Towards a GDPR-compliant cloud architecture with data privacy controlled through sticky policies.

Data privacy is one of the biggest challenges facing system architects at the system design stage. Especially when certain laws, such as the General Data Protection Regulation (GDPR), have to be complied with by cloud environments. In this article, we want to help cloud providers comply with the GDPR by proposing a GDPR-compliant cloud architecture. To do this, we use model-driven engineering techniques to design cloud architecture and analyze cloud interactions. In particular, we develop a complete framework, called MDCT, which includes a Unified Modeling Language profile that allows us to define specific cloud scenarios and profile validation to ensure that certain required properties are met. The validation process is implemented through the Object Constraint Language (OCL) rules, which allow us to describe the constraints in these models. To comply with many GDPR articles, the proposed cloud architecture considers data privacy and data tracking, enabling safe and secure data management and tracking in the context of the cloud. For this purpose, sticky policies associated with the data are incorporated to define permission for third parties to access the data and track instances of data access. As a result, a cloud architecture designed with MDCT contains a set of OCL rules to validate it as a GDPR-compliant cloud architecture. Our tool models key GDPR points such as user consent/withdrawal, the purpose of access, and data transparency and auditing, and considers data privacy and data tracking with the help of sticky policies.

A bout of aerobic exercise in the heat increases carbohydrate use but does not enhance the disposal of an oral glucose load, in healthy active individuals.

We investigated if a bout of exercise in a hot environment (HEAT) would reduce the postprandial hyperglycemia induced by glucose ingestion. The hypothesis was that HEAT stimulating glycogen use would increase the disposal of the ingested glucose (i.e., OGTT; 75 g of glucose). Separated by at least 1 week, nine young-healthy individuals underwent three trials after an overnight fast in a randomized order. Two trials included 50 min of pedaling at 58±5% VO2MAX either in a thermoneutral (21±1ºC; NEUTRAL) or in a hot environment (33±1ºC; HEAT) eliciting similar energy expenditure (503±101 kcals). These two trials were compared to a no-exercise trial (NO EXER). Twenty min after exercise (or rest), subjects underwent an OGTT, while carbohydrate oxidation (CHOxid, using indirect calorimetry) plasma blood glucose, insulin concentrations (i.e., [glucose], [insulin]), and double tracer glucose kinetics ([U- 13C] glucose ingestion and [6,6-2H2] glucose infusion) were monitored for 120 min. At rest, [glucose], [insulin], and rates of appearance/disappearance of glucose in plasma (glucose Ra/Rd) were similar among trials. During exercise, heart rate, tympanic temperature, [glucose], glycogen oxidation, and total CHOxid were higher during HEAT than NEUTRAL (i.e., 149±35 vs 124±31 µmol·kg-1·min-1, p=0.010). However, during the following OGTT glucose Rd was similar in HEAT and NEUTRAL (i.e., 25.1±3.6 vs 25.2±5.3 µmol·kg-1·min-1, p=0.981). Insulin sensitivity (i.e., ISIMATSUDA) only improved in NEUTRAL compared to NO EXER (10.1±4.6 vs 8.8±3.7 a.u.; p=0.044). In summary, stimulating carbohydrate use with exercise in a hot environment does not improve postprandial plasma glucose disposal or insulin sensitivity in a subsequent OGTT.

RENO Study: Clinical characteristics, treatment patterns and survival results in patients with metastatic renal cell carcinoma in Northern Spain.

