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Background: High-flow nasal oxygen (HFNO) improves exercise capacity, oxygen saturation, and symptoms in patients with chronic obstructive pulmonary disease (COPD). Due to the need of electricity supply, HFNO has not been applied during free ambulation. Objective: We evaluated whether HFNO delivered during walking by a battery-supplied portable device was more effective than usual portable oxygen in improving exercise capacity in patients with COPD and severe exercise limitation. The effects on 6-min walking tests (6MWTs) were the primary outcome. Methods: After a baseline 6MWT, 20 stable patients requiring an oxygen inspiratory fraction (FiO2) 2. Walked distance, perceived dyspnea, pulse oximetry, and inspiratory capacity at end of the tests as well as patients’ comfort were compared between the tests. Results: As compared to baseline, walked distance improved significantly more in HFNO than in the control test (by 61.1 ± 37.8 and 39.7 ± 43.8 m, respectively, p = 0.01). There were no significant differences between the tests in dyspnea, peripheral oxygen saturation, or inspiratory capacity, but HFNO test was appreciated as more comfortable. Conclusion: In patients with COPD and severe exercise limitation, HFNO delivered by a battery-supplied portable device was more effective in improving walking distance than usual oxygen supplementation.

Background The Barthel Index dyspnea (BId) is responsive to physiological changes and pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). However, the minimum clinically important difference (MCID) has not been established yet. Aim To identify the MCID of BId in patients with COPD stratified according to the presence of chronic respiratory failure (CRF) or not. Materials and Methods Using the Medical Research Council (MRC) score as an anchor, receiver operating characteristic curves and quantile regression were retrospectively evaluated before and after pulmonary rehabilitation in 2327 patients with COPD (1151 of them with CRF). Results The median post-rehabilitation changes in BId for all patients were -10 (interquartile range = -17 to -3, p

STUDY OBJECTIVES: There are few studies evaluating (1) exercise capacity as assessed by the 6-minute walking distance (6MWD) test in large populations with obstructive sleep apnea (OSA); and (2) correlations with patients’ comorbidities. METHODS: This study presents a cluster analysis performed on the data of 1,228 patients. Severity of exercise limitation was defined on the basis of 6MWD. RESULTS: Sixty-one percent showed exercise limitation (29.2% and 31.9% mild and severe exercise limitation, respectively). About 60% and 40% of patients were included in cluster 1 (CL1) and 2 (CL2), respectively. CL1 included younger patients with high prevalence of apneas, desaturations, and hypertension with better exercise tolerance. CL2 included older patients, all with chronic obstructive pulmonary disease (COPD), high prevalence of chronic respiratory failure (CRF), fewer apneas but severe mean desaturation, daytime hypoxemia, more severe exercise limitation, and exercise-induced desaturations. Only CRF and COPD significantly (P < .001) correlated with 6MWD < 85% of predicted value. 6MWD correlated positively with apnea-hypopnea index, oxygen desaturation index, nocturnal pulse oxygen saturation (SpO(2)), resting arterial oxygen tension, mean SpO(2) on exercise, and negatively with age, body mass index, time spent during night with SpO(2) < 90%, mean nocturnal desaturation, arterial carbon dioxide tension, and number of comorbidities. Patients without severe comorbidities had higher exercise capacity than those with severe comorbidities, (P < .001). Exercise limitation was significantly worse in OSA severity class I when compared to other classes (P < .001). CONCLUSIONS: A large number of patients with OSA experience exercise limitation. Older age, comorbidities such as COPD and CRF, OSA severity class I, severe mean nocturnal desaturation, and daytime hypoxemia are associated with worse exercise tolerance. CITATION: Vitacca M, Paneroni M, Braghiroli A, et al. Exercise capacity and comorbidities in patients with obstructive sleep apnea. J Clin Sleep Med. 2020;16(4):531–538.

Background For some SARS-CoV-2 survivors, recovery from the acute phase of the infection has been grueling with lingering effects. Many of the symptoms characterized as the post-acute sequelae of COVID-19 (PASC) could have multiple causes or are similarly seen in non-COVID patients. Accurate identification of PASC phenotypes will be important to guide future research and help the healthcare system focus its efforts and resources on adequately controlled age- and gender-specific sequelae of a COVID-19 infection. Methods In this retrospective electronic health record (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3–6 and 6–9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston Metropolitan Area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized. Results We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94–3.46]), alopecia (OR 3.09, 95% CI [2.53–3.76]), chest pain (OR 1.27, 95% CI [1.09–1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22–2.10]), shortness of breath (OR 1.41, 95% CI [1.22–1.64]), pneumonia (OR 1.66, 95% CI [1.28–2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22–1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65. Conclusions The findings of this study confirm many of the post-COVID-19 symptoms and suggest that a variety of new diagnoses, including new diabetes mellitus and neurological disorder diagnoses, are more common among those with a history of COVID-19 than those without the infection. Additionally, more than 63% of PASC phenotypes were observed in patients under 65 years of age, pointing out the importance of vaccination to minimize the risk of debilitating post-acute sequelae of COVID-19 among younger adults.

