code is associated with worse outcomes after listing in pediatric heart transplantation.

BACKGROUND: The Child Opportunity Index (COI) comprehensively measures children's social determinants of health. We describe association between COI and outcomes after listing for heart transplantation. METHODS: We conducted a retrospective review of the United Network for Organ Sharing (UNOS) database for U.S. children listed for heart transplant between 2012 and 2020. ZIP codes were utilized to assign COI. Primary outcome was survival from time of listing. Secondary outcomes included waitlist survival, 1-year post-transplant survival, and conditional 1-year post-transplant survival. Cox regression was performed adjusting for payor, age, race, diagnosis, and support at listing for all outcomes except waitlist survival, for which Fine-Gray competing risk analysis was performed. RESULTS: Of 5,723 children listed, 109 were excluded due to missing ZIP codes. Race/ethnicity and payor were associated with COI (p < 0.001). Patients living in very low COI ZIP codes compared to all others had increased mortality from time of listing (HR 1.16, CI 1.03-1.32, p = 0.02) with 1-, 5-, and 9-year survival of 79.3% vs 82.2%, 66.5% vs 73.0%, and 53.6% vs 64.7% respectively, were more likely to be removed from the waitlist due to death or being too sick (subdistribution HR 1.26, 95% CI 1.10-1.42), and had increased mortality conditional on one-year post-transplant survival (HR 1.38, 1.09-1.74, p = 0.008) with 1-, 3-, and 5- year survival of 94.7% vs 97.3%, 87.0% vs 93.1%, and 78.6% vs 86.9%. CONCLUSIONS: Children living in lower opportunity ZIP codes had poorer survival from time of listing, poorer waitlist survival, and poorer conditional one-year post-transplant survival.

Unsupervised Segmentation of Knee Bone Marrow Edema-like Lesions Using Conditional Generative Models.

Bone marrow edema-like lesions (BMEL) in the knee have been linked to the symptoms and progression of osteoarthritis (OA), a highly prevalent disease with profound public health implications. Manual and semi-automatic segmentations of BMELs in magnetic resonance images (MRI) have been used to quantify the significance of BMELs. However, their utilization is hampered by the labor-intensive and time-consuming nature of the process as well as by annotator bias, especially since BMELs exhibit various sizes and irregular shapes with diffuse signal that lead to poor intra- and inter-rater reliability. In this study, we propose a novel unsupervised method for fully automated segmentation of BMELs that leverages conditional diffusion models, multiple MRI sequences that have different contrast of BMELs, and anomaly detection that do not rely on costly and error-prone annotations. We also analyze BMEL segmentation annotations from multiple experts, reporting intra-/inter-rater variability and setting better benchmarks for BMEL segmentation performance.

Outcomes associated with initial narrow-spectrum versus broad-spectrum antibiotics in children hospitalized with urinary tract infections.

OBJECTIVE: The aim of this study is to describe the proportion of children hospitalized with urinary tract infections (UTIs) who receive initial narrow- versus broad-spectrum antibiotics across children's hospitals and explore whether the use of initial narrow-spectrum antibiotics is associated with different outcomes. DESIGN, SETTING AND PARTICIPANTS: We performed a retrospective cohort analysis of children aged 2 months to 17 years hospitalized with UTI (inclusive of pyelonephritis) using the Pediatric Health Information System (PHIS) database. MAIN OUTCOME AND MEASURES: We analyzed the proportions of children initially receiving narrow- versus broad-spectrum antibiotics; additionally, we compiled antibiogram data for common uropathogenic organisms from participating hospitals to compare with the observed antibiotic susceptibility patterns. We examined the association of antibiotic type with adjusted outcomes including length of stay (LOS), costs, and 7- and 30-day emergency department (ED) revisits and hospital readmissions. RESULTS: We identified 10,740 hospitalizations for UTI across 39 hospitals. Approximately 5% of encounters demonstrated initial narrow-spectrum antibiotics, with hospital-level narrow-spectrum use ranging from <1% to 25%. Approximately 80% of hospital antibiograms demonstrated >80% Escherichia coli susceptibility to cefazolin. In adjusted models, those who received initial narrow-spectrum antibiotics had shorter LOS (narrow-spectrum: 33.1 (95% confidence interval [CI]: 30.8-35.4) h versus broad-spectrum: 46.1 (95% CI: 44.1-48.2) h) and reduced costs [narrow-spectrum: $4570 ($3751-5568) versus broad-spectrum: $5699 ($5005-$6491)]. There were no differences in ED revisits or hospital readmissions. In summary, children's hospitals have low rates of narrow-spectrum antibiotic use for UTIs despite many reporting high rates of cefazolin-susceptible E. coli. These findings, coupled with the observed decreased LOS and costs among those receiving narrow-spectrum antibiotics, highlight potential antibiotic stewardship opportunities.