BACKGROUND: The current available evidence on the management of metastatic renal cell cancer (mRCC) in real life is scarce in our environment. We present a summary of the existing real-world data and the results of an analysis describing the clinical characteristics, treatments, and health outcomes of patients with mRCC in northern Spain. METHODS: Retrospective observational study. Adult patients diagnosed with mRCC between Jan 2007 and Dec 2019 were included. Epidemiological, efficacy and toxicity data were collected. Median overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method. RESULTS: A total of 829 patients were included (median age at diagnosis:63 years;73% men). Median follow-up was 180 months. The preponderant histology was clear cell (85%). In 50% the initial diagnosis was advanced disease. The distribution according to IMDC prognosis was good (24%), intermediate (50%) and poor (26%). The most frequent metastatic locations were lung (68.3%) and lymph node (41.0%). Most patients (95%) received a first line (1L) systemic treatment, 60% were treated with a second line (2L) of therapy and 37% received third line (3L). A VEGFR-TKIs was the most common treatment (1L: 90%, n = 507; 2L: 49%, n = 233; 3L: 54%, n = 156) followed by mTOR inhibitors (1L: 2%, n = 4; 2L: 27%, n = 126; 3L: 23%, n = 68) and immunotherapy (1L: 3.7%, n = 25; 2L: 27%, n = 126). Median OS was 24.5 months in the general population. According to IMDC prognostic groups, OS was 52.5, 25.7 and 9 months respectively. From the start of the 1L, 2L, and 3L treatment, median PFS was: 1L: 7.8 (6.8-9.0); 2L: 4.9 (4.3-5.5); 3L: 4.3 (3.8-4.8) months. No unexpected toxicity was reported. CONCLUSIONS: The Real-World Data on the management of mRCC in Northern Spain are comparable in epidemiology, efficacy, and safety to studies conducted in other areas of the world. The significant reduction in the number of patients receiving second and subsequent lines of therapy hampers the access to new therapies developed in this context.

Comparison of DNA damage in granulosa cells of women undergoing controlled ovarian stimulation in in vitro fertilization protocols with the recombinant human follicle-stimulating hormones Corneumon®, Gonal-F®, Pergoveris® and Puregon®: a randomized trial.

PURPOSE: To compare the DNA damage in granulosa cells (GCs) of women undergoing ovarian-stimulated cycles with four widely used recombinant human follicle-stimulating hormones (rhFSH) in in vitro fertilization (IVF) protocols (Corneumon®, Gonal-F®, Pergoveris® and Puregon®). METHODS: A randomized trial was carried out at a Mexican hospital. GCs were isolated from 18 women with infertility undergoing assisted reproductive techniques (ART). Four controlled ovarian stimulation (COS) protocols including Corneumon®, Gonal-F®, Pergoveris® or Puregon® were used. GCs DNA damage was assessed by the Comet assay. Two parameters were measured: comet tail length (CTL), and Olive tail moment (OTM, the percentage of DNA in the tail multiplied by the distance between the center of the tail and head). RESULTS: Use of the different hrFSH in COS caused variable and statistically significant levels of DNA damage in GCs of infertile women. CTL was similar in the Corneumon® and Pergoveris® groups (mean values of 48.73 and 55.18, respectively) and Corneumon® CTL was significantly lower compared to the Gonal-F® and Puregon® groups (mean values of 61.98 and 91.17, respectively). Mean OTM values were significantly lower in Corneumon® and Pergoveris® groups, compared to Gonal-F® and Puregon® groups (25.59, 27.35, 34.76, and 47.27, respectively). CONCLUSION: Use of Corneumon® and Pergoveris® in COS caused statistically significantly lower levels of DNA damage in GCs of infertile women undergoing ART, which could potentially correlate with better reproductive outcomes.

Epidemiology and outcomes of pediatric cardiac arrest in a cardiovascular unit at a public hospital in Argentina.

BACKGROUND: Children with congenital heart disease present a higher frequency of cardiorespiratory arrest (CRA) than the general pediatric population. The epidemiology of CRA is not exactly known in our setting, nor are the mortality risk or the neurological evolution factors. OBJECTIVE: To describe the epidemiology and outcomes associated with pediatric cardiopulmonary resuscitation in a cardiovascular recovery unit. The primary endpoint was the survival to discharge and the secondary endpoints were the return to spontaneous circulation, the survival at 24 hours and the remote neurological condition. METHODS: Descriptive, prospective, longitudinal cohort study in children under 18 years of age who required cardiopulmonary resuscitation between 2016 and 2019. Demographic variables, characteristics of cardiopulmonary arrest, resuscitation and outcome were analyzed. An uni- and multivariate analysis was performed comparing survivors and deceased. RESULTS: Out of 1,842 hospitalized patients, 4.1% presented CRA. Fifty patients with complete records were analyzed. Seventy-eight percent (39) returned to spontaneous circulation with a high survival rate of 46%. Resuscitation > 6 min and the use of vasoactive drugs were predictors of mortality; 16/23 patients were followed up, 10 of them with normal development for age at 6 months, six had pervasive developmental disorder. CONCLUSIONS: 4.1% of patients presented CRA, with a rate of 3.4 CRA per 1,000 patient-days. Survival at hospital discharge (n = 50) was 46%. Resuscitation > 6 min and the use of vasoactive drugs were independent predictors of mortality. At six months, 63% had normal neurological development for age.