Made available in DSpace on 2022-04-29T08:35:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 Division of Intramural Research, National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases National Institute of Allergy and Infectious Diseases National Center for Advancing Translational Sciences National Heart, Lung, and Blood Institute National Institute of Environmental Health Sciences U.S. National Library of Medicine National Institute of Neurological Disorders and Stroke Division of Cancer Prevention, National Cancer Institute Neurological complications worsen outcomes in COVID-19. To define the prevalence of neurological conditions among hospitalized patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test in geographically diverse multinational populations during early pandemic, we used electronic health records (EHR) from 338 participating hospitals across 6 countries and 3 continents (January–September 2020) for a cross-sectional analysis. We assessed the frequency of International Classification of Disease code of neurological conditions by countries, healthcare systems, time before and after admission for COVID-19 and COVID-19 severity. Among 35,177 hospitalized patients with SARS-CoV-2 infection, there was an increase in the proportion with disorders of consciousness (5.8%, 95% confidence interval [CI] 3.7–7.8%, pFDR < 0.001) and unspecified disorders of the brain (8.1%, 5.7–10.5%, pFDR < 0.001) when compared to the pre-admission proportion. During hospitalization, the relative risk of disorders of consciousness (22%, 19–25%), cerebrovascular diseases (24%, 13–35%), nontraumatic intracranial hemorrhage (34%, 20–50%), encephalitis and/or myelitis (37%, 17–60%) and myopathy (72%, 67–77%) were higher for patients with severe COVID-19 when compared to those who never experienced severe COVID-19. Leveraging a multinational network to capture standardized EHR data, we highlighted the increased prevalence of central and peripheral neurological phenotypes in patients hospitalized with COVID-19, particularly among those with severe disease. Department of Biostatistics Epidemiology and Informatics University of Pennsylvania Perelman School of Medicine Department of Biomedical Informatics Harvard Medical School Department of Neurology University of Pittsburgh, Biomedical Science Tower 3, Suite 7014, 3501 5th Avenue Department of Pediatrics Wake Forest School of Medicine Department of Critical Care National University Health Systems Department of Preventive Medicine Northwestern University Department of Biomedical Informatics University of Pittsburgh Department of Surgery National University Health Systems Department of Internal Medicine University of Kansas Medical Center Data Analytics Center University of Pennsylvania Health System Department of Computational Medicine and Bioinformatics University of Michigan Department of Biomedical Informatics University of Kentucky Department of Legal Economic and Social Sciences University Magna Graecia of Catanzaro Health Catalyst INC. Department of Surgery ASST Pavia Lombardia Region Health System Clinical Research Unit of Botucatu Medical School São Paulo State University Pediatric Emergency Department Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris National Center for Infectious Diseases Tan Tock Seng Hospital Departments of Biomedical Informatics Pediatrics Cincinnati Children’s Hospital Medical Center University of Cincinnati Department of Pediatrics Medical University of South Carolina Department of Surgery St. Luke’s University Health Network Department of Medicine David Geffen School of Medicine at UCLA UOC Ricerca Innovazione e Brand Reputation ASST Papa Giovanni XXIII Department of Electrical Computer and Biomedical Engineering University of Pavia IT Department Innovation & Data APHP Greater Paris University Hospital I.T. Department ASST Pavia Health Informatics Hospital Universitario, 12 de Octubre Strategy and Transformation Department APHP Greater Paris University Hospital Faculty of Medicine and Medical Center University of Freiburg Digital Research Informatics and Virtual Environments (DRIVE), Great Ormond Street Hospital for Children Scientific Direction IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano North Carolina Translational and Clinical Sciences (NC TraCS) Institute University of North Carolina BIOMERIS (BIOMedical Research Informatics Solutions) Department of Biomedical Informatics HEGP APHP Greater Paris University Hospital Department of Medical and Surgical Sciences Data Analytics Research Center University Magna Graecia of Catanzaro Department of Anesthesia St. Luke’s University Health Network Université Paris-Saclay Inria CEA INRIA Sophia-Antipolis–ZENITH Team LIRMM Computational Health Informatics Program Boston Children’s Hospital Department of Internal Medicine University of Kentucky Unit of Internal Medicine and Endocrinology Istituti Clinici Scientifici Maugeri SpA SB IRCCS Department of Internal Medicine and Therapeutics University of Pavia Informatics Institute University of Alabama at Birmingham IAM Unit Bordeaux University Hospital/ERIAS-Inserm U1219 BPH Biomedical Informatics Center Medical University of South Carolina Clinical Research Informatics Boston Children’s Hospital Department of Biomedical and Health Informatics Children’s Hospital of Philadelphia SED/SIERRA Inria Centre de Paris Health Information Technology & Services University of Michigan Internal Medicine Department Botucatu Medical School São Paulo State University Heinrich-Lanz-Center for Digital Health University Medicine Mannheim Heidelberg University Department of Anesthesiology Critical Care and Pain Medicine Boston Children’s Hospital Department of Learning Health Sciences University of Michigan Medical School MSHI Medical University of South Carolina Department of Medicine Massachusetts General Hospital Division of Human Genetics Department of Pediatrics The Children’s Hospital of Philadelphia Center for Medical Information and Communication Technology University Hospital Renaissance Computing Institute/Department of Computer Science University of North Carolina Clinical Research Unit Saint Antoine Hospital APHP Greater Paris University Hospital Clevy.io Department of Biostatistics Harvard T.H. Chan School of Public Health VA Informatics and Computing Infrastructure VA Salt Lake City Health Care System MICHR Informatics University of Michigan Laboratory of Informatics and Systems Engineering for Clinical Research Istituti Clinici Scientifici Maugeri SpA SB IRCCS Harvard Catalyst Harvard Medical School Clinical Research Unit Paris Saclay APHP Greater Paris University Hospital Department of Anesthesiology and Critical Care Children’s Hospital of Philadelphia VA Informatics and Computing Infrastructure Tennessee Valley Healthcare System Veterans Affairs Medical Center École Normale Supérieure PSL Université Paris BIG-ARC The University of Texas Health Science Center at Houston School of Biomedical Informatics Pediatric Infectious Disease Department Hospital Universitario, 12 de Octubre Department of Infectious Diseases Great Ormond Street Hospital for Children Department of Neurology Massachusetts General Hospital Internal Medicine Department of Botucatu Medical School São Paulo State University Department of Pediatrics Boston Children’s Hospital Center for Biomedical Informatics Wake Forest School of Medicine Department of Medical Informatics University of Erlangen-Nürnberg Department of Veterans Affairs Office of Research and Development Biomedical Data Science Lab ITACA Institute Universitat Politècnica de València Nurse Department of FMB-Medicine School of Botucatu Management Engineering ASST Pavia Lombardia Region Health System Department of Anesthesiology University Hospital Erlangen FAU Erlangen-Nürnberg Critical Care Medicine Department of Medicine St. Luke’s University Health Network Department of Medicine National University Hospital Department of Information Management Chang Gung University Clinical & Translational Science Institute Medical College of Wisconsin Montréal Neurological Institute McGill University SequeL Inria Lille Respiratory Department ICS S Maugeri IRCCS Department of Health Management and Informatics University of Missouri Department of Oncology ASST Papa Giovanni XXIII Clinical Research Unit of Botucatu Medical School São Paulo State University Internal Medicine Department Botucatu Medical School São Paulo State University Internal Medicine Department of Botucatu Medical School São Paulo State University Division of Intramural Research, National Institute of Allergy and Infectious Diseases: AI11679 Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases: AI11679 National Institute of Allergy and Infectious Diseases: AI11679 National Center for Advancing Translational Sciences: CTSA Award #UL1TR001878 National Center for Advancing Translational Sciences: CTSA Award #UL1TR002366 National Heart, Lung, and Blood Institute: K23HL148394 National Institute of Environmental Health Sciences: P30ES017885 U.S. National Library of Medicine: R01LM012095 National Institute of Neurological Disorders and Stroke: R01NS098023 Division of Cancer Prevention, National Cancer Institute: U24CA210967 National Center for Advancing Translational Sciences: UL1TR001420 National Center for Advancing Translational Sciences: UL1TR001857

