Dissociable hindbrain GLP1R circuits for satiety and aversion.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

Natural history study of patients with familial platelet disorder with associated myeloid malignancy.

ABSTRACT: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK.

OBJECTIVES: To describe the clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK. METHODS: We investigated the incidence and factors associated with COVID-19 in a previously established and well-characterized cohort of black people with HIV. Primary outcomes were COVID-19 acquisition and severe COVID-19 disease (requiring hospitalization and/or resulting in death). Cumulative incidence was analysed using Nelson-Aalen methods, and associations between demographic, pre-pandemic immune-virological parameters, comorbidity status and (severe) COVID-19 were identified using Cox regression analysis. RESULTS: COVID-19 status was available for 1847 (74%) of 2495 COVID-AFRICA participants (median age 49.6 years; 56% female; median CD4 cell count = 555 cells/µL; 93% HIV RNA <200 copies/mL), 573 (31%) of whom reported at least one episode of COVID-19. The cumulative incidence rates of COVID-19 and severe COVID-19 were 31.0% and 3.4%, respectively. Region of ancestry (East/Southern/Central vs. West Africa), nadir CD4 count and kidney disease were associated with COVID-19 acquisition. Diabetes mellitus [adjusted hazard ratio (aHR) = 2.39, 95% confidence interval (CI): 1.26-4.53] and kidney disease (aHR = 2.53, 95% CI: 1.26-4.53) were associated with an increased risk, and recent CD4 count >500 cells/µL (aHR = 0.49, 95% CI: 0.25-0.93) with a lower risk of severe COVID-19. CONCLUSIONS: Region of ancestry was associated with COVID-19 acquisition, and immune and comorbidity statuses were associated with COVID-19 disease severity in people of black ethnicity living with HIV in the UK.

Feasibility of Noninvasive Assessment of Cardiac Output during Exercise in Healthy Adults by a Novel Elaboration on Systolic Time Intervals.

BACKGROUND: Although assessment of cardiovascular hemodynamics during exercise can provide clinical insights, it is challenging to acquire it in clinical settings. OBJECTIVES: Accordingly, this preliminary study was to determine whether a novel elaboration on systolic time interval measures (eSTICO) method of quantifying cardiac output and stroke volume was comparable to those obtained using a validated soluble gas (open circuit CO measure [OpCircCO]) method or calculation based on oxygen consumption (oxygen consumption-based CO [VO2CO]) during exercise. METHODS: For the present study, 14 healthy subjects (male: n = 12, female: n = 2) performed incremental exercise on a recumbent cycle ergometer. At rest and during exercise, cardiac output (CO) was obtained via the eSTICO method, while the OpenCircCO and VO2CO measures were obtained at the last minute of each workload. RESULTS: At peak, there was no difference between eSTICO and OpCircCO (12.39 ± 3.06 vs. 13.96 ± 2.47 L/min, p > 0.05), while there was a slight difference between eSTICO and VO2CO (12.39 ± 3.06 vs. 14.28 ± 2.55 L/min, p < 0.05). When we performed correlation analysis with all subjects and all measures of CO at all WL, between eSTICO and OpenCircCO, there was a good relationship (r = 0.707, p < 0.001) with a Bland and Altman agreement analysis demonstrating a -1.6 difference (95% LoA: -6.3-3.5). Between eSTICO and VO2CO, we observed an r = 0.865 (p < 0.001) and a Bland and Altman agreement analysis with a -1.2 difference (95% LoA: -4.8-2.4). CONCLUSION: A novel exploitation of cardiac hemodynamics using systolic timing intervals may allow a relatively good assessment of CO during exercise in healthy adults.

Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement.

BACKGROUND: Enzymes of the Golgi implicated in N-glycan processing are critical for brain development, and defects in many are defined as congenital disorders of glycosylation (CDG). Involvement of the Golgi mannosidase, MAN2A2 has not been identified previously as causing glycosylation defects. METHODS: Exome sequencing of affected individuals was performed with Sanger sequencing of the MAN2A2 transcript to confirm the variant. N-glycans were analysed in patient-derived lymphoblasts to determine the functional effects of the variant. A cell-based complementation assay was designed to assess the pathogenicity of identified variants using MAN2A1/MAN2A2 double knock out HEK293 cell lines. RESULTS: We identified a multiplex consanguineous family with a homozygous truncating variant p.Val1101Ter in MAN2A2. Lymphoblasts from two affected brothers carrying the same truncating variant showed decreases in complex N-glycans and accumulation of hybrid N-glycans. On testing of this variant in the developed complementation assay, we see the complete lack of complex N-glycans. CONCLUSION: Our findings show that pathogenic variants in MAN2A2 cause a novel autosomal recessive CDG with neurological involvement and facial dysmorphism. Here, we also present the development of a cell-based complementation assay to assess the pathogenicity of MAN2A2 variants, which can also be extended to MAN2A1 variants for future diagnosis.

Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans.

BACKGROUND: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder. METHODS: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants. RESULTS: We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures. CONCLUSION: Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-ß-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

Efficacy of an experimental toothpaste containing sodium bicarbonate, sodium hyaluronate and sodium fluoride on gingivitis.

BACKGROUND: Gingivitis is driven by plaque accumulation and, if left untreated, can progress to irreversible periodontitis. For many, the mechanical action of toothbrushing does not achieve adequate plaque control. The aim of this study was to investigate whether twice-daily use of a toothpaste containing 0.2% high molecular weight (HMW) sodium hyaluronate with 67% sodium bicarbonate and 0.221% sodium fluoride (experimental toothpaste) could improve gingival health compared with a regular fluoride toothpaste (negative control). The study also assessed whether the experimental toothpaste could provide additive gingival health benefit over a toothpaste containing only 67% sodium bicarbonate and 0.221% sodium fluoride (positive control). METHODS: This was a single-center, examiner-blinded, randomized, clinical study in healthy adults with mild-to-moderate gingivitis. At baseline, after abstaining from toothbrushing for 12 h, prospective participants underwent oral soft tissue (OST) and oral hard tissue examination followed by assessments for gingival inflammation (Modified Gingival Index [MGI]), gingival bleeding (Bleeding Index [BI]), and supra-gingival plaque (Turesky Plaque Index [TPI]). Eligible participants were stratified by gender and baseline number of bleeding sites (low: <45; high: ≥45 bleeding sites). Following randomization, participants underwent prophylactic dental treatment. Participants received a full OST examination, MGI, BI and TPI assessments after 3 days, 1, 2 and 6 weeks of product use. RESULTS: In total, 110 participants were screened for study entry and all were randomized to receive one of three toothpastes (experimental: sodium hyaluronate, sodium bicarbonate, sodium fluoride; positive control: sodium bicarbonate, sodium fluoride; negative control: regular fluoride toothpaste). For all measures, significant improvements were observed in participants receiving either sodium bicarbonate-containing toothpaste (experimental or positive control) compared with the regular fluoride toothpaste (negative control) at week 6. No significant difference was observed in any assessment or visit comparing the experimental toothpaste with the positive control. CONCLUSIONS: Both the experimental and the positive control toothpastes demonstrated clinically relevant improvements in gingival health compared with a regular fluoride toothpaste (negative control). However, no additional gingival health improvement was observed for the experimental toothpaste compared with the positive control, therefore, no additional gingival health benefit can be attributed to the inclusion of sodium hyaluronate in this formulation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04737538 (04/02/2021).

Plasma FGF23 is associated with left atrial remodeling in children on hemodialysis.

BACKGROUND: FGF23 mediates cardiac fibrosis through the activation of pro-fibrotic factors in in vitro models and is markedly elevated in kidney disease. Left atrial global longitudinal strain (LA GLS) derived by echocardiographic speckle-tracking measures longitudinal shortening of the LA walls, quantifies atrial performance and may enable detection of early LA remodeling in the setting of normal ventricular function. We hypothesized that LA GLS is abnormal in children on hemodialysis (HD) compared to healthy controls of comparable age/sex distribution and that, among HD patients, greater FGF23 levels are associated with abnormal LA GLS. METHODS: Clinical and echocardiographic data from 29 children receiving HD and 13 healthy controls were collected in a cross-sectional single-center study. Plasma FGF23 concentrations were measured using ELISA. The primary outcome was LA GLS measured using 2D speckle-tracking strain analysis. Linear regression analysis was used to investigate predictors of LA GLS in HD. RESULTS: Median dialysis vintage was 1.5 (IQR 0.5-4.3) years. Median intact FGF23 levels were substantially higher in the HD vs. control group (1206 [215, 4707] vs. 51 [43, 66.5] pg/ml; P = 0.0001), and LA GLS was 39.9% SD 11.6 vs. 32.8% SD 5.7 (P = 0.04). Among HD patients, higher FGF23 was associated with lower LA GLS (ß per unit Ln-FGF23: - 2.7; 95% CI slope - 5.4, - 0.1; P = 0.04 after adjustment for age, body size, and HD vintage. FGF23 was not associated with LA phasic reservoir, conduit, or contractile strain. CONCLUSIONS: In children on HD and preserved left ventricular ejection fraction, greater FGF23 is associated with lower LA GLS (indicative of impaired atrial performance). A higher resolution version of the Graphical abstract is available as Supplementary information.