ANTECEDENTES: Los niños con cardiopatías congénitas experimentan paro cardiorrespiratorio (PCR) con mayor frecuencia que la población pediátrica general. Se desconoce la epidemiología exacta del PCR en nuestro medio, al igual que el riesgo de mortalidad y los factores que influyen en la evolución neurológica. OBJETIVO: Describir la epidemiología y los resultados asociados con la reanimación cardiopulmonar pediátrica en una unidad de recuperación cardiovascular. El criterio de valoración primario fue la supervivencia al momento del alta hospitalaria; los secundarios fueron el retorno de la circulación espontánea, la supervivencia a las 24 horas y la condición neurológica en el largo plazo. MÉTODO: Estudio de cohorte longitudinal, descriptivo, prospectivo, en menores de 18 años que requirieron reanimación cardiopulmonar entre 2016 y 2019. Se analizaron las variables demográficas y las características del paro cardiorrespiratorio y de la reanimación, así como su resultado. Se realizaron análisis de una y múltiples variables para comparar a los pacientes sobrevivientes con los fallecidos. RESULTADOS: De los 1,842 pacientes internados, el 4.1% experimentó PCR. Se analizaron 50 pacientes con expedientes completos. Se logró el retorno de la circulación espontánea en el 78% (39), con una supervivencia alta del 46%. La reanimación > 6 min y el uso de fármacos vasoactivos fueron factores predictivos de mortalidad; se realizó el seguimiento de 16/23 pacientes, 10 de ellos con desarrollo normal para la edad luego de seis meses, seis tenían trastorno generalizado del desarrollo. CONCLUSIONES: El 4.1% de los pacientes presentó un PCR, con una tasa de 3.4 PCR por 1,000 días-paciente. La supervivencia al egreso hospitalario (n = 50) fue del 46%. La reanimación > 6 min y la utilización de fármacos vasoactivos fueron factores predictivos independientes de mortalidad. Luego de seis meses, el 63% tenía desarrollo neurológico normal para la edad.

Atypical Hemolytic Uremic Syndrome: A Nationwide Colombian Pediatric Series.

Objectives. Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease with genetic predisposition and represents up to 10% of pediatric hemolytic uremic syndrome (HUS) cases. Few studies have evaluated aHUS in Latin American population. We studied a Colombian pediatric cohort to delineate disease presentation and outcomes. Methods. A multicenter cohort of 27 Colombian children with aHUS were included. Patients were grouped by age at onset. Clinical features were compared using analysis of variance (ANOVA) and Fisher exact tests. Renal biopsy was performed on 6 patients who were suspected of having other renal diseases before aHUS diagnosis. Results. Most patients were male (70%). The onset of aHUS occurred frequently before age 4 years (60%) and followed gastroenteritis as the main triggering event (52%). Age groups showed comparable clinical presentation, disease severity, treatment, and outcomes. Pulmonary involvement (67%) was the main extrarenal manifestation, particularly in the 1 to 7 age group (P = .01). Renal biopsies were as follows: 3 had membranoproliferative glomerulonephritis (MPGN) type I, one MPGN type III, one C3-glomerulonephritis, and one rapidly progressive GN. Genetic screening was available in 6 patients and identified 2xCFHR5, 2xMCP, 1xADAMTS13/THBD, and 1xDGKE mutations. A total of 15 relapses were seen, of which 8 (72%) occurred in the 1 to 7 age group. The renal outcome was not significantly different regardless of age group. Conclusion. In our cohort, we observed a relatively high frequency of extrarenal involvement at first presentation represented by pulmonary manifestations. The renal prognosis at initial presentation was worse than in previous reports.

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

AIM: To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). METHODS: Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. RESULTS: VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (ß standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). CONCLUSIONS: Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Oxidative Stress by the Mitochondrial Monoamine Oxidase B Mediates Calcium Pyrophosphate Crystal-Induced Arthritis.