Hospital costs and reimbursement for short-stay inpatient versus observation status hospitalizations for children with medical complexity.

BACKGROUND: There is a lack of uniformity across hospitals in applying inpatient versus observation status for short-stay (<48 h) pediatric hospitalizations, with negative financial implications associated with observation. Children with medical complexity (CMC) represent a growing population and incur high costs of care. The financial implications of inpatient and observation status for CMC have not been studied. OBJECTIVES: To compare costs and reimbursement for short-stay hospitalizations for CMC by inpatient and observation status, overall and stratified by payor. METHODS: We performed a cohort study of short-stay hospitalizations for CMC from 2016 to 2021 at 10 children's hospitals reporting reimbursement in the Pediatric Health Information System and Revenue Management Program. The primary outcome was the cost coverage ratio (CCR), defined as an encounter's reimbursement divided by the estimated cost. RESULTS: There were 89,282 encounters included. The median costs per encounter were similar across observation ($5206, IQR $3604-$7484) and inpatient ($6547, IQR $4725-$9349) encounters. For government payors, the median CCR was 0.6 (IQR 0.2-0.9) for observation encounters and 1.2 (IQR 0.8-1.9) for inpatient. For nongovernment payors, the median CCR was 1.6 (IQR 1.3-1.9) for observation and 1.6 (IQR 1.4-2) for inpatient. Government reimbursement was associated with increased risk for financial loss (OR 13.91, 95% CI 7.23, 26.77) and with a median net loss of $985,952 (IQR $389,871-$1,700,041) per hospital annually for observation encounters. CONCLUSIONS: Government-paid observation encounters for CMC are associated with significant financial loss at children's hospitals. This reimbursement model may pose a threat to children's hospitals' ability to care for CMC.

Noncompetitive, voltage-dependent NMDA receptor antagonism by hydrophobic anions.

NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease. Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers. We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABA(A) receptor function by a mechanism indistinguishable from that of sulfated neurosteroids. Because sulfated neurosteroids also modulate NMDARs, here we examined the effects of DPA on NMDAR function. In rat hippocampal neurons DPA inhibited currents gated by 300 µM NMDA with an IC(50) of 2.3 µM. Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a noncompetitive profile. DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations. Surprisingly, similar to cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent. Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism. Furthermore, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments. Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions. Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating. Overall, we conclude that DPA noncompetitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists.

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.

Adding Nocturnal Advanced Practice Providers to an Academic Inpatient Neurology Service Improves Residents' Educational Experience.

