Search

Technology bears important relationships to our health and wellness and has been utilized over the past two decades as an aid to support both self-management goals as well as collaboration among treatment teams.However, when chronic illnesses such as eating disorders (ED) are managed outside of institutionalized care settings, designing effective technology to support collaboration in treatment necessitates that we understand the relationships between patients, clinicians, and support networks. We conducted in-depth, semi-structured, interviews with 9 ED patients and 10 clinicians to understand the ED journey through the lens of collaborative efforts, technology use, and potential detriments. Based on our analysis of these 19 interviews, we present novel findings on various underlying disconnects within the collaborative ED treatment process disconnects among clinicians, between treatment foci, among preferences in tracking, within support networks, and inpatients' own identities. Our findings highlight how these various disconnects are concomitant with and gaps can stem from a lack of collaboration between different stakeholders in the ED journey. We also identify methods of facilitating collaboration in these disconnects through technological mediators.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.

Lacosamide, an antiepileptic drug prescribed for children with refractory focal epilepsy, is generally well tolerated, with dose-dependent adverse effects. We describe 4 children who developed a movement disorder in conjunction with the initiation and/or uptitration of lacosamide. Three patients developed dyskinesias involving the face or upper extremity whereas the fourth had substantial worsening of chronic facial tics. The patients all had histories suggestive of opercular dysfunction: 3 had seizure semiologies including hypersalivation, facial and upper extremity clonus while the fourth underwent resection of polymicrogyria involving the opercula. Onset, severity, and resolution of dyskinesias correlated with lacosamide dosing. These cases suggest that pediatric patients with dysfunction of the opercular cortex are at increased risk for developing drug-induced dyskinesias on high-dose lacosamide therapy. Practitioners should be aware of this potential side effect and consider weaning lacosamide or video electroencephalography (EEG) for differential diagnosis, particularly in pediatric patients with underlying opercular dysfunction.

BACKGROUND: Post-surgical changes in adjacent segment motion are considered a factor in further development of degeneration and cervical radiculopathy. The objective was to examine the extent of correlations between physiological motion of cervical foramina and long-term patient reported outcomes (PRO). METHODS: Biplane X-ray imaging and CT-based markerless tracking were used to measure 3D static and dynamic dimensions during neck axial rotation and extension from 18 patients treated for C5–6 radiculopathy with fusion or arthroplasty. Minimum foraminal height (FH.Min) and width (FW.Min), and their range (FH.Range and FW.Range) achieved during a motion task were calculated for adjacent levels (C4–5 and C6–7) at 2.0±0.6 years post-surgery. The modified Japanese Orthopedic Association score (mJOAS), the Neck Disability Index (NDI) including the visual analogue scale (VAS) for neck and arm pain, and the EuroQol EQ-5D score were recorded at 6.5±1.1 years post-surgery. The relationships between 6.5-year outcomes and 2-year foraminal motion were examined using regression. RESULTS: Worsening patient-reported outcomes were generally associated with lower values of FW.Min (P

Purpose Children with benign epilepsy with centrotemporal spikes have rare seizures emerging from the motor cortex, which they outgrow in adolescence, and additionally may have language deficits of unclear etiology. We piloted the use of transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG, TMS-EEG) to test the hypotheses that net cortical excitability decreases with age and that use-dependent plasticity predicts learning. Methods We assessed language and motor learning in 14 right-handed children with benign epilepsy with centrotemporal spikes. We quantified two TMS metrics of left motor cortex excitability: the resting motor threshold (measure of neuronal membrane excitability) and amplitude of the N100-evoked potential (an EEG measure of GABAergic tone). To test plasticity, we applied 1 Hz repetitive TMS to the motor cortex to induce long-term depression-like changes in EMG- and EEG-evoked potentials. Results Children with benign epilepsy with centrotemporal spikes tolerate TMS; no seizures were provoked. Resting motor threshold decreases with age but is elevated above maximal stimulator output for half the group. N100 amplitude decreases with age after controlling for resting motor threshold. Motor cortex plasticity correlates significantly with language learning and at a trend level with motor learning. Conclusions Transcranial magnetic stimulation is safe and feasible for children with benign epilepsy with centrotemporal spikes, and TMS-EEG provides more reliable outcome measures than TMS-EMG in this group because many children have unmeasurably high resting motor thresholds. Net cortical excitability decreases with age, and motor cortex plasticity predicts not only motor learning but also language learning, suggesting a mechanism by which motor cortex seizures may interact with language development.

Background Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients’ clinical phenotypes and analyse the differential clinical course. Methods We performed a hierarchical cluster analysis based on Ward’s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients’ prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27–3.62; HR 3.42, 95%CI 2.72–4.31; HR 2.79, 95%CI 2.32–3.35), and Cluster 1 (HR 1.88, 95%CI 1.48–2.38; HR 2.50, 95%CI 1.98–3.15; HR 2.09, 95%CI 1.74–2.51) reported a higher risk for the three outcomes respectively. Conclusions In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.