OBJECTIVE: Calcium pyrophosphate (CPP) crystal deposition in the joints is associated with a heterogeneous set of debilitating syndromes characterized by inflammation and pain, for which no effective therapies are currently available. Because we found that the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a fundamental role in promoting inflammatory pathways, this study aims at assessing the efficacy of two clinical-grade inhibitors (iMAO-Bs) in preclinical models of this disease to pave the way for a novel treatment. METHODS: We tested our hypothesis in two murine models of CPP-induced arthritis, by measuring cytokine and chemokine levels, along with immune cell recruitment. iMAO-Bs (rasagiline and safinamide) were administered either before or after crystal injection. To elucidate the molecular mechanism, we challenged in vitro primed macrophages with CPP crystals and assessed the impact of iMAO-Bs in dampening proinflammatory cytokines and in preserving mitochondrial function. RESULTS: Both in preventive and therapeutic in vivo protocols, iMAO-Bs blunted the release of proinflammatory cytokines (interleukin [IL]-6 and IL1-ß) and chemokines (CXCL10, CXCL1, CCL2 and CCL5) (n > 6 mice/group). Importantly, they also significantly reduced ankle swelling (50.3% vs 17.1%; P < 0.001 and 23.1%; P = 0.005 for rasagiline and safinamide, respectively). Mechanistically, iMAO-Bs dampened the burst of reactive oxygen species and the mitochondrial dysfunction triggered by CPP crystals in isolated macrophages. Moreover, iMAO-Bs blunted cytokine secretion and NLRP3 inflammasome activation through inhibition of the NF-κB and STAT3 pathways. CONCLUSION: iMAO-Bs dampen inflammation in murine models of crystal-induced arthropathy, thereby uncovering MAO-B as a promising target to treat these diseases.

Dynamic Configuration on a Chiral-at-Rhodium Catalyst Featuring a Flexible Tetradentate Ligand.

The unique dynamic configuration of an enantioselective chiral-at-metal catalyst based on Rh(III) and a non-chiral tetradentate ligand is described and resolved. At room temperature, the catalyst undergoes a dynamic configuration process leading to the formation of two interconvertible metal-stereoisomers, remarkably without racemization. Density functional theory (DFT) calculations indicate that this metal-isomerization proceeds via a concerted transition state, which features a trigonal bipyramidal geometry stabilized by the tetradentate ligand. Furthermore, the resolved enantiopure complex shows high catalytic enantioinduction in the Friedel-Crafts reaction, achieving enantiomeric ratios as high as 99 : 1.

Assessing nutrition status, sarcopenia, and frailty in adult transplant recipients.

The assessment of nutrition status, sarcopenia, and frailty holds significant relevance in the context of adult transplantation, as these factors are associated with an unfavorable prognosis; thus, transplant candidates must undergo a full nutrition assessment. Screening tools may be used to prioritize patients, this can be done using the Nutrition Risk Screening 2002 or Royal Free Hospital-Nutritional Prioritizing Tool. Subsequently, a thorough nutrition-focused physical examination should be conducted to evaluate clinical signs of nutrition deficiencies, fat and muscle loss, and fluid overload; dietary history and current intake must also be assessed. Apart from physical examination, specific testing for sarcopenia and frailty are recommended. For sarcopenia assessment, specifically for muscle quantification, the gold standard is the cross-sectional measurement of the muscle at L3 obtained from a computed tomography scan or magnetic resonance imaging; dual-energy x-ray absorptiometry is also a good tool especially when appendicular skeletal muscle index is calculated. Other more readily available options include phase angle from bioelectrical impedance or bioimpedance spectroscopy. In the sarcopenia assessment, muscle function evaluation is required, handgrip strength stands as the primary test for this purpose; this test is also part of the subjective global assessment and is included in some frailty scores. Finally, for frailty assessment, the Short Physical Performance Battery is useful for evaluating physical frailty, and for a multidimensional evaluation, the Fried frailty phenotype can be used. Specifically for liver transplant candidates, the use of Liver Frailty Index is recommended.