Background Persistence of breathlessness after recovery from SARS-CoV-2 pneumonia is frequent. Recovery from acute respiratory failure (ARF) is usually determined by normalized arterial blood gases (ABGs), but the prevalence of persistent exercise-induced desaturation (EID) and dyspnea is still unknown. Methods We investigated the prevalence of EID in 70 patients with normal arterial oxygen at rest after recovery from ARF due to COVID-19 pneumonia. Patients underwent a 6-min walking test (6MWT) before discharge from hospital. We recorded dyspnea score and heart rate during 6MWT. We also investigated the possible role of lung ultrasound (LU) in predicting EID. Patients underwent a LU scan and scores for each explored area were summed to give a total LU score. Results In 30 patients (43%), oxygen desaturation was >4% during 6MWT. These patients had significantly higher dyspnea and heart rate compared to non-desaturators. LU score >8.5 was significantly able to discriminate patients with EID. Conclusion In SARS-CoV-2 pneumonia, ABGs at discharge cannot predict the persistence of EID, which is frequent. LU may be useful to identify patients at risk who could benefit from a rehabilitation program.

This cohort study aims to describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19., Key Points Question What are international trends in hospitalizations for children and youth with SARS-CoV-2, and what are the epidemiological and clinical features of these patients? Findings This cohort study of 671 children and youth found discrete surges in hospitalizations with variable trends and timing across countries. Common complications included cardiac arrhythmias and viral pneumonia, and laboratory findings included elevations in markers of inflammation and abnormalities of coagulation; few children and youth were treated with medications directed specifically at SARS-CoV-2. Meaning These findings suggest large-scale informatics-based approaches used to incorporate electronic health record data across health care systems can provide an efficient source of information to monitor disease activity and define epidemiological and clinical features of pediatric patients hospitalized with SARS-CoV-2 infections., Importance Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients. Objective To describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19. Design, Setting, and Participants This retrospective cohort study included pediatric patients hospitalized between February 2 and October 10, 2020. Patient-level electronic health record (EHR) data were collected across 27 hospitals in France, Germany, Spain, Singapore, the UK, and the US. Patients younger than 21 years who tested positive for COVID-19 and were hospitalized at an institution participating in the Consortium for Clinical Characterization of COVID-19 by EHR were included in the study. Main Outcomes and Measures Patient characteristics, clinical features, and medication use. Results There were 347 males (52%; 95% CI, 48.5-55.3) and 324 females (48%; 95% CI, 44.4-51.3) in this study’s cohort. There was a bimodal age distribution, with the greatest proportion of patients in the 0- to 2-year (199 patients [30%]) and 12- to 17-year (170 patients [25%]) age range. Trends in hospitalizations for 671 children and youth found discrete surges with variable timing across 6 countries. Data from this cohort mirrored national-level pediatric hospitalization trends for most countries with available data, with peaks in hospitalizations during the initial spring surge occurring within 23 days in the national-level and 4CE data. A total of 27 364 laboratory values for 16 laboratory tests were analyzed, with mean values indicating elevations in markers of inflammation (C-reactive protein, 83 mg/L; 95% CI, 53-112 mg/L; ferritin, 417 ng/mL; 95% CI, 228-607 ng/mL; and procalcitonin, 1.45 ng/mL; 95% CI, 0.13-2.77 ng/mL). Abnormalities in coagulation were also evident (D-dimer, 0.78 ug/mL; 95% CI, 0.35-1.21 ug/mL; and fibrinogen, 477 mg/dL; 95% CI, 385-569 mg/dL). Cardiac troponin, when checked (n = 59), was elevated (0.032 ng/mL; 95% CI, 0.000-0.080 ng/mL). Common complications included cardiac arrhythmias (15.0%; 95% CI, 8.1%-21.7%), viral pneumonia (13.3%; 95% CI, 6.5%-20.1%), and respiratory failure (10.5%; 95% CI, 5.8%-15.3%). Few children were treated with COVID-19–directed medications. Conclusions and Relevance This study of EHRs of children and youth hospitalized for COVID-19 in 6 countries demonstrated variability in hospitalization trends across countries and identified common complications and laboratory abnormalities in children and youth with COVID-19 infection. Large-scale informatics-based approaches to integrate and analyze data across health care systems complement methods of disease surveillance and advance understanding of epidemiological and clinical features associated with COVID-19 in children and youth.

Background: Currently, evidence-based learning systems to increase knowledge and evidence level of wound care are unavailable to wound care nurses in Denmark, which means that they need to learn about diabetic foot ulcers from experience and peer-to-peer training, or by asking experienced colleagues. Interactive evidence-based learning systems built on case-based reasoning (CBR) have the potential to increase wound care nurses’ diabetic foot ulcer knowledge and evidence levels. Method: A prototype of a CBR-interactive, evidence-based algorithm-operated learning system calculates a dissimilarity score (DS) that gives a quantitative measure of similarity between a new case and cases stored in a case base in relation to six variables: necrosis, wound size, granulation, fibrin, dry skin, and age. Based on the DS, cases are selected by matching the six variables with the best predictive power and by weighing the impact of each variable according to its contribution to the prediction. The cases are ranked, and the six cases with the lowest DS are visualized in the system. Results: Conventional education, that is, evidence-based learning material such as books and lectures, may be less motivating and pedagogical than peer-to-peer training, which is, however, often less evidence-based. The CBR interactive learning systems presented in this study may bridge the two approaches. Showing wound care nurses how individual variables affect outcomes may help them achieve greater insights into pathophysiological processes. Conclusion: A prototype of a CBR-interactive, evidence-based learning system that is centered on diabetic foot ulcers and related treatments bridges the gap between traditional evidence-based learning and more motivating and interactive learning approaches.

Background The genetic architecture of Brugada syndrome (BrS) is emerging as an increasingly complex area of investigation. The identification of genetically homogeneous populations can provide mechanistic insights and improve genotype-phenotype correlation. Objective To characterize and define the clinical implications of a novel BrS founder mutation. Using a haplotype-based approach we investigated whether 2 SCN5A genetic variants could derive from founder events. Methods Single nucleotide polymorphisms were genotyped in 201 subjects, haplotypes reconstructed, and mutational age estimated. Clinical phenotypes and historical records were collected. Results A SCN5A variant (c.3352C>T; p.Gln1118Ter) was identified in 3 probands with BrS originating from south Italy. The same mutation was identified in a proband from central Italy and in 1 U.S. resident subject with Italian ancestry. The 5 individuals carried a common core haplotype, whose frequency was extremely low in local noncarrier probands and in population controls (0%–6.06%). The clinical presentation included multigenerational dominant transmission of Brugada electrocardiographic pattern, high incidence of sudden cardiac death (SCD), and cardiac conduction defects (CCD). We reconstructed 7-generation pedigrees with common geographic origin. Variant’s age estimates suggested that origin of the p.Gln1118Ter dates back 76 generations (95% confidence interval: 28–200). A second SCN5A variant (c.5350G>A; p.Glu1784Lys) identified in the region did not show similar founder signal. Conclusion p.Gln1118Ter is a novel BrS/CCD/SCD founder mutation. We illustrate how these findings provide insights on the inheritance patterns and phenotypes associated with SCN5A mutation.

Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting.Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated. Six minute walking distance (6MWT), body weight-walking distance product tests, dyspnoea and arterial blood gases were assessed at admission and discharge. Differences in post rehabilitation changes in outcome measures as function of baseline characteristics were evaluated.After rehabilitation, patients showed improvements in all outcome measures (p 0.05), regardless of the underlying diagnosis or disease severity. Patients needing oxygen therapy at rest showed reduced benefits. Baseline 6MWD inversely correlated with its changes at discharge. Non-significant greater benefits after rehabilitation were found in IPF patients under antifibrotic therapy. In a subset of 50 patients assessed on average 10.3 ± 3.5 months after discharge, the benefits in 6MWD were not maintained (312.9 ± 139.4, 369.7 ± 122.5 and 310.8 ± 139.6 m at admission, discharge and follow up respectively: p 0.0001).Pulmonary rehabilitation may improve dyspnoea, exercise capacity and fatigue in patients with ILD of different aethiologies and level of severity. The long-term effects need to be established.

A bulk of evidence in the field of translational medicine applied to clinical toxicology and rehabilitation has highlighted the possibility of using biomarkers as a support in the diagnosis of alcohol-related diseases and in monitoring of alcohol withdrawal. In a cohort of 55 subjects admitted to a 4-week residential rehabilitation period for alcohol detoxification, we applied a complementary approach correlating novel and conventional peripheral blood and urine parameters in combination with clinical and functional evaluation, contextually considered with the patient's history. Biomarkers of oxidative, inflammatory, hepatic, and neurochemical effects paralleled by alcohol craving and clinical scale measurements were determined at two specific time points, i.e., admission and discharge. Concerning the post-discharge assessment (i.e., relapse evaluation one month after discharge), a follow-up oral interview during a clinical examination was applied to evaluate alcohol abstinence.Selected biomarkers, i.e., MCP1, F2-IsoPs, and SOD1, were altered in chronic alcoholics at admission, and then showed a clearly changing trend during hospitalization. Our findings demonstrated that these specific non-traditional biomarkers, measured together with more conventional ones (e.g., CDT, EtG, IL8, ALT, AST, GGT), could represent novel key parameters for monitoring alcohol use disorders and withdrawal, being also suggestive of the complexity of the psychoneuroimmune response to alcohol. A general improvement in psychological functioning (i.e., decreases in anxiety, depression, and psychological distress) was also revealed during the 4-week rehabilitation treatment, paralleled by an increase of well-being and positive changes in terms of scores. Moreover, a positive association between SOD1 and drink craving at admission was evidenced. Notably, both SOD1 and well-being displayed a significant relation with lower risk of alcohol relapse one month after discharge, indicating that SOD1 is a good predictor of reduced relapse probability. This 4-week residential rehabilitation protocol represents a sound strategy enabling identification of alcohol use disorders and monitoring of alcohol addiction state and withdrawal. However, it has to be emphasized that results derived from this pilot study need to be extensively validated in large and independent cohorts of subjects.

Objectives Despite the widespread diffusion of continuous glucose monitoring (CGM) systems, which includes both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), an effective application of CGM technology in clinical practice is still limited. The study aimed to investigate the relationship between isCGM-derived glycemic metrics and glycated hemoglobin (HbA1c), identifying overall CGM targets and exploring the inter-subject variability. Methods A group of 27 children and adolescents with type 1 diabetes under multiple daily injection insulin-therapy was enrolled. All participants used the isCGM Abbott’s FreeStyle Libre system on average for eight months, and clinical data were collected from the Advanced Intelligent Distant-Glucose Monitoring platform. Starting from each HbA1c exam date, windows of past 30, 60, and 90 days were considered to compute several CGM metrics. The relationships between HbA1c and each metric were explored through linear mixed models, adopting an HbA1c target of 7%. Results Time in Range and Time in Target Range show a negative relationship with HbA1c (R2>0.88) whereas Time Above Range and Time Severely Above Range show a positive relationship (R2>0.75). Focusing on Time in Range in 30-day windows, random effect represented by the patient’s specific intercept reveals a high variability compared to the overall population intercept. Conclusions This study confirms the relationship between several CGM metrics and HbA1c; it also highlights the importance of an individualized interpretation of the CGM data.

Background Inconsistent data support the role of CACNA1C as a disease-causing gene responsible for Brugada syndrome (BrS). As of today, the only gene consistently linked with BrS is SCN5A. Several CACNA1c genetic variants have been reported in association wirh BrS; however, due to the limited evidence, CACNA1C is not suggested for routine genetic screening for BrS. Purpose In this study, we carried out a systematic screening of CACNA1C gene, including a functional evaluation of the identified variants, in order to determine the yield of screening in a large series of BrS probands and to address the hypothesis that an appropriate clinical selection of patients would substantially improve the yield of genetic testing. Methods and results Overall 564 consecutive patients, referred for BrS genetic testing, were sequenced for CACNA1C gene. Patients were divided in two groups: discovery cohort (n=200 patients) and confirmation cohort (n=363 patients). Furthermore, analysis of the clinical phenotypes of a matched SCN5A positive BrS cohort (n=146) was included for phenotype characterization. In the discovery cohort we identified 11 different genetic variants of whom 2 (18%) were considered as potentially causative based on ACMG guidelines. However, a large proportion (81%) was classified as variants of unknown significance (VUS). Functional evaluation of the identified variants, including pathogenic and VUS, was assessed by patch-clamp and immunofluorescence studies. Re-evaluation of the variants, including functional studies results, indicated an increase of pathogenic or likely pathogenic variants (81%) getting a yield of screening of 5% in the discovery cohort. Results from the confirmation cohort confirmed a low rate of CACNA1C carriers with a yield of screening of 2.2%. Analysing the clinical phenotype of all CACNA1C carriers showed a significantly shorter QTc [371 ms ± 16 ms vs. 399±18 ms; p=0.000004]. Furthermore, the prevalence of CACNA1C variants was highest (12.9%) among patients with a QTc in the lowest quartile (QTc Conclusion We confirmed that CACNA1C variants are not a common cause of BrS, with a yield of screening of 2–5%. However, pathogenic variants are more frequent (12.5%) in patients with a shorter QTc, suggesting a genetic testing strategy in this subgroup of BrS patients. Furthermore, our data highlights the impact of robust functional studies to improve variant classification and reduce uncertainties. Funding Acknowledgement Type of funding source: None