Decreased Risk of Preeclampsia in Women with Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy.

BACKGROUND: Evidence suggests that upregulation of tumor necrosis factor-alpha (TNF-α) plays a role in immune dysregulation in both preeclampsia and inflammatory bowel disease (IBD). AIMS: We aimed to investigate whether anti-TNF therapy during pregnancy decreases the risk of preeclampsia in women with IBD. METHODS: The study population included women with IBD and pregnancies who were followed at a tertiary care center from 2007 to 2021. Cases of preeclampsia were compared with controls with a normotensive pregnancy. Data on patient demographics, disease type and activity, pregnancy complications, and additional risk factors for preeclampsia were collected. The association between anti-TNF therapy and preeclampsia was analyzed using univariate analysis and multivariate logistic regression. RESULTS: Women with preeclampsia were more likely to have a preterm delivery (44% vs. 12%, p < 0.001). More women without preeclampsia were exposed to anti-TNF therapy during pregnancy than women with preeclampsia (55% vs. 30%, p = 0.029). The majority of women (32/44) on anti-TNF therapy, either adalimumab or infliximab, continued to have some degree of exposure during the third trimester. Though not significant, multivariate analysis showed a trend towards a protective effect of anti-TNF therapy against developing preeclampsia if exposed during the third trimester (OR 0.39; 95% CI 0.14-1.12, p = 0.08). CONCLUSIONS: In this study, anti-TNF therapy exposure was higher in IBD patients who did not develop preeclampsia than in those who did. While not significant, there was a trend towards a protective effect of anti-TNF therapy against preeclampsia if exposed during the third trimester.

The Local Market of Major Teaching Hospitals.

OBJECTIVE: The purpose of this study was to describe the local communities served by major teaching hospitals. METHODS: Using a dataset of hospitals around the United States provided by the Association of American Medical Colleges, we identified major teaching hospitals (MTHs) using the Association of American Medical Colleges' definition of those with an intern-to-resident bed ratio above 0.25 and more than 100 beds. We defined the local geographic market surrounding these hospitals as the Dartmouth Atlas hospital service area (HSA). Using MATLAB R2020b software, data from each ZIP Code Tabulation Area from the US Census Bureau's 2019 American Community Survey 5-Year Estimate Data tables were grouped by HSA and attributed to each MTH. One-sample t tests were used to evaluate for statistical differences between the HSAs and the US average data. We further stratified the data into regions as defined by the US Census Bureau: West, Midwest, Northeast, and South. One-sample t tests were used to evaluate for statistical differences between MTH HSA regional populations with their respective US regional population. RESULTS: The local population surrounding 299 unique MTHs covered 180 HSAs and was 57% White, 51% female, 14% older than 65 years old, 37% with public insurance coverage, 12% with any disability, and 40% with at least a bachelor's degree. Compared with the overall US population, HSAs surrounding MTHs had higher percentages of female residents, Black/African American residents, and residents enrolled in Medicare. In contrast, these communities also showed higher average household and per capita income, higher percentages of bachelor's degree attainment, and lower rates of any disability or Medicaid insurance. CONCLUSIONS: Our analysis suggests that the local population surrounding MTHs is representative of the wide-ranging ethnic and economic diversity of the US population that is advantaged in some ways and disadvantaged in others. MTHs continue to play an important role in caring for a diverse population. To support and improve policy related to the reimbursement of uncompensated care and care of underserved populations, researchers and policy makers must work to better delineate and make transparent local hospital markets.

Eye tracking technology in endoscopy: Looking to the future.