Clinical outcomes in patients with scaphoid non-union treated with the vascularized medial femoral condyle technique a case series.

INTRODUCTION: Non-union is a prevalent complication of scaphoid fractures. Late diagnosis is common and has a clinical impact due to functional limitations for the patient. Multiple treatments have been proposed to manage this complication, ranging from conservative (i.e., orthopedic) to surgical treatment. The vascularized medial femoral condyle technique has shown satisfactory clinical and paraclinical results, mainly in presence of avascular necrosis of the proximal pole but data regarding functional outcomes and patient satisfaction is scarce. This case series aims to describe the clinical and patient-reported outcomes in a consecutive series of patients with non-union of the proximal third of the scaphoid treated with vascularized medial femoral condyle technique. METHODS: Case series reporting results for a consecutive - initial cohort of patients who presented with a non united fracture of the proximal pole of the scaphoid, avascular necrosis of the proximal pole was documented by CT od MRI imaging preoperatively in all patients. Measurement instruments include the q-DASH and PRWE questionnaires, radiographic images, goniometry, and assessment of grip strength. RESULTS: Twelve consecutive patients are included and they represent the initial cases for all surgeons involved; bone union was obtained in 10 patients (83%) after a mean follow-up time of 31 months (6-72), successful improvement in the range of motion and grip strength was documented. A high rate of satisfaction expressed by the patient was obtained, with an average score in Q-DASH of 17.3 and 20.1 in PRWE. CONCLUSIONS: The vascularized medial condyle technique in cases of nonunion of scaphoid fracture is a reproducible treatment in clinical terms, both in imaging and functional terms, and in patient satisfaction. The learning curve is flat for a dedicated multi surgeon team.

Clinical Correlates of Cholestasis in Preterm Infants with Surgical Necrotizing Enterocolitis.

Background: We sought to investigate the clinical determinants and outcomes of cholestasis in preterm infants with surgical necrotizing enterocolitis (sNEC). Methods: Retrospective comparison of clinical information in preterm infants who developed cholestasis vs those who did not. Results: Sixty-two (62/91, 68.1%) infants with NEC developed cholestasis at any time following the onset of illness. Cholestasis was seen more frequently in those who had received ionotropic support at 24 hours following sNEC diagnosis (87.1% vs 58.6%; p = 0.002), had higher mean C-reactive protein levels 2 weeks after NEC diagnosis (p = 0.009), had blood culture-positive sepsis [25 (40.3%) vs 4 (13.8%); p = 0.011], received parenteral nutrition (PN) for longer durations (108.4 ± 56.63 days vs 97.56 ± 56.05 days; p = 0.007), had higher weight-for-length z scores at 36 weeks' postmenstrual age [-1.0 (-1.73, -0.12) vs -1.32 (-1.76, -0.76); p = 0.025], had a longer length of hospital stay (153.7 ± 77.57 days vs 112.51 ± 85.22 days; p = 0.024), had intestinal failure more often (61% vs 25.0%, p = 0.003), had more surgical complications (50% vs 27.6%; p = 0.044), and had >1 complication (21% vs 3.4%; p = 0.031). Using linear regression, the number of days after surgery when feeds could be started [OR 15.4; confidence interval (CI) 3.71, 27.13; p = 0.009] and the postoperative ileus duration (OR 11.9, CI 1.1, 22.8; p = 0.03) were independently associated with direct bilirubin between 2 and 5 mg/dL (mild-moderate cholestasis) at 2 months of age. The duration of PN was independently associated with direct bilirubin >5 mg/dL (severe cholestasis) at 2 months of age in these patients. Conclusion: Cholestasis was seen in 68% of infants following surgical NEC. The most likely contributive factors are intestinal failure and subsequent PN dependence for longer periods. Our data suggest that identification and prevention of risk factors such as sepsis and surgical complications and early feeds following NEC surgery may improve outcomes.

RAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes. In vitro THP1-based experiments indicate that monocytes bind the SARS-CoV-2 S1-receptor binding domain (RBD) via RAGE, pointing to RAGE-Spike interaction enabling monocyte infection. Thus, our results demonstrate that RAGE is a functional receptor of SARS-CoV-2 contributing to COVID-19 severity.

