Azienda Ospedaliero-Universitaria di Modena

The definition presented here represents the first realistic attempt by the scientific community to standardize the definition of poor ovarian response (POR) in a simple and reproducible manner. POR to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for the diagnosis of POR. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal' criteria needed to select patients for future clinical trials, more homogeneous populations will be tested for any new protocols. Finally, by reducing bias caused by spurious POR definitions, it will be possible to compare results and to draw reliable conclusions.

BACKGROUND: A number of approaches have been used to grade levels of evidence and the strength of recommendations. The use of many different approaches detracts from one of the main reasons for having explicit approaches: to concisely characterise and communicate this information so that it can easily be understood and thereby help people make well-informed decisions. Our objective was to critically appraise six prominent systems for grading levels of evidence and the strength of recommendations as a basis for agreeing on characteristics of a common, sensible approach to grading levels of evidence and the strength of recommendations. METHODS: Six prominent systems for grading levels of evidence and strength of recommendations were selected and someone familiar with each system prepared a description of each of these. Twelve assessors independently evaluated each system based on twelve criteria to assess the sensibility of the different approaches. Systems used by 51 organisations were compared with these six approaches. RESULTS: There was poor agreement about the sensibility of the six systems. Only one of the systems was suitable for all four types of questions we considered (effectiveness, harm, diagnosis and prognosis). None of the systems was considered usable for all of the target groups we considered (professionals, patients and policy makers). The raters found low reproducibility of judgements made using all six systems. Systems used by 51 organisations that sponsor clinical practice guidelines included a number of minor variations of the six systems that we critically appraised. CONCLUSIONS: All of the currently used approaches to grading levels of evidence and the strength of recommendations have important shortcomings.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. METHODS: In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. RESULTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).

CV Cardiovascular CYP Cytochrome P (CYP) Unfractionated heparin ULN Upper limit of normal VENTURE-AF Active-controlled multi-center study with blind-adjudication designed to evaluate the safety of uninterrupted Rivaroxaban and uninterrupted vitamin K antagonists in subjects undergoing catheter ablation for non-valvular Atrial Fibrillation VHD Valvular heart disease VKA Vitamin K antagonist VTE Venous thromboembolic event WOEST What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary stenting X-VeRT Explore the efficacy and safety of once daily oral rivaroxaban for the prevention of cardiovascular events in patients with non-valvular atrial fibrillation scheduled for cardioversion a SmPC: 110 mg BID if age > _80 years, concomitant verapamil (both based on pharmacokinetics/pharmacodynamics analyses; not studied in this setting). b Not specifically studied, follow-up data available up to 12 months in phase III trial. c SmPc: 20 mg QD in patients at high risk of recurrence. 2021 EHRA Practical Guide on the use of NOACs AF, atrial fibrillation; CrCl, creatinine clearance; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; NSAID, non-steroidal anti-inflammatory drug; TIA, transient ischaemic attack; VKA, vitamin K antagonist. For frequency of visits: see Figure 3.

Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more focused definition allows for classification of patients into distinct prognostic and therapeutic subgroups for both clinical and research purposes. Ideally, individuals sharing a unique phenotype would also ultimately be determined to have a similar underlying biologic or physiologic mechanism(s) to guide the development of therapy where possible. It follows that any proposed phenotype, whether defined by symptoms, radiography, physiology, or cellular or molecular fingerprint will require an iterative validation process in which "candidate" phenotypes are identified before their relevance to clinical outcome is determined. Although this schema represents an ideal construct, we acknowledge any phenotype may be etiologically heterogeneous and that any one individual may manifest multiple phenotypes. We have much yet to learn, but establishing a common language for future research will facilitate our understanding and management of the complexity implicit to this disease.

For many years, hereditary hemochromatosis was regarded as a clinically and genetically unique entity marked by a classic presentation consisting of diabetes, bronze skin pigmentation, and cirrhosis. In 1996, identification of “the hemochromatosis gene,” HFE, was reported; since then, several other iron-metabolism genes have also been identified. This article reviews the current understanding and management of hereditary iron-overload disorders.

BACKGROUND: In women, anti-Müllerian hormone (AMH) levels may represent the ovarian follicular pool and could be a useful marker of ovarian reserve. The clinical application of AMH measurement has been proposed in the prediction of quantitative and qualitative aspects in assisted reproductive technologies (ART). In men AMH is secreted in both the serum and seminal fluid. Its measurement may be useful in clinical evaluation of the infertile male. METHODS: The PubMed database was systematically searched for studies published until the end of January 2009, search criteria relevant to AMH, ovarian reserve, ovarian response to gonadotrophin stimulation, spermatogenesis and azoospermia were used. RESULTS: AMH seems to be a better marker in predicting ovarian response to controlled ovarian stimulation than age of the patient, FSH, estradiol and inhibin B. A similar performance for AMH and antral follicular count has been reported. In clinical practice, AMH measurement may be useful in the prediction of poor response and cycle cancellation and also of hyper-response and ovarian hyperstimulation syndrome. In the male, the wide overlap of AMH values between controls and infertile men precludes this hormone from being a useful marker of spermatogenesis. CONCLUSIONS: As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing. Regarding the role of AMH in the evaluation of infertile men, AMH as single marker of spermatogenesis does not seem to reach a satisfactory clinical utility.

The coronavirus disease 2019 (COVID-19) pandemic is a scientific, medical, and social challenge. The complexity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is centered on the unpredictable clinical course of the disease that can rapidly develop, causing severe and deadly complications. The identification of effective laboratory biomarkers able to classify patients based on their risk is imperative in being able to guarantee prompt treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine mediated coagulation disorders as the principal actors of multi organ failure in patients with severe COVID-19 complications. The following biomarkers have been identified: hematological (lymphocyte count, neutrophil count, neutrophil-lymphocyte ratio (NLR)), inflammatory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT)), immunological (interleukin (IL)-6 and biochemical (D-dimer, troponin, creatine kinase (CK), aspartate aminotransferase (AST)), especially those related to coagulation cascades in disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). New laboratory biomarkers could be identified through the accurate analysis of multicentric case series; in particular, homocysteine and angiotensin II could play a significant role.

Abstract The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients’ T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1 + CD57 + exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4 + T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.

BACKGROUND AND AIM: The magnitude of the risk of incident type 2 diabetes (T2D) and metabolic syndrome (MetS) among patients with nonalcoholic fatty liver disease (NAFLD) is poorly known. We gauged the risk of developing T2D and MetS in patients with NAFLD diagnosed by either serum liver enzymes (aminotransferases or gamma-glutamyltransferase [GGT]) or ultrasonography. METHODS: Pertinent prospective studies were identified through extensive electronic database research, and studies fulfilling enrolment criteria were included in the meta-analysis. RESULTS: Overall, in a pooled population of 117020 patients (from 20 studies), who were followed-up for a median period of 5 years (range: 3-14.7 years), NAFLD was associated with an increased risk of incident T2D with a pooled relative risk of 1.97 (95% confidence interval [CI], 1.80-2.15) for alanine aminotransferase, 1.58 (95% CI, 1.43-1.74) for aspartate aminotransferase, 1.86 (95% CI, 1.71-2.03) for GGT (last vs first quartile or quintile), and 1.86 (95% CI, 1.76-1.95) for ultrasonography, respectively. Overall, in a pooled population of 81411 patients (from eight studies) who were followed-up for a median period of 4.5 years (range: 3-11 years), NAFLD was associated with an increased risk of incident MetS with a pooled relative risk of 1.80 (95% CI, 1.72-1.89) for alanine aminotransferase (last vs first quartile or quintile), 1.98 (95% CI, 1.89-2.07) for GGT, and 3.22 (95% CI, 3.05-3.41) for ultrasonography, respectively. CONCLUSIONS: Nonalcoholic fatty liver disease, as diagnosed by either liver enzymes or ultrasonography, significantly increases the risk of incident T2D and MetS over a median 5-year follow-up.

BACKGROUND: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. OBJECTIVES: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. MAIN RESULTS: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. AUTHORS' CONCLUSIONS: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. MAIN BODY: Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities. CONCLUSIONS: Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

BACKGROUND: Mechanisms purported to contribute to the pathophysiology of heart failure with normal ejection fraction (HFnlEF) include diastolic dysfunction, vascular and left ventricular systolic stiffening, and volume expansion. We characterized left ventricular volume, effective arterial elastance, left ventricular end-systolic elastance, and left ventricular diastolic elastance and relaxation noninvasively in consecutive HFnlEF patients and appropriate controls in the community. METHODS AND RESULTS: Olmsted County (Minn) residents without cardiovascular disease (n=617), with hypertension but no heart failure (n=719), or with HFnlEF (n=244) were prospectively enrolled. End-diastolic volume index was determined by echo Doppler. End-systolic elastance was determined using blood pressure, stroke volume, ejection fraction, timing intervals, and estimated normalized ventricular elastance at end diastole. Tissue Doppler e' velocity was used to estimate the time constant of relaxation. End-diastolic volume (EDV) and Doppler-derived end-diastolic pressure (EDP) were used to derive the diastolic curve fitting (alpha) and stiffness (beta) constants (EDP=alphaEDVbeta). Comparisons were adjusted for age, sex, and body size. HFnlEF patients had more severe renal dysfunction, yet smaller end-diastolic volume index and cardiac output and increased EDP compared with both hypertensive and healthy controls. Arterial elastance and ventricular end-systolic elastance were similarly increased in hypertensive controls and HFnlEF patients compared with healthy controls. In contrast, HFnlEF patients had more impaired relaxation and increased diastolic stiffness compared with either control group. CONCLUSIONS: From these cross-sectional observations, we speculate that the progression of diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure: Conversion to objectively defined secondary progressive MS. Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

UNLABELLED: The use of tissue engineering for cartilage repair has emerged as a potential therapeutic option and has led to the development of Hyalograft C, a tissue-engineered graft composed of autologous chondrocytes grown on a scaffold entirely made of HYAFF 11, an esterified derivative of hyaluronic acid. Here we present the results of an ongoing multicenter clinical study conducted with the primary objective to investigate the subjective symptomatic, functional and health-related quality of life outcomes of patients treated with Hyalograft C. Clinical results on the cohort of 141 patients with followup assessments ranging from 2 to 5 years (average followup time: 38 months), are reported. At followup 91.5% of patients improved according to the International Knee Documentation Committee subjective evaluation; 76% and 88% of patients had no pain and mobility problems respectively assessed by the EuroQol-EQ5D measure. Furthermore, 95.7% of the patients had their treated knee normal or nearly normal as assessed by the surgeon; cartilage repair was graded arthroscopically as normal or nearly normal in 96.4% of the scored knees; the majority of the second-look biopsies of the grafted site histologically were assessed as hyaline-like. Importantly, a very limited complication rate was recorded in this study. The positive clinical results obtained indicate that Hyalograft C is a safe and effective therapeutic option for the treatment of articular cartilage lesions. LEVEL OF EVIDENCE: Therapeutic study, Level III-2 (retrospective cohort study). See the Guidelines for Authors for a complete description of levels of evidence.

Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests) and is used to justify preprocedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet count), and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR &gt;1.8 and/or platelet count &lt;50 × 10 9 /L) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG‐guided transfusion strategy or standard of care (SOC; 1:1 TEG:SOC). The TEG group would receive FFP if the reaction time (r) was &gt;40 min and/or PLT if maximum amplitude (MA) was &lt;30 mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions versus 5 in the TEG group (100% vs. 16.7%; P &lt; 0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone ( P &lt; 0.0001 vs. SOC), 2 received PLT (6.7%; P = 0.009 vs. SOC), and 3 both FFP and PLT (not significant). Postprocedure bleeding occurred in only 1 patient (SOC group) after large‐volume paracentesis. Conclusions : In patients with cirrhosis and significant coagulopathy before invasive procedures, TEG‐guided transfusion strategy leads to a significantly lower use of blood products compared to SOC (transfusion guided by INR and platelet count), without an increase in bleeding complications. Remarkably, even in patients with significant coagulopathy, postprocedure bleeding was rare, indicating that TEG thresholds should be reevaluated. (H epatology 2016;63:566–573)

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.