Background and Aim: The Barthel Dyspnoea Index (BDi) is responsive to change in patients with chronic obstructive pulmonary disease (COPD). However, the minimum clinically important difference (MCID) has not been established. We aimed to identify the MCID for the BDi using anchor-based and distribution-based methods. Methods: In a retrospective analysis we assessed BDi before and after inpatient pulmonary rehabilitation in 2328 patients with COPD (1152 with chronic respiratory failure - CRF). The Medical Research Council (MRC) score was measured concurrently as anchors. We used receiver operating characteristic (ROC) curves, linear regression, and distribution-based methods to estimate the MCID for the BDi; we included only patients with paired BDi scores in the analysis. Results: The mean change for the whole group in BDi score with pulmonary rehabilitation was -10 (IQR -17 : -3; p Conclusions: The most conservative estimate of the MCID for the BDi is -9 points in patients with COPD and -12 in patients without CRF. This estimate could be useful in the clinical interpretation of BDi data, particularly in response to intervention studies.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Background: Progesterone receptor (PgR) negative breast cancer (BC) is an aggressive subtype with poor prognosis and reduced response to endocrine treatments. Several studies have suggested that androgen receptor (AR) expression is associated with a favorable tumor biology, longer recurrence free survival (RFS), and overall survival. In the literature no data exist regarding the role of AR expression in early stage estrogen receptor (ER)+/PgR– BCs. The aim of this study was to evaluate the prognostic role of AR expression in this setting. Patients and methods: This is a monocentric retrospective study in which 208 patients who underwent surgical intervention for ER+/PgR−/Human Epidermal growth factor Receptor 2 (HER2)– BC were included. The primary objective was to analyze the relationship between AR expression and RFS. Results: At a median follow-up of 77 months, 75 patients (36%) had a disease relapse (all sites included). AR expression was significantly higher in patients who did not relapse compared with those who relapsed with an impact on RFS (hazard ratio [HR] = 0.99, p = 0.025). Patients with AR expression ⩾80% had a lower risk of relapse compared with those with AR Conclusions: The results of this study support the potential prognostic role of AR in patients with ER+/PgR− BCs and may contribute to the identification of subgroups of high-risk patients.

The presented collection of data comprises of a set of 12 linear and nonlinear indices computed at different time scales and extracted from Fetal Heart Rate (FHR) traces acquired through Hewlett Packard CTG fetal monitors (series 1351A), connected to a PC. The sampling frequency of the recorded FHR signal is equal 2 Hz. The recorded populations consist of two groups of fetuses: 60 healthy and 60 Intra Uterine Growth Restricted (IUGR) fetuses. IUGR condition is a fetal condition defined as the abnormal rate of fetal growth. In clinical practice, diagnosis is confirmed at birth and may only be suspected during pregnancy. The pathology is a documented cause of fetal and neonatal morbidity and mortality. The described database was employed in a set of machine learning approaches for the early detection of the IUGR condition: “Integrating machine learning techniques and physiology based heart rate features for antepartum fetal monitoring” [1]. The added value of the proposed indices is their interpretability and close connection to physiological and pathological aspect of FHR regulation. Additional information on data acquisition, feature extraction and potential relevance in clinical practice are discussed in [1]. Keywords: Fetal heart rate monitoring, Cardiotocography, Intra uterine growth restricted, Physiology-based features, Multivariate analysis, Predictive analytics

Objective The study aimed to evaluate whether high-flow oxygen therapy (HFOT) during training was more effective than oxygen in improving exercise capacity in hypoxemic chronic obstructive pulmonary disease (COPD). Methods A total of 171 patients with COPD and chronic hypoxemia were consecutively recruited in 8 rehabilitation hospitals in a randomized controlled trial. Cycle-ergometer exercise training was used in 20 supervised sessions at iso inspiratory oxygen fraction in both groups. Pre- and post-training endurance time (Tlim), 6-minute walking distance (6MWD), respiratory and limb muscle strength, arterial blood gases, Barthel Index, Barthel Dyspnea Index, COPD Assessment Test, Maugeri Respiratory Failure questionnaire, and patient satisfaction were evaluated. Results Due to 15.4% and 24.1% dropout rates, 71 and 66 patients were analyzed in HFOT and Venturi mask (V-mask) groups, respectively. Exercise capacity significantly improved after training in both groups with similar patient satisfaction. Between-group difference in post-training improvement in 6MWD (mean: 17.14 m; 95% CI = 0.87 to 33.43 m) but not in Tlim (mean: 141.85 seconds; 95% CI = −18.72 to 302.42 seconds) was significantly higher in HFOT. The minimal clinically important difference of Tlim was reached by 47% of patients in the V-mask group and 56% of patients in the HFOT group, whereas the minimal clinically important difference of 6MWD was reached by 51% of patients in the V-mask group and 69% of patients in the HFOT group, respectively. Conclusion In patients with hypoxemic COPD, exercise training is effective in improving exercise capacity. Impact Statement The addition of HFOT during exercise training is not more effective than oxygen through V-mask in improving endurance time, the primary outcome, whereas it is more effective in improving walking distance.

Background and objectives Intrauterine Growth Restriction (IUGR) is a fetal condition defined as the abnormal rate of fetal growth. The pathology is a documented cause of fetal and neonatal morbidity and mortality. In clinical practice, diagnosis is confirmed at birth and may only be suspected during pregnancy. Therefore, designing an accurate model for the early and prompt identification of pathology in the antepartum period is crucial in view of pregnancy management. Methods We tested the performance of 15 machine learning techniques in discriminating healthy versus IUGR fetuses. The various models were trained with a set of 12 physiology based heart rate features extracted from a single antepartum CardioTocographic (CTG) recording. The reason for the utilization of time, frequency, and nonlinear indices is based on their standalone documented ability to describe several physiological and pathological fetal conditions. Results We validated our approach on a database of 60 healthy and 60 IUGR fetuses. The machine learning methodology achieving the best performance was Random Forests. Specifically, we obtained a mean classification accuracy of 0.911 [0.860, 0.961 (0.95 confidence interval)] averaged over 10 test sets (10 Fold Cross Validation). Similar results were provided by Classification Trees, Logistic Regression, and Support Vector Machines. A features ranking procedure highlighted that nonlinear indices showed the highest capability to discriminate between the considered fetal conditions. Nevertheless, is the combination of features investigating CTG signal in different domains, that contributes to an increase in classification accuracy. Conclusions We provided validation of an accurate artificially intelligence framework for the diagnosis of IUGR condition in the antepartum period. The employed physiology based heart rate features constitute an interpretable link between the machine learning results and the quantitative estimators of fetal wellbeing.