Efficacy of morning versus afternoon aerobic exercise training on reducing metabolic syndrome components: A randomized controlled trial.

A supervised intense aerobic exercise program improves the health of individuals with metabolic syndrome (MetS). However, it is unclear whether the timing of training within the 24 h day would influence those health benefits. The present study aimed to determine the influence of morning vs. afternoon exercise on body composition, cardiometabolic health and components of MetS. One hundred thirty-nine individuals with MetS were block randomized into morning (AMEX; n = 42) or afternoon (PMEX; n = 59) exercise training groups, or a non-training control group (Control; n = 38). Exercise training was comprised of 48 supervised high-intensity interval sessions distributed over 16 weeks. Body composition, cardiorespiratory fitness (assessed by V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ), maximal fat oxidation (FOmax ), blood pressure and blood metabolites were assessed before and after the intervention. Compared with the non-training Control, both exercise groups improved similarly body composition (-0.7% fat loss; P = 0.002), waist circumference (-2.1 cm; P < 0.001), diastolic blood pressure (-3.8 mmHg; P = 0.004) and V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ (3.5 mL kg-1   min-1 ; P < 0.001) with no differences between training groups. AMEX, in comparison with PMEX, reduced systolic blood pressure (-4% vs. -1%; P = 0.019), plasma fasting insulin concentration (-12% vs. -5%; P = 0.001) and insulin resistance (-14% vs. -4%; P = 0.006). Furthermore, MetS Z score was further reduced in the AMEX compared to PMEX (-52% vs. -19%; P = 0.021) after training. In summary, high-intensity aerobic exercise training in the morning in comparison to training in the afternoon is somewhat more efficient at reducing cardiometabolic risk factors (i.e. systolic blood pressure and insulin sensitivity). KEY POINTS: The effect of exercise time of day on health promotion is an area that has gained interest in recent years; however, large-scale, randomized-control studies are scarce. People with metabolic syndrome (MetS) are at risk of developing cardiometabolic diseases and reductions in this risk with exercise training can be precisely gauged using a compound score sensitive to subtle evolution in each MetS component (i.e. Z score). Supervised aerobic exercise for 16 weeks (morning and afternoon), without dietary restriction, improved cardiorespiratory and metabolic fitness, body composition and mean arterial pressure compared to a non-exercise control group. However, training in the morning, without changes in exercise dose or intensity, reduced systolic blood pressure and insulin resistance further compared to when training in the afternoon. Thus, high-intensity aerobic exercise training in the morning is somewhat more efficient in improving the health of individuals with metabolic syndrome.

The Use of Dexmedetomidine in Preterm Infants: A Single Academic Center Experience.

OBJECTIVE: Preterm newborns (PTNBs) often require sedation and analgesia. Dexmedetomidine (DEX) is used to provide sedation in extremely PTNBs, even though information on such use is limited. The objective of this research is to describe the use of DEX in these patients in a single academic center. METHODS: This is a retrospective study of PTNBs receiving DEX from January 1, 2010, through December 31, 2018, at the Cleveland Clinic Children's Hospital, a tertiary academic center operating 2 Level III and 1 Level IV neonatal intensive care units (NICUs). Inclusion criteria were gestational age (GA) <36 weeks and receipt of DEX for >2 days. Adequacy of clinical response was based on achieving Neonatal Pain, Agitation and Sedation Scale (N-PASS) scores <3. Hypotension, bradycardia, and respiratory depression were recorded as the incidence as adverse events. RESULTS: A total of 105 patients were included. The birth weight median was 870 g (IQR, 615-1507); the GA median was 26 weeks (IQR, 24-31). The duration of DEX infusion averaged 7 days. The DEX dose averaged 0.4 mcg/kg (IQR, 0.3-0.45). Bradycardia was observed in 35 patients (57%) weighting <1 kg and in 7 patients (18%) >1 kg (p < 0.01). There was no difference in the incidence of other adverse events between these groups. However, infants <1 kg required more pharmacologic interventions to maintain N-PASS score <3. CONCLUSIONS: DEX was well tolerated overall and provided adequate sedation to PTNBs in this cohort. From this study, we recommend a starting dose of 0.2 to 0.4 mcg/kg/hr and titrating up hourly until adequate sedation is achieved.