Background and Objectives: In the inpatient academic medical center, increased demand for clinical services often equates to an increased workload for trainees, which could have a positive or negative impact on their educational experience. In 2020, our academic medical center hired Advanced Practice Providers (APPs) to provide continuous additional overnight coverage for our neurology ward teaching service. We hypothesized that adding APPs and reducing overnight clinical workload for residents would have a positive impact on resident education. Methods: We performed a mixed-methods, prospective study that included needs-assessments by residents, semi-structured interviews with both residents and APPs, and surveys to residents and nursing staff. In addition, we collected quantitative data such as hours of sleep, number of admissions, and number of pages to capture the impact of APPs on resident overnight shifts. Results: The addition of APPs overnight increased the median hours of sleep overnight from 1 hour to 3 hours (P < .001) and decreased the median number of pages overnight from 31.5 to 17 (P < .001). The median number of patients the resident was responsible for cross-covering overnight decreased from 24 patients to 14 patients (P < .001). The majority of resident responses (94%) agreed that the addition of APPs benefited their education by reducing workload and increasing time allotted to reading and formulating plans for overnight admissions. 88% of residents agreed that the addition of APPs improved quality of life and reduced risk of burnout. Conclusion: Advanced Practice Providers significantly reduced resident workload, leading residents to report improvements in the educational experience overnight and reduced perceived risk of burnout.

National cross-sectional study on cost consciousness, cost accuracy, and national medical waste reduction initiative knowledge among pediatric hospitalists in the United States.

BACKGROUND/OBJECTIVE: Despite initiatives to reduce waste and spending, there is a gap in physician knowledge regarding the cost of commonly ordered items. We examined the relationship between pediatric hospitalists' knowledge of national medical waste reduction initiatives, self-reported level of cost-consciousness (the degree in which cost affects practice), and cost accuracy (how close an estimate is to its hospital cost) at a national level. METHODS: This cross-sectional study used a national, online survey sent to hospitalists at 49 children's hospitals to assess their knowledge of national medical waste reduction initiatives, self-reported cost consciousness, and cost estimates for commonly ordered laboratory studies, medications, and imaging studies. Actual unit costs for each hospital were obtained from the Pediatric Health Information System (PHIS). Cost accuracy was calculated as the percent difference between each respondent's estimate and unit costs, using cost-charge ratios (CCR). RESULTS: The hospitalist response rate was 17.7% (327/1850), representing 40 hospitals. Overall, 33.1% of respondents had no knowledge of national medical waste reduction initiatives and 24.3% had no knowledge of local hospital costs. There was no significant relationship between cost accuracy and knowledge of national medical waste reduction initiatives or high self-reported cost consciousness. Hospitalists with the highest self-reported cost consciousness were the least accurate in estimating costs for commonly ordered laboratory studies, medications, or imaging studies. Respondents overestimated the cost of all items with the largest percent difference with medications. Hospitalists practicing over 15 years had the highest cost accuracy. CONCLUSIONS: A large proportion of pediatric hospitalists lack knowledge on national waste reduction initiatives. Improving the cost-accuracy of pediatric hospitalists may not reduce health care costs as they overestimated many hospital costs. Median unit cost lists could be a resource for educating medical students and residents about health care costs.

Impact of anakinra use on clinical outcomes in children with moderate or severe multisystem inflammatory syndrome in children: a propensity score matched retrospective cohort study.

BACKGROUND: The treatment of children with multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 infection involves immunomodulatory therapies such as IVIG and steroids. Anakinra, an interleukin-1 receptor inhibitor, has also been used, but its effectiveness is not established yet. As optimal regimens for MIS-C remain unknown, we aimed to assess the effect of anakinra in reducing hospital stay in patients with MIS-C. METHODS: We included children admitted from May 2020 to May 2021 diagnosed with MIS-C based on CDC criteria. The exposure of interest was anakinra use at any point during admission. The anakinra exposed group and the anakinra unexposed group were propensity score matched based on demographic and clinical severity indicators at initial presentation. Our primary outcome was length of hospital stay. Secondary outcomes were duration of vasoactive support, vasoactive inotropic score (VIS), level of respiratory support, time to fever resolution, reduction of CRP levels, and length of ICU stay. We used Wilcoxon rank sum, t-test, Chi square and Fisher's exact tests. RESULTS: Of 138 children diagnosed with MIS-C, 79% had moderate or severe illness and 41% received anakinra. Of those, 31 patients who received anakinra were propensity score matched to 31 who did not. The length of stay in the hospital but not in the ICU was longer in the anakinra group. There were no differences in median duration of vasoactive support, fever resolution, CRP reduction, or VIS. CONCLUSIONS: In patients with moderate to severe MIS-C, use of anakinra was associated with longer duration of hospital stay.

Risk of Target Organ Damage in Children With Primary Ambulatory Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Target organ damage (TOD) such as left ventricular hypertrophy (LVH), abnormal pulse wave velocity, and elevated carotid intima-media thickness are common among adults with hypertension and are associated with overt cardiovascular events. The risk of TOD among children and adolescents with hypertension confirmed by ambulatory blood pressure monitoring is poorly understood. In this systematic review, we compare the risks of TOD among children and adolescents with ambulatory hypertension to normotensive individuals. METHODS: A literature search was conducted to include all relevant English-language publications from January 1974 to March 2021. Studies were included if patients underwent 24-hour ambulatory blood pressure monitoring and ≥1 TOD was reported. Ambulatory hypertension was defined by society guidelines. Primary outcome was the risk of TOD, including LVH, left ventricular mass index, pulse wave velocity, and carotid intima-media thickness among children with ambulatory hypertension compared with those with ambulatory normotension. Meta-regression calculated the effect of body mass index on TOD. RESULTS: Of 12 252 studies, 38 (n=3609 individuals) were included for analysis. Children with ambulatory hypertension had an increased risk of LVH (odds ratio, 4.69 [95% CI, 2.69-8.19]), elevated left ventricular mass index (pooled difference, 5.13 g/m2.7; [95% CI, 3.78-6.49]), elevated pulse wave velocity (pooled difference, 0.39 m/s [95% CI, 0.20-0.58]), and elevated carotid intima-media thickness (pooled difference, 0.04 mm [95% CI, 0.02-0.05]), compared with normotensive children. Meta-regression showed a significant positive effect of body mass index on left ventricular mass index and carotid intima-media thickness. CONCLUSIONS: Children with ambulatory hypertension have adverse TOD profiles, which may increase their risk for future cardiovascular disease. This review highlights the importance of optimizing blood pressure control and screening for TOD in children with ambulatory hypertension. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020189359.

Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Prevalence of Pediatric Masked Hypertension and Risk of Subclinical Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Masked hypertension (MH) occurs when office blood pressure is normal, but hypertension is confirmed using out-of-office blood pressure measures. Hypertension is a risk factor for subclinical cardiovascular outcomes, including left ventricular hypertrophy, increased left ventricular mass index, carotid intima media thickness, and pulse wave velocity. However, the risk factors for ambulatory blood pressure monitoring defined MH and its association with subclinical cardiovascular outcomes are unclear. A systematic literature search on 9 databases included English publications from 1974 to 2023. Pediatric MH prevalence was stratified by disease comorbidities and compared with the general pediatric population. We also compared the prevalence of left ventricular hypertrophy, and mean differences in left ventricular mass index, carotid intima media thickness, and pulse wave velocity between MH versus normotensive pediatric patients. Of 2199 screened studies, 136 studies (n=28 612; ages 4-25 years) were included. The prevalence of MH in the general pediatric population was 10.4% (95% CI, 8.00-12.80). Compared with the general pediatric population, the risk ratio (RR) of MH was significantly greater in children with coarctation of the aorta (RR, 1.91), solid-organ or stem-cell transplant (RR, 2.34), chronic kidney disease (RR, 2.44), and sickle cell disease (RR, 1.33). MH patients had increased risk of subclinical cardiovascular outcomes compared with normotensive patients, including higher left ventricular mass index (mean difference, 3.86 g/m2.7 [95% CI, 2.51-5.22]), left ventricular hypertrophy (odds ratio, 2.44 [95% CI, 1.50-3.96]), and higher pulse wave velocity (mean difference, 0.30 m/s [95% CI, 0.14-0.45]). The prevalence of MH is significantly elevated among children with various comorbidities. Children with MH have evidence of subclinical cardiovascular outcomes, which increases their risk of long-term cardiovascular disease.