The visual patterns of an endoscopist, that is, what the endoscopist is looking at during luminal endoscopy, is an interesting area with an evolving evidence base. The tools required for gaze analysis have become cheaper and more easily accessible. A comprehensive literature search was undertaken identifying 19 relevant papers. Gaze analysis has been used to identify certain visual patterns associated with higher polyp detection rates. There have also been increasing applications of gaze analysis as an objective study tool to compare the effectiveness of endoscopic imaging technologies. Gaze analysis also has the potential to be incorporated into endoscopic training. Eye movements have been used to control and steer a robotic endoscope. This review presents the current evidence available in this novel and evolving field of endoscopic research.

Safety and Performance of Narhinel 0.9% Sodium Chloride Monodose and Otrisal 0.74% Sodium Chloride Monodose Nasal Saline Solutions and Nasal Aspirators in Real-World Settings: Postmarket Clinical Follow-up Study Results.

Background: Blocked or stuffy nose is a common and bothersome symptom of colds, particularly for young children who are unable to clear their noses on their own. Nasal saline solutions and nasal aspirators are designed to gently cleanse and remove blocking nasal secretions. Objective: To assess the safety and performance of 2 monodose isotonic saline solutions (Narhinel 0.9% and Otrisal 0.74% sodium chloride; GSK Consumer Healthcare SARL, a Haleon company, Nyon, Switzerland) and 2 nasal aspirators with disposable hard- and soft-nozzle refills used as a standalone or combination treatment. Methods: We conducted 2 observational, online questionnaire-based, postmarket clinical follow-up studies in Europeans who had used any of the devices ≥1 time in the past 6 months. Coprimary objectives were to confirm the safety and performance of the saline solutions (Narhinel and Otrisal, Study 1) and nasal aspirators (with hard- and soft-nozzle refills, Study 2). Safety was assessed via the proportion of patients reporting adverse events and/or device malfunctions while using the devices within the previous 6 months, and performance was assessed by satisfaction rated on a 5-point scale, with "satisfied" and "very satisfied" being the highest performance ratings. Results: A total of 1136 (Study 1) and 1237 (Study 2) questionnaires were initiated by volunteer participants. Less than 2% of participants reported adverse events for any evaluated product in the previous 6 months. Most participants were "satisfied" or "very satisfied" with the devices for their intended use, with 78% to 91% of participants in the Narhinel arm, 73%-94% in the Otrisal arm, 71% to 95% in the soft-nozzle arm, and 71% to 80% in the hard-nozzle arm giving these ratings. Conclusions: These data support the safety and performance of 2 monodose saline solutions (Narhinel and Otrisal) for nasal cleansing, nasal moisturization, and/or loosening nasal secretions, and of nasal aspirators (with hard- and soft-nozzle refills) for clearing a blocked nose and removing nasal secretions.

Patient-parent perceptions of transition readiness in Turner syndrome and associated factors.

OBJECTIVE: Medical care transition to adult care presents challenges for individuals with complex medical conditions such as Turner syndrome (TS). The goals of this study were to: (1) identify factors associated with transition readiness; (2) examine associations and differences between patients' and parents' perceptions of readiness using Transition Readiness Assessment Questionnaire (TRAQ). METHODS: In a prospective cross-sectional study, girls with TS 12-25 years and one parent were recruited from 11/2019 to 12/2020. Three questionnaires were administered (demographic/clinical questionnaire, TRAQ, and TS Transition Readiness Assessment Questionnaire [TS-TRAQ]). Medical records were reviewed for karyotype and personal medical history. Descriptive statistics, Spearman's correlation, paired sample t tests, and linear regression were used to examine readiness and associated factors. RESULTS: Of 44 eligible patients, 35 patients and 30 parents completed the study. Patient age, education, and life skills were associated with a higher TRAQ score (p < .001). Greater TS knowledge was associated with higher readiness (p < .05). Readiness score for patient and parental perception of patient's readiness were correlated (r = .83; p < .01). Within patient-parent dyads, patients had higher readiness (p < .01). TRAQ and TS-TRAQ scores were correlated (r = .69; p < .01). CONCLUSIONS: Increasing patient age, patient education, life skills, confidence, and higher social/emotional scores were associated with a higher total TRAQ. Patient and parent perceived readiness were correlated and scores within dyads were different. Patients had higher perceived readiness. Positive correlations between TRAQ and TS-TRAQ suggest this tool may be a useful resource. Given the unique neurocognitive profile and social/emotional challenges among girls with TS, future research should include both patients and parents, and focus on validating TS-specific transition readiness tools.

A meta-analysis of variability in conjunctival microvascular hemorheology metrics.

Conjunctival hemorheology has been used analytically to assess qualities of blood flow associated with various forms of cardiovascular disorders including diabetes mellitus, stroke, and sickle cell disease. Although conjunctival axial red blood cell velocity (Vax) has been demonstrated in varying disease states, benchmark measures of Vax are not well-defined. Due to various methodologic differences in assessment of Vax, interstudy consistency of hemorheological metrics is susceptible to both systematic and random error. Our study examines interstudy heterogeneity of Vax as measured in the conjunctival microvasculature of healthy subjects and assesses the overall perturbation of Vax based on disease state. Furthermore, our study aims to establish a potential range of normative Vax by comparing inter-study measurements in healthy patients. The most widely employed analytic approach to assess Vax was space-time analysis (n = 30). Using a meta-analytic approach, the prediction interval for Vax in healthy subjects among 20 studies ranged from 0.32-2.60 mm/s with a combined effect size of 0.52 ± 0.03 (CI: 0.46-0.59) mm/s. Inter-study comparison of Vax in healthy patients showed a high degree of variability (I2: 98.96%), due to studies with low measurement precision and/or dissimilar analytic methodology. Neither age nor diameter was a clinically significant moderator of Vax measurements in healthy patients. The combined effect size, defined as the composite Hedge's g of studies comparing healthy and disease state mean Vax, was 0.21 ± 0.13. High heterogeneity (I2: 80.48%) was observed in studies analyzing the difference between mean Vax in healthy and disease state patients. This heterogeneity was also observed when the difference in mean Vax between healthy and disease state patients was assessed in subgroups based on disease condition (I2: vascular disease 33%, sickle cell disease 62.22%, other 83.43%). Age was found to be a significant moderator (p = 0.048, ß = -0.40) of Hedge's g while diameter was not. No significant publication bias was observed in studies presenting healthy patient Vax or in studies comparing Vax between healthy and disease state patients. In summary, although homogeneity can be seen in healthy group Vax measurements, a high degree of statistical heterogeneity is found in Vax assessment comparing healthy and disease conditions that is not fully explained by methodologic variability.

Hand and foot dermatitis in patients referred for patch testing: Analysis of North American Contact Dermatitis Group Data, 2001-2018.

BACKGROUND: Dermatitis localized to hands (HD), feet (FD), or both hands and feet (HFD) has multiple etiologies, including atopic dermatitis, irritant contact dermatitis, and allergic contact dermatitis. Unfortunately, little is known about clinical differences between patients with HD, FD, and HFD. OBJECTIVE: To characterize differences in demographics, etiology, and patch testing results among patients presenting with HD, FD, or HFD referred for patch testing. METHODS: A retrospective analysis of patients patch tested by the North American Contact Dermatitis Group between 2001 and 2018. RESULTS: Of 43,677 patients who were patch tested, 22.8% had HD, 2.9% had FD, and 3.7% had HFD. Allergic and currently relevant patch test reactions to ≥1 North American Contact Dermatitis Group screening allergen occurred in similar proportions in all 3 study groups. However, HD (18.0%) had higher proportions of occupationally relevant reactions than HFD (8.9%) or FD (4.0%). Nickel and fragrance mix I were in the top 5 currently relevant allergens for HD, FD, and HFD. Other top allergens, as well as allergen sources, differed between HD, FD, and HFD. LIMITATIONS: No data on HD or FD morphology or distribution. CONCLUSION: HD, FD, and HFD have several differences with respect to patient characteristics, etiologies, and clinically relevant allergens.

Patch testing with cobalt in children and adolescents: North American contact dermatitis group experience, 2001-2018.

BACKGROUND: Allergic contact dermatitis (ACD) to cobalt is more common in children and adolescents than adults. However, detailed information on sites and sources of cobalt ACD is limited. OBJECTIVES: To assess trends in positive and clinically relevant patch test reactions to cobalt in children and associated patient characteristics, common sources and body sites affected. METHODS: A retrospective analysis of children (<18 years) patch tested to cobalt by the North American Contact Dermatitis Group between 2001 and 2018. RESULTS: Of 1919 children patch tested, 228 (11.9%) and 127 (6.6%) had a positive/allergic or currently relevant patch test reaction to cobalt, respectively. The most common primary body sites affected were scattered generalized (30.0%), face, not otherwise specified (10.6%) and trunk (10.1%). Patients with allergic and currently relevant allergic patch test reactions were more likely to have a primary site of trunk (p = 0.0160 and p = 0.0008) and ears (p = 0.0005 and p < 0.0001). Affected body site(s) varied by cobalt source among patients with currently relevant reactions, especially for less common sources. The most commonly identified sources of cobalt included jewellery, belts and clothing. CONCLUSIONS: Positive patch test reactions to cobalt were common in children. The most common body site was scattered generalized and the sources of cobalt varied by body site.