Background Currently, a major point of concern in the management of Inflammatory Bowel Diseases (IBD) is the absence of accurate and specific circulating biomarkers able to drive diagnosis in a timely and noninvasive manner. Aim of the present study was to explore blood biomarkers of IBD by coupling the targeted detection of circulating fibroblast activation protein (FAP), a recognized valuable marker of bowel lesion in IBD, and Raman spectroscopy (RS), a quick and label-free metabolomic technique that provides a real-time biochemical characterization of plasma samples without any previously known target. Methods Blood samples were collected from over 140 patients with IBD and 170 control subjects matched for gender and age. Isolated plasma was analysed by enzyme-linked immunosorbent assay for quantitative detection of circulating form of FAP. RS was performed on dry droplets of plasma, with the aim to decipher specific fingerprint of IBD in peripheral blood. A predictive model was built on FAP and Raman data separately, to determine specificity, sensitivity and accuracy of the two approaches in patients classification. Supervised multivariate model was applied on a subset of 203 patients to discriminate IBD and control subjects based on combined datasets. Results FAP levels were reduced in patients with IBD as compared to controls (p Conclusion RS and FAP dosage enable new discoveries in the biological fingerprint of IBD plasma and provide novel candidate biomarkers of IBD. Our preliminary results strongly suggest that novel blood-based approaches could represent a fast noninvasive way to triage patents with suspected IBD in first care diagnostic, to be applied prior to further specific evaluation.

Introduction: Automatic event detection (AED) of residual apnea-hypopnea index (AHI) by ventilators is a current practice in sleep and mechanical ventilation Units but this methodology has not been validated in an unselected population of OSA patients. Aim of the present study was to assess in a “real-life” condition the reliability of AED during PAP therapy by the in-built software compared to full polysomnography during follow-up. Methods: We enrolled 300 OSA patients (105 F; AHI 45.3 ± 27.8) already on Positive airway pressure (PAP) therapy: 53% of the patients were on CPAP while other modalities were used in the rest of the sample. Results: Overall, the built-in software identified residual obstructive AHI (AHIPAP) > 5, 10 or 15 in 18.7, 8.6 or 4.6% of patients, respectively. By using AHIPAP, 28.4% of patients were wrongly classified as “well controlled” despite a residual AHIPSG>5 (6% considering a residual AHIVENT >15); 7% of patients were classified as not controlled while AHIPSG was 15). Type of ventilation, ventilator parameters, adherence to treatment and level of baseline or follow-up Epworth Sleepiness Scale score were similar between groups. The sensitivity and positive predicted values were very low. Positive likelihood ratio appears adequate only for residual AHIPAP ≥10, but negative likelihood ratio was inconclusive for all the cut-off considered. Discussion: The results of the present study suggest a more cautious approach in the follow-up of OSA patients, since a protocol based only on AED detection and symptoms assessment may not be accurate especially for AHIPAP

Discussion about patients' end-of-life (E-o-L) preferences should be part of the routine practice. Using a semi-structured interview with a scenario-based decision, we performed a prospective multicentre study to elicit the patients' E-o-L preferences in very severe chronic obstructive pulmonary disease (COPD). We also checked their ability to retain this information and the respect of their decisions when they die. Forty-three out of ninety-one of the eligible patients completed the study. The choice of E-o-L practice was equally distributed among the three proposed options: endotracheal intubation (ETI), 'ceiling' non-invasive ventilation (NIV), and palliation of symptoms with oxygen and morphine. NIV and ETI were more frequently chosen by patients who already experienced them. ETI preference was also associated with the use of anti-depressant drugs and a low educational level, while a higher educational level and a previous discussion with a pneumologist significantly correlated with the preference for oxygen and morphine. Less than 50% of the patients retained a full comprehension of the options at 24 hours. About half of the patients who died in the follow-up period were not treated according to their wishes. In conclusion, in end-stage COPD more efforts are needed to improve communication, patients' knowledge of the disease and E-o-L practice.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS. This work was supported by the Ricerca Corrente funding scheme of the Italian Ministry of Health. Dr. Ortiz has received personal fees from Health in Code, SL. Dr. Monserrat is a shareholder in Health in Code, SL. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sí

Background:. The combination of surgery and postoperative radiotherapy allows for the most effective results with keloids. In this trial, surgery and intraoperative radiation therapy (IORT) technology were used—the hypothesis being that the earlier the application of postoperative radiotherapy, the better the wound healing evolution. Methods:. The study included 16 patients with 21 keloids. The keloids were radically excised and repaired with direct suture or local skin flaps. Collimated electron radiotherapy was applied within 45 minutes of surgery. The outcomes were assessed according to the modified Patient and Observer Scar Assessment Scale; the modified Vancouver Scar Scale; and the modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders. Results:. Recurrences were observed in one out of 16 patients, and in two out of 21 keloids (9.5%). The modified Patient and Observer Scar Assessment Scale demonstrated a statistically significant improvement in pain, itching, color, stiffness, thickness, and irregularity after the treatment. The modified Patient and Observer Scar Assessment Scale displayed a statistically significant improvement in the scar vascularity, pigmentation, thickness, and pliability after the treatment. The modified Vancouver Scar Scale demonstrated a statistically significant improvement in 90.48% of the scars after the treatment. The modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders demonstrated an improvement in erythema multiforme and skin pain across the whole sample, with a temporary hyperpigmentation in 19% of the scars after the treatment. Conclusion:. The combination of surgery and collimated electron radiotherapy with IORT technology demonstrated favorable results in 90.5% of the cases.

Lombardy was the first area in Italy to have an outbreak of coronavirus disease 19 (COVID-19) at the beginning of 2020. In this context, cancer has been reported as a major risk factor for adverse outcomes and death, so oncology societies have quickly released guidelines on cancer care during the pandemic. The aim of this study was to investigate the management of cancer patients and oncological treatments during the COVID-19 pandemic and to describe the containment measures performed in our outpatient clinic at Pavia (Lombardy). A comparison with the same period of the four previous years (2019, 2018, 2017, and 2016) was also performed. Using our electronic databases, we evaluated the number and characteristics of patients accessing the hospital for anticancer drug infusion from 24 February, 2020 to 30 April, 2020 and the number of radiological exams performed. Although a significant reduction in access for therapy was seen when compared with 2019 (2590 versus 2974, access rate ratio (ARR) = 0.85, p &lt, 0.001), no significant differences in access numbers and ARR was evident between 2020 and 2018, 2017, or 2016 (2590 versus 2626 (ARR = 0.07), 2660 (ARR = 0.99), and 2694 (ARR = 0.96), respectively, p &gt, 0.05). In 2020, 63 patients delayed treatment: 38% for &ldquo, pandemic fear&rdquo, 18% for travel restrictions, 13% for quarantine, 18% for flu syndrome other than COVID-19, and 13% for worsening of clinical conditions and death. Only 7/469 patients developed COVID-19. A significant reduction in radiological exams was found in 2020 versus all the other years considered (211 versus 360, 355, 385, 390 for the years 2020, 2019, 2018, 2017, and 2016, respectively, p &lt, 0.001). The low incidence of COVID-19 among our cancer patients, along with the hospital policy to control infection, enabled safe cancer treatment and a continuum of care in most patients, while a small fraction of patients experienced a therapeutic delay due to patient-related reasons.