OBJECTIVE In patients treated for DKA, decrease the rate of visits experiencing one or more BG

Visual Abstract, Highlights • LDGs are a subset of neutrophils that were elevated in psoriasis and associated with the severity of disease. • In psoriasis, LDGs associated with noncalcified coronary plaque burden beyond cardiovascular risk factors and in vitro, induced endothelial cell damage. • Compared to normal-density granulocyte neutrophils, platelet-associated biological pathways were upregulated in LDGs, suggesting enhanced platelet adherence to the LDG surface. • LDGs co-localized with platelets in circulation, and the LDG-platelet interaction associated more strongly with non-calcified coronary burden by coronary CTA compared to LDGs alone., Summary Psoriasis is an inflammatory skin disease associated with increased cardiovascular risk and serves as a reliable model to study inflammatory atherogenesis. Because neutrophils are implicated in atherosclerosis development, this study reports that the interaction among low-density granulocytes, a subset of neutrophils, and platelets is associated with a noncalcified coronary plaque burden assessed by coronary computed tomography angiography. Because early atherosclerotic noncalcified burden can lead to fatal myocardial infarction, the low-density granulocyte−platelet interaction may play a crucial target for clinical intervention.

Background Motor impairment after stroke is due not only to direct tissue loss but also to disrupted connectivity within the motor network. Mixed results from studies attempting to enhance motor recovery with Transcranial Magnetic Stimulation (TMS) highlight the need for a better understanding of both connectivity after stroke and the impact of TMS on this connectivity. This study used TMS-EEG to map the causal information flow in the motor network of healthy adult subjects and define how stroke alters these circuits. Methods Fourteen stroke patients and 12 controls received TMS to two sites (bilateral primary motor cortices) during two motor tasks (paretic/dominant hand movement vs. rest) while EEG measured the cortical response to TMS pulses. TMS-EEG based connectivity measurements were derived for each hemisphere and the change in connectivity (ΔC) between the two motor tasks was calculated. We analyzed if ΔC for each hemisphere differed between the stroke and control groups or across TMS sites, and whether ΔC correlated with arm function in stroke patients. Results Right hand movement increased connectivity in the left compared to the right hemisphere in controls, while hand movement did not significantly change connectivity in either hemisphere in stroke. Stroke patients with the largest increase in healthy hemisphere connectivity during paretic hand movement had the best arm function. Conclusions TMS-EEG measurements are sensitive to movement-induced changes in brain connectivity. These measurements may characterize clinically meaningful changes in circuit dynamics after stroke, thus providing specific targets for trials of TMS in post-stroke rehabilitation.

Chronic exposure to psychosocial and environmental stressors (PSES) has been shown to increase risk for diabetes, obesity, and cardiovascular disease and alter immune cell distribution and function. In Natural Killer (NK) cells, the impact of PSES has been demonstrated by a loss of NK cell numbers or function and a shift in NK cell subpopulations. NKp46 is an activating receptor on NK cells crucial for NK cell function. In this study, we aimed to determine if PSES is associated with NKp46 expression. We recruited 27 African-American women (age 59.85±1.91; BMI 34.06±1.67), characterized NKp46 expression from blood samples using flow cytometry, and determined serum cytokine levels using Luminex. Furthermore, study participants answered questionnaires to determine various psychosocial measures, socioeconomic status (SES), and home address for neighborhood deprivation (NDI). First, we determined that social isolation significantly associated with NKp46 expression (β=-0.51, p=0.02), while NDI and SES did not. Second, we identified biomarkers associated with social isolation. Social isolation significantly associated with the cytokine RANTES (β=0.64, p=0.01) after adjustment for cardiovascular risk and BMI. Third, we determined that RANTES also associated with NKp46 expression after adjustment (β=-0.54, p=0.01). We performed a mediation analysis using structural equation modeling to determine if RANTES could be a potential biological mediator between social isolation and NKp46 expression levels; this revealed that RANTES mediates 51.07% of the association (Figure). Thus, our study highlights the importance of further understanding the impact of PSES on immune cells and inflammation. Work to unravel the biology of adversity is crucial to address health disparities. In the future, larger studies should be conducted to identify underlying signaling molecules and pathways altering NK cells during chronic PSES that accelerate disease development and progression and ultimately, serve as targets for intervention.

Eating disorders (EDs) constitute a mental illness with the highest mortality. Today, mobile health apps provide promising means to ED patients for managing their condition. Apps enable users to monitor their eating habits, thoughts, and feelings, and offer analytic insights for behavior change. However, not only have scholars critiqued the clinical validity of these apps, their underlying design principles are not well understood. Through a review of 34 ED apps, we uncovered 11 different data types ED apps collect, and 9 strategies they employ to support collection and reflection. Drawing upon personal health informatics and visualization frameworks, we found that most apps did not adhere to best practices on what and how data should be collected from and reflected to users, or how data-driven insights should be communicated. Our review offers suggestions for improving the design of ED apps such that they can be useful and meaningful in ED recovery.