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

BACKGROUND AND AIMS: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. APPROACH AND RESULTS: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. CONCLUSIONS: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.

Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome.

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.

A novel gaze-controlled flexible robotized endoscope; preliminary trial and report.

BACKGROUND: Interventional endoluminal therapy is rapidly advancing as a minimally invasive surgical technique. The expanding remit of endoscopic therapy necessitates precision control. Eye tracking is an emerging technology which allows intuitive control of devices. This was a feasibility study to establish if a novel eye gaze-controlled endoscopic system could be used to intuitively control an endoscope. METHODS: An eye gaze-control system consisting of eye tracking glasses, specialist cameras and a joystick was used to control a robotically driven endoscope allowing steering, advancement, withdrawal and retroflexion. Eight experienced and eight non-endoscopists used both the eye gaze system and a conventional endoscope to identify ten targets in two simulated environments: a sphere and an upper gastrointestinal (UGI) model. Completion of tasks was timed. Subjective feedback was collected from each participant on task load (NASA Task Load Index) and acceptance of technology (Van der Laan scale). RESULTS: When using gaze-control endoscopy, non-endoscopists were significantly quicker when using gaze-control rather than conventional endoscopy (sphere task 3:54 ± 1:17 vs. 9:05 ± 5:40 min, p = 0.012, and UGI model task 1:59 ± 0:24 vs 3:45 ± 0:53 min, p < .001). Non-endoscopists reported significantly higher NASA-TLX workload total scores using conventional endoscopy versus gaze-control (80.6 ± 11.3 vs 22.5 ± 13.8, p < .001). Endoscopists reported significantly higher total NASA-TLX workload scores using gaze control versus conventional endoscopy (54.2 ± 16 vs 26.9 ± 15.3, p = 0.012). All subjects reported that the gaze-control had positive 'usefulness' and 'satisfaction' score of 0.56 ± 0.83 and 1.43 ± 0.51 respectively. CONCLUSIONS: The novel eye gaze-control system was significantly quicker to use and subjectively lower in workload when used by non-endoscopists. Further work is needed to see if this would translate into a shallower learning curve to proficiency versus conventional endoscopy. The eye gaze-control system appears feasible as an intuitive endoscope control system. Hybrid gaze and hand control may prove a beneficial technology to evolving endoscopic platforms.

TRANSITION-RELATED DISCUSSIONS AMONG ADOLESCENT FEMALES WITH TURNER SYNDROME: CURRENT PRACTICES AND ASSOCIATED FACTORS.

OBJECTIVE: To examine the current transition practices and factors associated with the occurrence and timing of transition-related discussions among adolescents with Turner syndrome (TS). METHODS: A retrospective chart review was conducted at a large pediatric academic center among females with TS seen between 12 and 25 years of age. Medical/developmental characteristics, the age at transition, documented transition-related discussions, and the utilization of transition readiness assessment tools were abstracted. Analyses were conducted to examine the age/occurrence of discussions and associated factors. RESULTS: Records of 112 patients were reviewed. The average age of TS diagnosis was 7.6 ± 5.8 years, and the average age of those that transitioned from pediatric to adult care (n = 21) was 20.1 ± 2.0 years. Only 22% of individuals had documented discussions regarding transition to adult care, and no transition readiness tools were utilized. The majority of transition-related discussions began between 11 and 15 years. Estrogen and cardiovascular counseling were common (84% and 75%, respectively). Less than half of the subjects had reproductive (40%), lifestyle (43%), and psychosocial (12%) discussions. Cardiovascular conditions were associated with transition to adult care discussions, and neurodevelopmental conditions were associated with psychosocial counseling. In those that transitioned to adult care, transition-related discussions occurred in only half of patients. CONCLUSION: Our findings emphasize the need for the development and implementation of a standardized transition process for adolescents with TS, with particular attention to transition to adult care and reproductive, lifestyle, and psychosocial counseling. The utilization of formal transition tools may also help prepare these girls for transition to adult care.