Objectives: This study aims at the identification of the distribution of basal cell carcinomas (BCCs) in the auricle in correlation with the currently most credited sites of the embryonic fusion planes of the auricle. Methods: An overall number of 69 patients with 72 BCCs of the auricle were enrolled in the study over a period of 14 years, from June 2003 to October 2017. All the cases underwent medical preoperative digital photography and the specific location of each BCC was coded on an original full-size anatomical diagram of the auricle derived from the reports by Streeter, Wood-Jones, Park, Porter, and Minoux showing the currently most credited sites of the embryonic fusion planes arbitrarily featured as two 5-mm-wide ribbon-like areas: (1) the hyoid-mandibular fusion plane (HM-FP) running from the upper margin of the tragus toward the concha and then deflecting toward the lower margin of the tragus and (2) the free ear fold-hyoid fusion plane (FEFH-FP) running from the cranial-most portion of the helix to the mid-portion of the ascending helix. The latter fusion planes were comprehensively termed embryological fusion planes (EFP) while all of the remaining surface of the auricle was comprehensively termed non-fusion area (NFA). The surfaces of all of the latter areas were calculated using the ImageJ software. Results: According to our data, the greatest number of BCCs was observed within the currently most credited sites of the embryonic fusion planes of the auricle. The latter sites displayed a 12-fold increased tumor incidence in comparison with the remaining surface of the ear. Conclusions: A correspondence between the sites of onset of BCCs and the sites of merging and/or fusion of embryonal processes was demonstrated in the auricle. Therefore, the latter sites might be considered as high-risk areas for the development of a BCC. Such an evidence provides further support to the hypothesis of an embryological pathogenesis of BCC.

Background The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), also referred to as overlap syndrome (OS), is associated with a high rate of morbidity, COPD exacerbations and mortality. Treatment with continuous positive airway pressure (CPAP) has proven to significantly decrease the rate of these complications. However, data concerning the effect of CPAP on pulmonary function are scarce and conflicting. The aim of our study was to evaluate the effect of 1 year of CPAP treatment on arterial blood gases (ABGs) and pulmonary function tests in patients with OS and its potential relationship with the baseline severity of airway obstruction. A secondary aim was to search for predictors of changes in the evaluated parameters. Methods A retrospective study on a cohort of 92 patients (74 males) discharged from the Pulmonary Rehabilitation Unit of the Istituti Clinici Scientifici Maugeri in Pavia (Italy) from January 2013 to January 2016, with a diagnosis of OS and a prescription of CPAP, was conducted. Collected data at discharge were compared with 1-year follow-up data. Results After 1 year of CPAP, we observed the following: (I) a significant improvement in ABGs in all patients [median pO2 65.0 (59.0-70.0) vs. 71 (64.8-77.1) mmHg, pCO2 39.8 (36.2-43.5) vs. 38.3 (32.3-44.2) at baseline and after 1 year respectively, P

The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size.The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1,1 cm; G2, 1-2 cm; G3,3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI.The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P.0001, respectively) and in the G1 and G2 subgroups.The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.

Purpose The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. Patients and Methods We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. Results Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. Conclusion Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34+ cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P = .049) and blast transformation (BT)–free survival (76.7 months vs 261 months; P = .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio = 3.3; P = .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT.

Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (p=6x10-3 7 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 11 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (p=1.1×10-4 13 ). Pathway analysis implicated ascorbate and aldarate metabolism (p=9×10-6), and pentose and glucuronate interconversions (p=3×10-6 14 ) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

Background— Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function. Methods and Results— Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin–deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21). Conclusions— Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients.

Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury. Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R–like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34 + cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle. Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.

Among the scientific challenges posed by complex diseases with a strong genetic component, two stand out. One is unveiling the role of rare and common genetic variants; the other is the design of classification models to improve clinical diagnosis and predictive models for prognosis and personalized therapies. In this paper, we present a data fusion framework merging gene, domain, pathway and protein-protein interaction data related to a next generation sequencing epilepsy gene panel. Our method allows integrating association information from multiple genomic sources and aims at highlighting the set of common and rare variants that are capable to trigger the occurrence of a complex disease. When compared to other approaches, our method shows better performances in classifying patients affected by epilepsy.

In patients with chronic obstructive pulmonary disease, the coexistence of obstructive sleep apnea (overlap syndrome) is associated with a heavy health burden and treatment with continuous positive pressure ventilation (CPAP) has been shown to improve outcome. In a selected group of overlap patients admitted to our Division in the last 3 years, we evaluated the effects of CPAP therapy on respiratory function and arterial blood gases and, in case of amelioration, searched for predictors of improvement. 94 overlap patients (76 males, median age 66) were enrolled. At enrollment, stepwise logistic regression analysis, showed that a lower forced expiratory volume in one second (FEV1) and a baseline higher apnea-hypopnea index (AHI) were independent predictors of hypercapnia. In multivariate analysis, basal FEV1/VC was an independent predictive factor for severity of nocturnal oxygen desaturation, expressed as time spent with saturation 0.05). However, the FEV1 improvement after 1 year was significantly and inversely correlated with basal FEV1% (r=-0.36, p

AIMS/HYPOTHESIS: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.METHODS: We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).RESULTS: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p CONCLUSIONS/INTERPRETATION: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Background: The embryologic fusion planes might be related with the sites of onset of basal cell carcinoma (BCC), thus supporting an embryologic role for its pathogenesis. Methods: A study involving 495 patients with 627 BCCs of the head and neck was carried out over a period of 5 years by correlating the distribution of all BCCs with the sites of congenital clefts of the head and neck using (1) the original anatomic diagram of the Tessier classification of craniofacial clefts, (2) the anatomic diagram by Moore et al featuring the paths of the “hairline indicators” of craniofacial clefts that represent the cranial extensions of the Tessier classification, and (3) an anatomical diagram featuring the sites of congenital clefts of the neck. Results: The proportion of BCCs localized within a cleft site was significantly higher than those in the noncleft sites. The age of patients with BCCs localized within the Tessier cleft number 3 was the lowest among all cleft regions. Conclusions: A topographic correspondence between the sites of BCCs and the sites of congenital clefts was demonstrated in the head and neck. This evidence would support the hypothesis of an embryologic role for the pathogenesis of BCC. The existence of clusters of embryological stem cells in the sites of fusion and/or merging of embryonic processes might therefore be proposed. There may be special biology/physiology along these cleft lines that predispose BCC formation.