Ogden syndrome is a rare lethal X‐linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N‐terminal acetyltransferase A complex (NatA). So far eight boys of two different families have been described in the literature, all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias. Here, we report the ninth case of Ogden syndrome with an independent recurrence of the Ser37Pro variant. We were able to follow the clinical course of the affected boy and delineate the evolving phenotype from his birth until his unfortunate death at 7 months. We could confirm the associated phenotype as well as the natural history of this severe disease. By describing new presenting features, we are further expanding the clinical spectrum associated with Ogden syndrome and review other phenotypes associated with NAA10 variants.

Mechanisms explaining the link between psoriasis, a pro-inflammatory condition, and cardiovascular disease (CVD) are not fully known. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism and clinical trials targeting PCSK9 reduce CVD. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict CV events. We used two separate human psoriasis cohorts and the K14-Rac1V12(−/+) murine model of psoriasis to investigate PCSK9 and CV risk in psoriasis. In both psoriasis cohorts, (n=88 and n=20), PCSK9 levels were 20% and 13% higher than age, sex, and cholesterol matched controls respectively (p

It is evident that health disparities exist during the COVID-19 pandemic, a pandemic caused by the novel coronavirus SARS-CoV-2. Underlying reasons for COVID-19 health disparities are multi-factorial. However, social determinants, including those regarding socioeconomic status, social inequalities, health behaviors, and stress, may have implications on these disparities. Exposure to one or more of these social determinants is associated with heightened inflammatory responses, particularly increases in the cytokine interleukin-6 (IL-6), as well as immune system dysfunction. Thus, an amplified effect during COVID-19 could occur, potentially resulting in vulnerable patients experiencing an intensified cytokine storm due to a hyperactive and dysfunctional immune response. Further understanding how social determinants play a mechanistic role in COVID-19 disparities could potentially help reduce health disparities overall and in future pandemics.

Name of the disease (synonyms) Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870. Name of the analysed genes or dna/chromosome segments GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

Rationale: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis. Objective: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis. Methods and Results: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index , and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P P =0.020) and oxHDL (β=−0.11; P =0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P =0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P P =0.03). Conclusions: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.

Structure and thermolysis of NiC2O4·2H2O (I) and Ni(HCO2)2·2H2O (II) were studied for the precipitated powders from the water solutions of precursors. The compound (I) has a disordered structure (C2/c, a=11.7916(5), b= 5.31798(14), c= 9.7806(7) A, β = 127.014(6)°, V= 489.73(4)A3) which is described via the displacement vector applied to the basis atoms and the part of the shifted atoms. Thermal dehydration of (I) leads to formation of the disordered β-NiC2O4 (III), the structure of which (P21/n, a=5.8294(9), b= 5.1685(13), c= 5.2712(4) A, β = 117.793(12)°, V= 140.50(5)A3) was refined from the powder diffraction. Oxalates (I) and (III) are both characterized by the essential part of the shifted atoms causing the extinction of some lines in XRPD pattern. The final product of thermal decomposition of (I) in air is NiO, whereas thermolysis of (II) leads to formation of Ni/NiO mixture. The content of Ni in the latter depends on the thickness of the decaying layer in the sample because the gaseous products of the reaction prevent the oxidation of the nickel formed initially.

Perfluoroalkyl substances (PFAS) are widely distributed suspected obesogens that cross the placenta. However, few data are available to assess potential fetal effects of PFAS exposure on children's adiposity in diverse populations. To address the data gap, we estimated associations between gestational PFAS concentrations and childhood adiposity in a diverse mother-child cohort. We considered 6 PFAS in first trimester blood plasma, measured using ultra-high-performance liquid chromatography with tandem mass spectrometry, collected from non-smoking women with low-risk singleton pregnancies (n = 803). Body mass index (BMI), waist circumference (WC), fat mass, fat-free mass, and % body fat were ascertained in 4-8 year old children as measures of adiposity. We estimated associations of individual gestational PFAS with children's adiposity and overweight/obesity, adjusted for confounders. There were more non-Hispanic Black (31.7 %) and Hispanic (42.6 %) children with overweight/obesity, than non-Hispanic white (18.2 %) and Asian/Pacific Islander (16.4 %) children (p 0.0001). Perfluorooctane sulfonate (PFOS; 5.3 ng/mL) and perfluorooctanoic acid (2.0 ng/mL) had the highest median concentrations in maternal blood. Among women without obesity (n = 667), greater perfluoroundecanoic acid (PFUnDA) was associated with their children having higher WC z-score (β = 0.08, 95%CI: 0.01, 0.14; p = 0.02), fat mass (β = 0.55 kg, 95%CI: 0.21, 0.90; p = 0.002), and % body fat (β = 0.01 %; 95%CI: 0.003, 0.01; p = 0.004), although the association of PFUnDA with fat mass attenuated at the highest concentrations. Among women without obesity, the associations of PFAS and their children's adiposity varied significantly by self-reported race-ethnicity, although the direction of the associations was inconsistent. In contrast, among the children of women with obesity, greater, PFOS, perfluorononanoic acid, and perfluorodecanoic acid concentrations were associated with less adiposity (n = 136). Our results suggest that specific PFAS may be developmental obesogens, and that maternal race-ethnicity may be an important modifier of the associations among women without obesity.

Introduction: Mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL) are subtypes of non-Hodgkin's lymphoma. Collectively, these subtypes constitute a large proportion of all B-cell malignancies; however, they are typically associated with survival spanning several years with multiple interspersed treatment periods due to frequent relapses. This can predispose patients to repeated hospitalization resulting in significant economic impact. The objectives of this study were to examine real-world treatment patterns, costs and healthcare resource utilization for patients with these lymphomas, as well as identify disparities and risk factors associated with costs incurred in US hospitals. Methods: A retrospective study was conducted using the Premier Healthcare Database, a geographically diverse all-payer, hospital administrative database containing more than one billion inpatient and hospital-based outpatient encounters. Patients aged ≥18 years with at least 1 inpatient or 2 hospital-based outpatient visits with a MCL, WM, CLL, or MZL diagnosis, and who received treatment for these conditions from 1/1/2014 to 10/31/2019 were included in the study. Descriptive analysis was conducted to examine patient sociodemographic and hospital characteristics, all-cause and lymphoma-related healthcare resource utilization and costs. Costs were obtained from patients' discharge files and hospital billing records. Multivariable analysis was performed using generalized linear models to examine risk factors associated with costs and LOS for each lymphoma type. Treatment evaluated including any use of supportive care (blood transfusion, granulocyte colony stimulating factors [GCSF]), and by regimen (steroids alone, chemotherapy alone, chemo-immunotherapy, rituximab alone, targeted therapy alone, targeted therapy in combination with chemotherapy, other). Statistical significance was determined as a p-value of Results: The study population included 23,952 CLL, 3,387 MCL, 2,655 MZL, and 1,811 WM patients in the US hospital database. Patients with WM were statistically significantly older (77 ± 58.5 years) compared to patients with CLL (74.2 ± 30.2 years), MCL (70.7 ± 37.3 years) or MZL (69.3 ± 33.8 years). More male (71.7%) and white (87.8%) patients were identified in the MCL cohort compared to the general lymphoma cohorts (Males: 58.7%; whites: 86.3). The most common comorbidities included chronic pulmonary disease (27.1%), gastroesophageal reflux disease (17.6%), moderate-severe renal disease (16.6%), congestive heart failure (15.7%) and diabetes without chronic complications (15.2%). Overall, more than two-thirds of patients in each lymphoma group received treatment with steroids alone during hospitalizations. While the use of steroids alone was higher among whites compared to non-white patients (69.5% vs. 60.4%), the use of chemo-immunotherapy was lower in whites compared to non-whites (11.9% vs. 16.2%). The average LOS of inpatient hospitalization ranged from 6.3 days for CLL to 7.4 days for MCL, with the mean costs per hospitalization from $19,566 (CLL) to $24,439 (MCL). Non-white patients have significantly longer mean LOS days compared with white patients (CLL: 18.3 vs. 14.8; MCL: 21.7 vs. 18.3; MZL: 21.6 vs. 18.5; WM 19.0 vs. 14.5). Across the 4 lymphoma types, multivariable regression confirmed the descriptive results and demonstrated that higher hospitals costs were associated with patients who were non-white, Hispanic/Latino, treated in hospitals located in the Northeast or West, or had Medicaid; statistically significant increased cost of care was also noted for patients who received targeted therapy or supportive care, such as blood transfusion or GCSF (Table 1). Conclusions: Real-world data demonstrated the significantly high total hospital costs once patients with MCL, WM, MZL, and CLL patients were hospitalized, with significantly higher impact to minority populations. Given the increased availability of effective oral therapeutics, optimal and timely disease control in the outpatients setting can potentially prevent or decrease hospitalizations and reduce economic burden on healthcare. Future studies are needed to explore the reason for admission, clinical outcomes, and potential preventive interventions. Figure 1 Figure 1. Disclosures Chanan-Khan: Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; Cellectar: Current equity holder in publicly-traded company; Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Cao: Premier, Inc.: Current Employment; BeiGene, Ltd.: Consultancy. Baumer: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Krishnaswami: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Endothelial cells (EC) play a key role in atherosclerosis. Although EC are in constant contact with low density lipoproteins (LDL), how EC process LDL and whether this influences atherogenesis, is unclear. Here we show that EC take up and metabolize LDL, and when overburdened with intracellular cholesterol, generate cholesterol crystals (CC). The CC are deposited on the basolateral side, and compromise endothelial function. When hyperlipidemic mice are given a high fat diet, CC appear in aortic sinus within 1 week. Treatment with cAMP-enhancing agents, forskolin/rolipram (F/R), mitigates effects of CC on endothelial function by not only improving barrier function, but also inhibiting CC formation both in vitro and in vivo. A proof of principle study using F/R incorporated into liposomes, designed to target inflamed endothelium, shows reduced atherosclerosis and CC formation in ApoE −/− mice. Our findings highlight an important mechanism by which EC contribute to atherogenesis under hyperlipidemic conditions., Atherosclerosis is characterized by subendothelial lipid retention believed to be the result of endothelial trancytosis. Here, the authors show that endothelium can take up and process LDL, generating cholesterol crystals that are deposited on the basolateral side of the cells, causing their dysfunction that can be prevented by forskolin/rolipram treatment.

Background: Shoulder injuries are common among competitive swimmers, and the progression of shoulder pathology is not well understood. The objective of this study was to assess the extent to which years of competitive swim training were associated with physical properties of the supraspinatus muscle and tendon, shoulder strength, and self-reported assessments of shoulder pain and function. Hypothesis: Increasing years of competition will be associated with declining physical properties of the supraspinatus muscle/tendon and declining self-reported assessments of pain and function. Study Design: Descriptive epidemiology study. Level of Evidence: Level 4. Methods: After institutional approval, 18 collegiate female swimmers enrolled in the study. For each swimmer, supraspinatus tendon thickness was measured; tendinosis was assessed using ultrasound imaging, supraspinatus muscle shear wave velocity was assessed using shear wave elastography, isometric shoulder strength was measured using a Biodex system, and self-reported assessments of pain/function were assessed using the Western Ontario Rotator Cuff (WORC) score. All subjects were tested before the start of the collegiate swim season. Linear regression was used to assess the association between years of competition and the outcome measures. Results: Years of participation was positively associated with tendon thickness ( P = 0.01) and negatively associated with shear wave velocity ( P = 0.04) and WORC score ( P < 0.01). Shoulder strength was not associated with years of participation ( P > 0.39). Conclusion: Long-term competitive swim training is associated with declining measures of supraspinatus muscle/tendon properties and self-reported measures of pain and function. Although specific injury mechanisms are still not fully understood, these findings lend additional insight into the development of rotator cuff pathology in swimmers. Clinical Relevance: Lengthy swimming careers may lead to a chronic condition of reduced mechanical properties in the supraspinatus muscle and tendon, thereby increasing the likelihood of rotator cuff pathology.

On the 9th March 2020, the first patient with COVID-19 was admitted to ICU in the Royal Gwent Hospital (RGH), Newport, Wales. We prospectively recorded the rate of ICU admissions of 52 patients with COVID-19 over 60 days, focusing on the epidemiology of ethnicity and deprivation because these factors have emerged as significant risk factors. Patients were 65% (34 of 52) male and had a median (IQR) age of 55 (48–62) years. Prevalent comorbidities included obesity (52%); diabetes (33%), and asthma (23%). COVID-19 hospital and ICU inpatient numbers peaked on days 23 and 39, respectively—a lag of 16 days. The ICU mortality rate was 33% (17 of 52). People of black, Asian, and minority ethnic descent (BAME group) represented 35% of ICU COVID-19 admissions (18 of 52) and 35% of deaths (6 of 17). Amongst the BAME group, 72% (13 of 18) of patients were found to reside in geographical areas representing the 20% most deprived in Wales, vs. 27% of patients in the Caucasian group (9 of 33). Less than 5% of the population within the area covered by RGH are of BAME descent, yet this group had a disproportionately high ICU admission and mortality rate from COVID-19. The interplay between ethnicity and deprivation, which is complex, may be a factor in our findings. This in turn could be related to an increased prevalence of co-morbidities; higher community exposure; larger proportion of lower band key worker roles; or genetic polymorphisms.\udKeywords: COVID-19, ethnicity, BAME, deprivation, mortality

Primary familial brain calcification (PFBC), otherwise known as Fahr's disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A. This case demonstrates that the ictal EEG is important for accurately classifying epilepsy in affected subjects with PFBC. Further, epilepsy in PFBC may be a polygenic disorder.

Background IV insulin therapy, the treatment for pediatric diabetic ketoacidosis (DKA), may lead to iatrogenic low blood glucose episodes (BG Objectives We aimed to decrease the percent of DKA patients experiencing BG Methods Multiple interventions linked to key drivers were tested using plan-do-study-act cycles including a standardized DKA guideline incorporating the two-bag fluid system, order panels, frequent blood glucose monitoring, and provider and nursing education. The primary outcome was the percent of DKA patients experiencing a BG 17), and admission rates. All outcomes were analyzed on statistical process control charts. Results From January 2017 through August 2019, 334 patients had confirmed DKA (bicarbonate level Conclusions Use of QI methodology and standardized DKA management resulted in a meaningful reduction in the number of patients with a BG

Background Early diagnosis and timely surgery are critical to treat children with testicular torsion. Only 33% of patients met the hospital goal of ‘critical diagnosis to operating room time of 60 minutes or less [CDOR60]’ prior to starting the QI project. Objectives The objective of the quality improvement project was to increase the utilization of TWIST score, a validated clinical scoring system from 0% to 80% over 12 months period for children evaluated for testicular torsion, as a means of increasing the number of patients with CDOR60. Methods Deploying the Institute for Healthcare Improvement Model for Improvement, we formulated an aim statement and identified key drivers. Of our interventions, successful implementation of the TWIST score in the emergency department (ED), with a guideline to support earlier notification of urology for high risk patients with testicular pain, was determined to be the highest impact intervention. We educated providers and gave biweekly feedback about guideline adherence, created order panels and documentation tabs in our electronic medical record to encourage documentation. Results Between September 2018 and April 2019, TWIST score documentation improved to >80% and was sustained at that rate for 4 months. After implementation of the guideline, the critical diagnosis to OR time of 60 minutes or less was achieved in 12 out of 16 patients diagnosed with testicular torsion in the ED [75%] compared to our baseline of 33%. Conclusions A quality improvement project to improve the timeliness of care for children with testicular torsion resulted in delivery of expedited surgical care for these patients.

IMPORTANCE: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis. OBJECTIVE: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year. EXPOSURES: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status. RESULTS: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P 50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (β = 0.14; 95% CI, 0.028-0.246; P = .02). CONCLUSIONS AND RELEVANCE: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

BACKGROUND: Diagnostic delays in the pediatric emergency department (ED) can lead to unnecessary interventions and prolonged ED length of stay (LOS), especially in patients with diabetes mellitus evaluated for diabetic ketoacidosis (DKA). At our institution, baseline DKA determination time (arrival to diagnosis) was 86 minutes, and 61% of patients did not meet DKA criteria. Subsequently, intravenous (IV) placement occurred in 85% of patients without DKA. We aimed to use point-of-care (POC) testing to reduce DKA determination time from 86 to 30 minutes and to reduce IV placements in patients without DKA from 85% to 20% over 18 months. METHODS: Four key interventions (POC tests, order panels, provider guidelines, and nursing guidelines) were tested by using plan-do-study-act cycles. DKA determination time was our primary outcome, and secondary outcomes included the percentage of patients receiving IV placement and ED LOS. Process measures included the rate of use of POC testing and order panels. All measures were analyzed on statistical process control charts. RESULTS: Between January 2015 and July 2018, 783 patients with diabetes mellitus were evaluated for DKA. After all 4 interventions, DKA determination time decreased from 86 to 26 minutes (P < .001). In patients without DKA, IV placement decreased from 85% to 36% (P < .001). ED LOS decreased from 206 to 186 minutes (P = .009) in patients discharged from the hospital after DKA evaluation. POC testing and order panel use increased from 0% to 98% and 90%, respectively. CONCLUSIONS: Using quality-improvement methodology, we achieved a meaningful reduction in DKA determination time, the percentage of IV placements, and ED LOS.

A smartphone app searches baby pictures for common and rare eye disorders., The “red reflex test” is used to screen children for leukocoria (“white eye”) in a standard pediatric examination, but is ineffective at detecting many eye disorders. Leukocoria also presents in casual photographs. The clinical utility of screening photographs for leukocoria is unreported. Here, a free smartphone application (CRADLE: ComputeR-Assisted Detector of LEukocoria) was engineered to detect photographic leukocoria and is available for download under the name “White Eye Detector.” This study determined the sensitivity, specificity, and accuracy of CRADLE by retrospectively analyzing 52,982 longitudinal photographs of children, collected by parents before enrollment in this study. The cohort included 20 children with retinoblastoma, Coats’ disease, cataract, amblyopia, or hyperopia and 20 control children. For 80% of children with eye disorders, the application detected leukocoria in photographs taken before diagnosis by 1.3 years (95% confidence interval, 0.4 to 2.3 years). The CRADLE application allows parents to augment clinical leukocoria screening with photography.

Background Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. Methods To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. Results The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. Conclusions Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants. Electronic supplementary material The online version of this article (10.1186/s10020-019-0073-6) contains supplementary material, which is available to authorized users.

Objectives To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US. Study design This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables. Results Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs. Conclusions Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.

Altres ajuts: This work was also supported by grants from the DCEXS is a 'Unidad de Excelencia María de Maeztu', funded by the AEI (CEX2018-000782-M) and Fundació La Marató de TV3 (20141210 to JF). Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19. The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p < 0.01), whereas altered consciousness/confusion were more frequent (p < 0.01). Risk factors for hospitalization and mortality were similar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complications and mortality, especially from age 40. Down Syndrome Affiliates in Action, DSMIG-USA, GiGi's Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices.

Background Infliximab is used in the treatment of inflammatory bowel disease. Previously reported neurological complications include central and peripheral demyelinating disorders and neuropathies occurring months into therapy. Patient Description A seven-year-old boy diagnosed with ulcerative colitis and primary sclerosing cholangitis received infliximab. Six hours following his uneventful infusion, he awoke with headache and emesis and rapidly became obtunded. Neurological examination revealed minimally reactive pupils and otherwise absent brainstem reflexes. Cranial computed tomography revealed hypodense lesions in the cerebral hemispheres, cerebellum, and pons accompanied by hemorrhage. Magnetic resonance imaging showed diffusion restriction concerning for ischemia with areas of ring enhancement suggestive of inflammation. Vessel imaging was normal, and cerebrospinal fluid and serum studies showed only an extremely elevated level of d-dimer. Echocardiogram showed depressed ventricular function but neither intracardiac shunt nor thrombus. Within four days he met criteria for brain death. Autopsy was refused. Conclusions This is the first report of a fulminant, fatal central nervous system process to occur after an initial dose of infliximab. The differential diagnosis includes multifocal arterial strokes and a devastating demyelinating process.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Several risk stratification tools were developed to predict disease progression in coronavirus disease 2019, with no external validation to date. We attempted to validate three previously published risk-stratification tools in a multicenter study. Primary outcome was a composite outcome of development of severe coronavirus disease 2019 disease leading to ICU admission or death censored at hospital discharge or 30 days. We collected data from 169 patients. Patients were 73 years old (59–82 yr old), 66 of 169 (39.1%) were female, 57 (33.7%) had one comorbidity, and 80 (47.3%) had two or more comorbidities. Area under the receiver operating characteristic curve (95% CI) for the COVID-GRAM score was 0.636 (0.550–0.722), for the CALL score 0.500 (0.411–0.589), and for the nomogram 0.628 (0.543–0.714).

Background Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation. Methods We utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo. Findings We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p Interpretation Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis. Funding Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).

Aims In recent years, stroke prevention in patients with atrial fibrillation (AF) has radically changed, with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs). Contemporary European data on AF thromboprophylaxis are needed. Methods and results We report 1-year follow-up data from the EURObservational Research Programme in Atrial Fibrillation (EORP-AF) General Long-Term Registry. Outcomes were assessed according to antithrombotic therapy. At 1-year follow-up, 9663 (88.0%) patients had available data for analysis: 586 (6.1%) were not treated with any antithrombotic; 681 (7.0%) with antiplatelets only; 4066 (42.1%) with vitamin K antagonist (VKA) only; 3167 (32.8%) with NOACs only; and 1163 (12.0%) with antiplatelet and oral anticoagulant. At 1-year follow-up, there was a low rate of stroke (0.7%) and any thromboembolic event (TE) (1.2%), while haemorrhagic events occurred in 222 patients (2.3%). Cardiovascular (CV) death and all-cause death occurred in 3.9% and 5.2% of patients, respectively. Cumulative survival for all the three main outcomes considered was highest amongst patients treated only with NOACs (P Conclusion The 1-year follow-up of EORP-AF General Long-Term Registry reported a low occurrence of thromboembolic and haemorrhagic events, although mortality was high. Both VKA and NOACs were associated with a lower risk of all main adverse outcomes. All treatments were associated with a lower risk for CV death and all-cause death.

Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures.Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis.Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenicNeonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.

Aims The use of biologic therapy has increased over the past decade well beyond primary autoimmune diseases. Indeed, a recent trial using an anti-IL-1beta antibody reduced second myocardial infarction (MI) in those who have had MI. Psoriasis is a chronic inflammatory disease often treated with biologics when severe, is associated with increased risk of MI, in part driven by high-risk coronary plaque phenotypes by coronary computed tomography angiography (CCTA). We hypothesized that we would observe a reduction in inflammatory-driven phenotypes of coronary plaque, including non-calcified coronary plaque burden and lipid-rich necrotic core in those treated with biologic therapy after one-year compared with non-biologic therapy. Methods and results In a prospective, observational study, 290 participants were recruited from 1 January 2013 through 31 October 2018 with 215 completing one-year follow-up. Of the 238, 121 consecutive participants who were biologic treatment naive at baseline were included. A blinded reader (blinded to patient demographics, visit and treatment) quantified total coronary plaque burden and plaque subcomponents (calcified and non-calcified) in the three main coronary vessels >2 mm using dedicated software (QAngio, Medis, Netherlands). Psoriasis patients were middle-aged [mean (standard deviation) age, 50.5 (12.1) years], mostly male (n = 70, 58%) with low cardiovascular risk by Framingham score [median (interquartile range, IQR), 3 (1-6)] and had moderate to severe skin disease at baseline [median (IQR) Psoriasis Area Severity Index, PASI, 8.6 (5.3-14.0)]. Biologic therapy was associated with a 6% reduction in non-calcified plaque burden (P = 0.005) reduction in necrotic core (P = 0.03), with no effect on fibrous burden (P = 0.71). Decrease in non-calcified plaque burden in the biologic treated group was significant compared with slow plaque progression in non-biologic treated (Δ, -0.07 mm2 vs. 0.06 mm2; P = 0.02) and associated with biologic treatment beyond adjustment for traditional cardiovascular risk factors (β = 0.20, P = 0.02). Conclusion In this observational study, we demonstrate that biologic therapy in severe psoriasis was associated with favourable modulation of coronary plaque indices by CCTA. These findings highlight the importance of systemic inflammation in coronary artery disease and support the conduct of larger, randomized trials.

Objective: Atherogenesis is an inflammatory process accelerated in psoriasis, a chronic inflammatory skin disease associated with premature cardiovascular diseases (CVD). Cholesterol crystal (CC) formation is implicated at onset and progression of atherosclerotic CVD, and we have recently shown CC formation to be upregulated in a murine model of psoriasis-related atherosclerosis. Therefore, we investigated inflammatory CC production in this psoriasis mouse model and also using psoriasis patient derived samples. Methods: K14-Rac1V12 psoriasis mouse aortas were examined for CC formation and structural abnormalities, such as subendothelial spaces, via electron microscopy and histology. Human aortic endothelial cells (HAoEC) were stimulated with sera from healthy and psoriatic volunteers (n=5 each), inflammatory markers TNFα+IFNγ, LDL or combination of TNFα+IFNγ+LDL. The effect on CC formation and lysosomal function was determined by advanced microscopy and flow cytometry. HAoECs were also treated with TNFα+IFNγ+LDL combined with β-cyclodextrin (CD), a stimulant for cholesterol release from cells, and analyzed for CC formation and lysosomal function. Results: Psoriatic mouse aortas showed enlarged subendothelial spaces and 40% increased CC formation under normolipidemic conditions compared to littermate controls. Treatment of HAoECs with psoriasis patient-sera (severe skin disease, low CVD risk score) or TNFα+IFNγ+LDL showed a 2-fold increase in CC formation and 30% increased lysosomal frequency compared to controls. Despite an increase in lysosome frequency, TNFα+IFNγ+LDL treatment decreased overall pH-related lysosomal activity. CD treatment diminished TNFα+IFNγ+LDL-induced CC formation (compared to vehicle), and restored lysosomal function without affecting lysosome frequency. Conclusion: Psoriasis mice displayed accelerated CC formation in the absence of hyperlipidemic conditions suggesting chronic systemic inflammation accelerates CC formation in vivo and in vitro , accompanied by lysosomal dysfunction in ECs. These findings suggest that dyslipidemia and systemic inflammation in psoriasis are important contributors to early atherogenesis and should be treatment targets for CVD risk mitigation.

Introduction: Psoriasis (PSO), a chronic inflammatory disease associated with increased Cardiovascular (CV) risk provides an ideal model to study the role of vitamin D, a known anti-inflammatory molecule in PSO associated CV disease. Vitamin D exists as inactive 25-hydroxyvitamin D (25(OH)D) in the bloodstream which is converted to active 1,25-dihydroxyvitaminD (1,25(OH)2D) in target tissues. Cohort studies reporting CV disease among individuals with low vitamin D are inconsistent and solely measure 25(OH)D. While serum 25(OH)D is routinely measured , we propose that measurement of 1,25(OH)2D may perform better than 25(OH)D as a surrogate for CV disease. Methods: Consecutive PSO patients (N=122) and healthy controls (N=35) underwent FDG PET/CT and CCTA scans to measure vascular inflammation/ abdominal adiposity volume and coronary plaque burden respectively. Blood levels of both 1,25(OH)2D and 25(OH)D were measured by chemiluminescence (LIASON XL DIaSorin, Stillwater, MN). Results: PSO patients were middle-aged, mostly male, had moderate PSO severity and were at low CV risk by 10-year Framingham risk. PSO patients had lower serum 1,25(OH)2D compared to healthy controls (mean±SEM: 52.4±1.4 pg/ml versus 57.5±2.0, p Conclusion: Our data support that active 1,25(OH)2D may more accurately capture cardiometabolic disturbance compared to inactive 25(OH)D in humans.

Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.

Background: Glenohumeral joint (GHJ) dislocations are common, and the resulting shoulder instability is often treated with arthroscopic stabilization. These procedures result in favorable clinical outcomes, but abnormal GHJ motion may persist, which may place patients at risk for developing osteoarthritis. However, the effects of shoulder instability and arthroscopic stabilization on GHJ motion are not well understood. Hypothesis: GHJ motion is significantly influenced by anterior instability and arthroscopic stabilization, but postsurgical measures of GHJ motion are not different from those of control subjects. Study Design: Controlled laboratory study. Methods: In vivo GHJ motion was measured by applying a computed tomographic model-based tracking technique to biplane radiographic images acquired during an apprehension test in healthy control subjects (n = 11) and anterior instability patients (n = 11). Patients were tested before surgery and at 6 months after surgery. Control subjects were tested once. Shoulder strength, active range of motion (ROM), and the Western Ontario Shoulder Instability (WOSI) index were also measured. Results: Before surgery, the humerus of the instability patients during the apprehension test was located significantly more anteriorly on the glenoid (7.9% of glenoid width; 2.1 mm) compared with that of the controls ( P = .03), but arthroscopic stabilization moved this joint contact location posteriorly on the glenoid (4.7% of glenoid width; 1.1 mm; P = .03). After surgery, GHJ excursion during the apprehension test was significantly lower (14.7% of glenoid width; 3.6 mm) compared with presurgical values (19.4% of glenoid width; 4.7 mm; P = .01) and with that of the controls (22.4% of glenoid width; 5.7 mm; P = .01). The external and internal rotation strength of patients was significantly lower than that of the controls before surgery ( P < .05), but differences in strength did not persist after surgery ( P > .17). External rotation ROM in patients was significantly lower than that in control subjects both before and after arthroscopic stabilization ( P < .01). The WOSI score improved significantly, from 48.3 ± 13.1 presurgery to 86.3 ± 16.5 after surgery ( P = .0002). Conclusion: In patients with anterior instability, arthroscopic stabilization significantly improves measures of strength, ROM, and clinical outcome. However, GHJ excursion is not fully restored to levels seen in the control subjects. Clinical Relevance: Although arthroscopic stabilization satisfactorily restores most clinical outcome measures, GHJ excursion and external rotation ROM remain compromised compared with healthy control subjects and may contribute to the development of osteoarthritis in patients with anterior instability.