Bioinformatics, 29 (22), ISSN:1367-4803, ISSN:1460-2059

Skin cancers are the most common types of cancer and their incidence has shown an increase of ∼4 to 8% per year over the last 40 years. The majority of skin cancers (∼97%) are non-melanoma skin cancers, mainly represented by basal cell (80%) and squamous cell carcinomas (20%). The use of intra-operative frozen section remains controversial in the surgical treatment of non-melanoma skin cancer, being commonly considered an optional tool, the reliability and effectiveness of which remain questionable. A large retrospective study was conducted to examine 670 surgical excisions of non-melanoma skin cancers of the head and neck in 481 patients over a period of nine years, between May, 2002 and December, 2011, at the Plastic and Reconstructive Surgery Unit of the University of Pavia, Salvatore Maugeri Research and Care Institute, Pavia, Italy. Results demonstrated the paradoxical ineffectiveness of an intra-operative frozen section biopsy in pursuing higher rates of radical excision in non-melanoma skin cancers. Nevertheless, a more detailed analysis on the use of frozen sections focusing on the various anatomical sites of the body demonstrated a reverse trend in the eyelids and canthi, where a higher success rate (87.50 vs. 69.77%) in the surgical treatment of non-melanoma skin cancers was obtained with the use of an intra-operative frozen section biopsy. Results of the present study suggested that intra-operative frozen section biopsy be routinely used in the surgical treatment of nonmelanoma skin tumors involving the eyelids and canthi.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac conduction disorders affecting many people. Recent studies on sporadic cases of AF/AFL showed a significant association of the single nucleotide polymorphism rs2200733T with the disease, suggesting a genetic factor in the development of the disease. Objectives: To determine the association of rs2200733 with AF/AFL derived from an Italian population sample. Subjects: 78 patients with AF/AFL and 348 controls took part in the study. Design: Genetic case–control study. Results: The results indicate that there is a positive, significant association between the rs2200733 T allele and patients with AF/AFL of Italian origin (allelic p,0.001 with OR = 2.17). Conclusion: These results derived from a sample of the Italian population agree with previously reported findings from an Icelandic study, which also found that the minor allele rs2200733 was associated with AF/AFL disease. Cardiac conduction disorders may depend upon a variety of predisposing factors, including developmental and congenital defects, acquired injuries or ischaemia of the conduction system and rarely inherited genetic defects that alter the electrophysiological properties of the heart. Atrial fibrillation (AF) is the most common sustained arrhythmia (supraventricular tachyarrhythmia). 1 It is associated with increased cardiovascular morbidity and mortality and it is a leading cause of stroke. 2 Other predisposing disease states include diabetes mellitus, essential hypertension (EH), congestive heart failure, valvular disease and myocardial infarction. The electrophysiological mechanism underlying AF may include the following events: myocardial electrical conduction and structural remodelling, genetic changes, ectopic electrical activity within the pulmonary veins and oxidative stress of the cardiac tissue. 13 Thus, more than one mechanism may be involved in the onset of AF. AF and atrial flutter (AFL) are closely related. 4

Giovanni Nicoletti,1–3 Andrea Sasso,1 Alberto Malovini,4,5 Luisa Ponchio,6 Silvia Scevola,2 Angela Faga,1–3 Aldo Pontone1 1Plastic and Reconstructive Surgery, Department of Clinical Surgical Diagnostic and Pediatric Sciences, 2Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Centre, University of Pavia, Pavia, Italy; 3Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, Pavia, Italy; 4Department of Computer Engineering and Systems Science, University of Pavia, Pavia, Italy; 5Laboratory of Informatics and Systems Engineering for Clinical Research, 6Oncology Unit, Salvatore Maugeri Research and Care Institute, Pavia, Italy Abstract: A randomized, prospective, controlled study was carried out at the Plastic and Reconstructive Surgery Unit of the University of Pavia, Salvatore Maugeri Research and Care Institute, Pavia, Italy, to evaluate the psychological benefits from corrective medical camouflage (CMC) following surgical treatment for skin cancer of the face. Twenty-four female patients, following recovery from facial skin cancer surgery, were enrolled in the study over a period of 1 year. The study was performed using two health-related quality of life tests, the Satisfaction Profile (SAT-P) test and the Body Uneasiness Test (BUT). The patients were randomized into two groups: group A, patients undergoing CMC; and group B, controls. Both the SAT-P and BUT demonstrated statistically significant better results in the treated patients versus the controls in the following functional parameters: Psychological Functionality (PsF), Physical Functionality (PhF), and Work Performance (WP) for the SAT-P test and Compulsive Self-Monitoring (CSM) for the BUT. The PsF demonstrated a better result 6 months post-treatment. Such a difference was particularly significant when comparing the performance at 6 months versus that at 3 months. The PhF demonstrated a better outcome at 6 months post-treatment. The WP demonstrated a better result comparing the performance at 6 months versus that at 3 months. The CSM demonstrated a better outcome at 6 months post-treatment. The CMC promoted a significant improvement in patients' physical appearance and in their self-image and perceived social role as a means of their desire to disguise their body disfiguration. Keywords: plastic surgery, skin cancer, camouflage, quality of life, psychological assessment

Doppel (PRND) is a paralogue of the mammalian prion (PRNP) gene. It is abundant in testis and, unlike PRNP, it is expressed at low levels in the adult central nervous system (CNS). Besides, doppel overexpression correlates with some prion-disease pathological features, such as ataxia and death of cerebellar neurons. Recently, ectopic expression of doppel was found in two different tumor types, specifically in glial and haematological cancers. In order to address clinical important issues, PRND mRNA expression was investigated in a panel of 111 astrocytoma tissue samples, histologically classified according to the World Health Organization (WHO) criteria (6 grade I pilocytic astrocytomas, 15 grade II low-grade astrocytomas, 26 grade III anaplastic astrocytomas and 64 grade IV glioblastoma multiforme). Real-time PRND gene expression profiling, after normalisation with GAPDH, revealed large differences between low (WHO I and II) and high grade (III and IV) of malignancy (P

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore)