Search

Donor selection may contribute to improve clinical outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy). Impact of second-degree related donor (SRD) was not fully elucidated in this platform. We retrospectively compared the outcome of patients receiving Haplo-SCT either from a SRD (n = 31) or a first-degree related donor (FRD, n = 957). Median time to neutrophil and platelet recovery did not differ between a SRD and a FRD transplant (p = 0.599 and 0.587). Cumulative incidence of grade II-IV acute graft-versus host disease (GVHD) and moderate-severe chronic GVHD was 13% and 19% after SRD vs 24% (p = 0.126) and 13% (p = 0.395) after FRD transplant. One-year cumulative incidence of non-relapse mortality (NRM) was 19% for SRD and 20% for FRD (p = 0.435) cohort. The 3-year probability of overall survival (OS) and progression-free survival (PFS) was 42% vs 55% (p = 0.273) and 49% vs 35% (p = 0.280) after SRD and FRD transplant, respectively. After propensity score adjustment or matched pair analysis, the outcome of patients receiving Haplo-SCT from a SRD or a FRD did not differ in terms of NRM, OS, PFS, acute and chronic GVHD. Our results suggest that a SRD is a viable option for Haplo-SCT with PT-Cy when a FRD is not available.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal, not malignant, hematological disease characterized by intravascular hemolysis, thrombophilia and bone marrow failure. While this latter presentation is due to a T-cell mediated auto-immune disorder resembling acquired aplastic anemia, the first two clinical presentations are largely driven by the complement pathway. Indeed, PNH is characterized by a broad impairment of complement regulation on affected cells, which is due to the lack of the complement regulators CD55 and CD59. The deficiency of these two proteins from PNH blood cells is due to the somatic mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene causing the disease, which impairs the surface expression of all proteins linked via the glycosylphosphatidylinositol anchor. The lack of the complement regulators CD55 and CD59 on PNH erythrocytes accounts for the hallmark of PNH, which is the chronic, complement-mediated intravascular hemolysis. This hemolysis results from the impaired regulation of the alternative pathway upstream in the complement cascade, as well as of the downstream terminal pathway. PNH represented the first indication for the development of anti-complement agents, and the therapeutic interception of the complement cascade at the level of C5 led to remarkable changes in the natural history of the disease. Nevertheless, the clinical use of an inhibitor of the terminal pathway highlighted the broader derangement of complement regulation in PNH, shedding light on the pivotal role of the complement alternative pathway. Here we review the current understanding of the role of the alternative pathway in PNH, including the emergence of C3-mediated extravascular hemolysis in PNH patients on anti-C5 therapies. These observations provide the rationale for the development of novel complement inhibitors for the treatment of PNH. Recent preclinical and clinical data on proximal complement inhibitors intercepting the alternative pathway with the aim of improving the treatment of PNH are discussed, together with their clinical implications which are animating a lively debate in the scientific community.

Reduced intensity conditionings (RIC) before after allogeneic hematopoietic stem cell transplantation (HSCT) allow older or unfit patients of being transplanted, but survival expectancy and burden of late complications are poorly described in this setting. All patients (N = 456) who were alive and relapse-free 2 years after HSCT following RIC were included. Cumulative incidences (CI), standardized incidence, or mortality, ratio (SIR or SMR), and competing risk models were used. The 10-year CIs of relapse and non-relapse mortality incidences were 13.9 and 13.4%, respectively. Seventy-eight patients died, late relapse being the most frequent cause of death leading to a SMR of 6.38 (95% CI, 5.1-8.0; p 0.001). Among non-relapsing patients (n = 412), 30 died (SMR 4.38; 95% CI, 3.3-5.8: p 0.001). A total of 37 patients developed 41 SM leading to a 10-year cumulative incidence of 12.9%, and a significant SIR relative to the general population (1.4). Finally, we found high CI of cardiovascular (CVC) and venous thromboembolic complications (VTE) (10-year CI; 15.1% and 11.7%, respectively). Older age was the only significant risk factor for CVC and VTE in multivariable analysis. In conclusion, with life expectancy rate of 70%, late survivors after RIC warrants long-term follow-up and active intervention on averting cardiovascular disease and screening cancers.

Not available.

When there is a predictive biomarker, enrichment can focus the clinical trial on a benefiting subpopulation. We describe a two-stage enrichment design, in which the first stage is designed to efficiently estimate a threshold and the second stage is a "phase III-like" trial on the enriched population. The goal of this paper is to explore design issues: sample size in Stages 1 and 2, and re-estimation of the Stage 2 sample size following Stage 1. By treating these as separate trials, we can gain insight into how the predictive nature of the biomarker specifically impacts the sample size. We also show that failure to adequately estimate the threshold can have disastrous consequences in the second stage. While any bivariate model could be used, we assume a continuous outcome and continuous biomarker, described by a bivariate normal model. The correlation coefficient between the outcome and biomarker is the key to understanding the behavior of the design, both for predictive and prognostic biomarkers. Through a series of simulations we illustrate the impact of model misspecification, consequences of poor threshold estimation, and requisite sample sizes that depend on the predictive nature of the biomarker. Such insight should be helpful in understanding and designing enrichment trials.

The treatment of paroxysmal nocturnal hemoglobinuria (PNH) was revolutionized by the introduction of the anti-C5 agent eculizumab, which resulted in sustained control of intravascular hemolysis, leading to transfusion avoidance and hemoglobin stabilization in at least half of all patients. Nevertheless, extravascular hemolysis mediated by C3 has emerged as inescapable phenomenon in PNH patients on anti-C5 treatment, frequently limiting its hematological benefit. More than 10 years ago we postulated that therapeutic interception of the complement cascade at the level of C3 should improve the clinical response in PNH. Compstatin is a 13-residue disulfide-bridged peptide binding to both human C3 and C3b, eventually disabling the formation of C3 convertases and thereby preventing complement activation via all three of its activating pathways. Several generations of compstatin analogs have been tested in vitro, and their clinical evaluation has begun in PNH and other complement-mediated diseases. Pegcetacoplan, a pegylated form of the compstatin analog POT-4, has been investigated in two phase I/II and one phase III study in PNH patients. In the phase III study, PNH patients with residual anemia already on eculizumab were randomized to receive either pegcetacoplan or eculizumab in a head-to-head comparison. At week 16, pegcetacoplan was superior to eculizumab in terms of hemoglobin change from baseline (the primary endpoint), as well as in other secondary endpoints tracking intravascular and extravascular hemolysis. Pegcetacoplan showed a good safety profile, even though breakthrough hemolysis emerged as a possible risk requiring additional attention. Here we review all the available data regarding this innovative treatment that has recently been approved for the treatment of PNH.

En este capítulo se destacan algunas experiencias significativas de la región, recogidas de diferentes autores, que se han desarrollado para construir y ampliar la educación intercultural participativa y dialógica, a partir de la problematización del sistema educativo general y las reflexiones a las que conduce esta mirada problematizadora. Con los casos presentados, reflexionamos no solo sobre la importancia de una construcción educativa participativa para los PICL, sino también que el conocimiento es una forma de comunicación e incidencia política que puede ayudar en sus luchas por garantizar sus derechos y gobernabilidad.

Sleep disturbances often result from inappropriate lifestyles, incorrect dietary habits, and/or digestive diseases. This clinical condition, however, has not been sufficiently explored in this area. Several studies have linked the circadian timing system to the physiology of metabolism control mechanisms, energy balance regulation, and nutrition. Sleep disturbances supposedly trigger digestive disorders or conversely represent specific clinical manifestation of gastrointestinal (GI) diseases. Poor sleep may worsen the symptoms of GI disorders, affecting the quality of life. Conversely, short sleep may influence dietary choices, as well as meal timing, and the circadian system drives temporal changes in metabolic patterns. Emerging evidence suggests that patients with inappropriate dietary habits and chronic digestive disorders often sleep less and show lower sleep efficiency, compared with healthy individuals. Sleep disturbances may thus represent a primary symptom of digestive diseases. Further controlled trials are needed to fully understand the relationship between sleep disturbances, dietary habits, and GI disorders. It may be also anticipated that the evaluation of sleep quality may prove useful to drive positive interventions and improve the quality of life in a proportion of patients. This review summarizes data linking sleep disorders with diet and a series of disease including gastro-esophageal reflux disease, peptic disease, functional gastrointestinal disorders, inflammatory bowel diseases, gut microbiota alterations, liver and pancreatic diseases, and obesity. The evidence supporting the complex interplay between sleep dysfunction, nutrition, and digestive diseases is discussed.

Steroid-refractory graft versus host disease (GVHD) represents a fearsome complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective study on outcomes and risk factors associated with acute and chronic steroid-refractory GVHD in a large cohort of 1207 patients receiving HSCT in Saint Louis Hospital between 2007 and 2017. Among patients who developed an acute and/or a chronic GVHD, the cumulative incidences of acute and chronic steroid-refractory disease were 31% and 48%, respectively, at day +100 and 1-year post-HSCT. Through a multivariable analysis we selected several risk factors associated with the development of a steroid-refractory disease. For acute GVHD steroid refractoriness, we identified (1) a very high disease risk index, (2) an unrelated donor, (3) the absence of in vivo T-depletion as GVHD prophylaxis, and (4) a reduced intensity conditioning regimen. For chronic GVHD, (1) the use of peripheral blood stem cells, (2) unrelated donors, and (3) absence of in vivo T-depletion were more likely associated with a steroid-refractory disease. After the construction of a multistate dynamic model, we found that the probability of being alive without relapse after the resolution of all GVHD episodes was about 36% in the long term.

About 50% of Crohn’s Disease (CD) patients undergo an intestinal resection during their lifetime. Although the patients experience a fairly long period of well-being after the intestinal resection, they presented a postoperative recurrence (POR) in 40% of cases within 5 years. In this case series, we aimed to evaluate the incidence of POR in CD patients with high risk for early POR, prophylactically treated with Vedolizumab. All consecutive CD patients (followed from 2017 to 2020) who underwent ileocolonic resection after the loss of response at anti-Tumor Necrosis Factor α (anti-TNFα) and with one or more risk factors for early POR were included. POR was defined as a Rutgeerts score (Ri) > 1 at the colonoscopic evaluation. All the included patients underwent a Magnetic resonance enterography (MRE) at least one year after the surgical resection. Six patients (4 Female; 2 Males) were included. At the first endoscopic evaluation, all patients were in endoscopic remission (5 patients Ri 0; 1 patient Ri 1). No stenosis nor other intestinal wall changes or complications were observed at MRE. Five patients underwent colonoscopy over two years of follow-up (median: 32 months; range 25–33). The Ri score was 0 in four patients, while the fifth patient showed severe endoscopic relapse. The same patient presented a clinical relapse (Harvey-Bradshaw index = 10) with a flare of disease in the colonic mucosa. These data suggest that early post-operative treatment with Vedolizumab could be a valuable strategy to be submitted to a prospective controlled trial for preventing POR.

Prevalence and incidence of Atrial Fibrillation (AF) is high in western countries. It is apparently lower in developing countries, because of unrecognition, undertreatment and related complications and mortality. Studies in subjects wearing cardiac implantable electronic devices showed a wide burden of AF, ranging from subclinical episodes to permanent AF. The aim of our study was to identify haematological and haemodynamic differences between Paroxysmal Atrial Tachyarrhythmias (PAT) compared to Non-Paroxysmal AF (NPAF), detected by 24 hours Holter ECG, and predictive negative factors associated with increased risk of evolution from paroxysmal to persistent or permanent AF. Our data highlight the dynamic nature of PAT and NPAF. PAT in young subjects is a red flag, requiring at least changes in lifestyle and further diagnostic examinations to avoid progression to irreversible pathological myocardial electrical and structural remodeling. Comorbidities, scarce compliance, or inappropriate treatments account for high incidence of acute cerebrovascular events with disabling outcomes in elderly patients. Further studies are needed on genetic susceptibility and vulnerability. Educational campaign is the most effective, long- term strategy. Personalized approach and therapeutical scheme are recommended based on patient compliance and actual risk. A holistic approach to patient is the pillar for any clinical decision and practice.

Eculizumab, the first anti-C5 monoclonal antibody approved for patients with paroxysmal nocturnal hemoglobinuria (PNH), has revolutionized the natural history of this disease, blocking intravascular hemolysis, reducing the risk of thromboembolic events, resulting in a significant improvement in survival and quality of life. However, the hematological response to eculizumab is extremely heterogeneous, with only one-third of PNH patients reaching normal hemoglobin levels.This article reviews the current new drugs being investigated in phase II and III trials for adult PNH patients. Literature search was performed using Medline and Clinicaltrials.org databases.The new molecules have been classified according to the target of the complement system on which they act; we have novel terminal complement inhibitors, which target C5, and proximal complement inhibitors, which interfere with C3 or even further upstream (factor B and D). Ravulizumab is the first next-generation C5 inhibitor, approved by FDA and EMA, which reproduced the excellent results achieved with eculizumab, trying to improve the convenience of patients. However, unresolved issues remain, such as C3-mediated extravascular hemolysis, on which novel proximal complement inhibitors are showing their efficacy. Pegcetacoplan is the first C3-inihibitor approved by FDA. Long-term safety data for novel complement inhibitors are needed.

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

Multi-arm clinical trials are complex experiments which involve several objectives. The demand for unequal allocations in a multi-treatment context is growing and adaptive designs are being increasingly used in several areas of medical research. For uncensored and censored exponential responses, we propose a constrained optimization approach in order to derive the design maximizing the power of the multivariate test of homogeneity, under a suitable ethical constraint. In the absence of censoring, we obtain a very simple closed-form solution that dominates the balanced design in terms of power and ethics. Our suggestion can also accommodate delayed responses and staggered entries, and can be implemented via response adaptive rules. While other targets proposed in the literature could present an unethical behavior, the suggested optimal allocation is frequently unbalanced by assigning more patients to the best treatment, both in the absence and presence of censoring. We evaluate the operating characteristics of our proposal theoretically and by simulations, also redesigning a real lung cancer trial, showing that the constrained optimal target guarantees very good performances in terms of ethical demands, power and estimation precision. Therefore, it is a valid and useful tool in designing clinical trials, especially oncological trials and clinical experiments for grave and novel infectious diseases, where the ethical concern is of primary importance.

Most industrial processes are composed of multiple subsequent steps. In this article, we provide a statistical approach to design experiments and to define the manufacturing design space of multi-step processes by taking into account the complex system of interactions among steps. We consider each intermediate outcome as an additional input factor in the next step and we plan experiments following a particular sequential structure. To encompass the potential deviations from the target levels of such input factors, designs are selected according to the D-optimality in average criterion and, in order to assess their prediction capabilities, a suitable extension of the fraction of design space technique has been proposed. The manufacturing design space of the process is then defined by combining the interconnected manufacturing design spaces of the process steps and by deriving the linear combination of the process inputs that ensures the required quality standard for the final outcome. Appealing properties of this approach are also shown by the application to a three-steps biochemical process of expression and purification of a recombinant protein in which 10 input factors are included in the design.

This paper develops a unified framework for deriving optimal designs for hypothesis testing in the presence of several heteroscedastic groups. In particular, the obtained optimal designs are generalized Neyman allocations involving only two experimental groups. In order to account for the ordering among the treatments, particularly relevant in the clinical context for ethical reasons, we provide the optimal design for testing under constraints reflecting their effectiveness. The advantages of the suggested allocations are illustrated both theoretically and through several numerical examples, also compared with other designs proposed in the literature, showing a substantial gain in terms of both power and ethics.

Persistent cytopenia due to poor graft function (PoGF) is a relatively common complication which may affect up to 20% of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Treatment options for PoGF remain limited, and reinfusion of additional HSC is often the only way to rescue hematopoiesis. Here we describe a retrospective single-center experience with the thrombopoietin-mimetic agent eltrombopag for the treatment of PoGF. Thirteen patients have received eltrombopag for either PoGF (n = 12) or primary graft failure (n = 1). In the 12 PoGF patients eltrombopag was started at the median time of 79 days after HSCT, due to persistent thrombocytopenia, with concomitant anemia and neutropenia in 7 and 3 patients, respectively. The treatment was started at the dose of 50 mg per day, and eventually increased up to 150 mg in case of lack of response. Hematological response was seen in 7 patients, with 6 complete responses. Hematological responses were seen both in patients with evidence of immune-mediated pathophysiology, and with possible infectious/iatrogenic causes. In responding patients, eltrombopag was discontinued in 6/7 patients without further relapse. These results suggest that eltrombopag is safe and possibly effective in the setting of the treatment of PoGF, and pave the way for future prospective studies.

This chapter aims to give visibility to participatory intercultural education experiences across the Amazon region. It starts with an examination of the issues with the general educational system, and then presents case studies which offer different paths forward. These case studies reflect not only the importance of participatory education for IPLCs, but also how knowledge is itself a form of communication and political influence that helps IPLCs guarantee their rights.

Background and study aims Functional dyspepsia is an exclusion diagnosis requiring different tests, including endoscopy , often repeated over time. Duodenal biopsies are frequently resorted to, not rarely revealing duodenal microscopic inflammation. Aim of the study is to confirm a previously supposed role of antro-duodenal low-grade inflammation in functional dyspepsia, evaluating the frequency of duodenal lymphocytosis , H. pylori infection and their association in a group of patients with functional dyspepsia compared to asymptomatic control subjects. Patients and methods A cross-sectional, observational study has been conducted screening all the patients who underwent duodenal biopsies during upper endoscopy, in a 30 months period. All the patients without endoscopic lesions were analysed. The study group consisted of patients compatible with the diagnosis of functional dyspepsia (Rome III criteria). The control group consisted of healthy asymptomatic subjects in the population subjected to endoscopy. The presence of duodenal lymphocytosis and of H. pylori infection in the two groups was evaluated. Results 216 patients were enrolled: 161 in the functional dyspepsia group and 55 as asymptomatic control group. The frequency of duodenal lymphocytosis was similar between cases and control groups (25.47% vs 25.45%; p = 0.99), as well as H. pylori infection (26.71% vs 23.64%; p = 0.78). Duodenal lymphocytosis was significantly associated with functional dyspepsia only in H. pylori positive dyspeptic patients (p = 0.047). 94% of the subjects with both lymphocytosis and H. pylori infection suffer from dyspepsia. Duodenal intraepithelial lymphocytosis is significantly associated with bloating (p = 0.0082). Conclusions In our cohort of dyspeptic patients, duodenal lymphocytosis is significantly associated with bloating and the simultaneous presence of duodenal lymphocytosis and H. pylori infection is significantly more prevalent than in control subjects.

Ulcerative colitis (UC) still has no definitive cure since its etiology remains unclear. In recent years, considerable progress has been made with regard to our knowledge of the pathogenesis of UC. Advances in biotechnology have led to the development of biologic therapies which selectively target single key mediators or receptors involved in the pathogenesis of the disease - ie, tumor necrosis factor (TNF)-α, integrin, interleukins 12/23. Biologic therapies caused a revolution in the treatment of UC, providing specific options for patients refractory to conventional treatment. In recent years, antibodies anti-TNFα and anti-integrin have shown efficacy in improving the course and prognosis of ambulatory patients with moderate-to-severe UC. Nevertheless, whether biologics have brought so many benefits also for hospitalized patients with acute severe UC is still debated. Acute severe UC is a potentially life-threatening condition that affects up to 25% of patients during the course of their disease. It requires hospital admission due to the risk of complications and death, and it can necessitate urgent colectomy. Major adverse outcomes of acute severe UC are mortality and colectomy. The aim of this systematic review of the literature was to analyze the impact of biologics, in particular infliximab, on the course and prognosis of acute severe UC. Mortality and colectomy rates were considered as outcome measures.

In this thesis, we deal with the design of experiments in the drug development process, focusing on the design of clinical trials for treatment comparisons (Part I) and the design of preclinical laboratory experiments for proteins development and manufacturing (Part II). In Part I we propose a multi-purpose design methodology for sequential clinical trials. We derived optimal allocations of patients to treatments for testing the efficacy of several experimental groups by also taking into account ethical considerations. We first consider exponential responses for survival trials and we then present a unified framework for heteroscedastic experimental groups that encompasses the general ANOVA set-up. The very good performance of the suggested optimal allocations, in terms of both inferential and ethical characteristics, are illustrated analytically and through several numerical examples, also performing comparisons with other designs proposed in the literature. Part II concerns the planning of experiments for processes composed of multiple steps in the context of preclinical drug development and manufacturing. Following the Quality by Design paradigm, the objective of the multi-step design strategy is the definition of the manufacturing design space of the whole process and, as we consider the interactions among the subsequent steps, our proposal ensures the quality and the safety of the final product, by enabling more flexibility and process robustness in the manufacturing.

Este estudio parte de la experiencia profesional y de práctica en Psicología de la Universidad Externado de Colombia en el acompañamiento y formación a siete docentes de dos instituciones educativas en el municipio de Carmen de Bolívar (departamento de Bolívar), en el año 2018. El objetivo general de esta investigación consistió en develar, a través de la sistematización de experiencias pedagógicas desarrollada por los docentes, cómo se reconstruyen los vínculos sociales y el tejido social por medio de la implementación de proyectos pedagógicos territoriales en las aulas, y cómo esta experiencia constituye una apuesta por la construcción de política pública desde la base. Los resultados dan cuenta de una oportunidad para el fortalecimiento de vínculos con el territorio, entre docentes y estudiantes, con los saberes propios y con la educación en sí misma a través de transformaciones curriculares que permiten incorporar los saberes, prácticas y recursos del territorio en las lógicas escolares. Esto se entiende como una propuesta de construcción de política pública en educación a través de la sistematización de experiencias realizada por los docentes para visibilizar el currículo en acción en los procesos formales de diseño curricular desarrollado por las instituciones educativas. The starting point of the following study is the experience that we performed in 2018 as a team composed of both professionals and interns of the Psychology’s Faculty of Externado de Colombia University, providing support and training to seven school teachers working in educational institutions located in the municipality of El Carmen de Bolívar, in Bolivar department. The main objective of this research was to unveil through a systematization of experiences made by teachers, how social bonds are restored when pedagogical projects rooted in a local perspective are implemented in the classroom and how this experience becomes a means to develop public educational policies in a participatory fashion. The findings demonstrate the existence of opportunities to strengthen bonds that teachers and students build among them, with the territory, with their knowledge and with the education itself through creating curricular transformations which allow the inclusion of practical expertise and resources from the territory into the school logics. Thus, this research is understood as a proposal to contribute in the development of public policies in the education sector, through the systematization of experiences carried out by teachers, so that the in-action curriculum can appear more visible when educational institutions are developing formal processes of curriculum design.

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.

Kein CA

The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn’s disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients’ colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships.

The haematological benefit of standard-of-care anti-C5 treatment for haemolytic paroxysmal nocturnal haemoglobinuria is limited by residual intravascular haemolysis or emerging C3-mediated extravascular haemolysis. Therefore, the aim of this phase 2 study was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics, and activity of the new complement factor B inhibitor, iptacopan, in patients with paroxysmal nocturnal haemoglobinuria who have active haemolysis despite anti-C5 therapy.In this multicentre, open-label, single-arm, phase 2 trial, we enrolled adult patients (aged 18-80 years) with paroxysmal nocturnal haemoglobinuria who showed signs of active haemolysis despite receiving eculizumab treatment. Patients were enrolled at Federico II University Hospital (Naples, Italy), Hôpital Saint-Louis (Paris, France), and University Hospital Essen (Essen, Germany). For enrolment, patients were required to show lactate dehydrogenase more than 1·5-times the upper limit of normal and a paroxysmal nocturnal haemoglobinuria type 3 erythrocyte or granulocyte clone size of 10% or greater. Patients with bone marrow failure, on systemic steroid or immunosuppressive drugs, or with severe comorbidities were excluded from the study. Iptacopan was given orally as an add-on therapy at a dose of 200 mg twice daily. The primary endpoint was the effect of iptacopan on the reduction of chronic residual intravascular haemolysis measured as change in lactate dehydrogenase from baseline value to week 13. At 13 weeks, patients could opt into a long-term study extension (ongoing), allowing for modifications of standard treatment. This trial is registered at ClinicialTrials.gov, NCT03439839.Between May 31, 2018, and April 9, 2019, ten patients had twice daily 200 mg iptacopan. Iptacopan resulted in marked reduction of lactate dehydrogenase from baseline versus at week 13 (mean 539 IU/L [SD 263] vs 235 IU/L [44], change from baseline -309·2 IU/L [SD 265·5], 90% CI -473·77 to -144·68, p=0·0081), associated with significant improvement of haemoglobin concentrations (mean 97·7 g/L [SD 10·5] vs 129·5 g/L [18·3] change from baseline 31·9 g/L [14·5], 90% CI 23·42-40·28, p0·0001). All biomarkers of haemolysis improved on iptacopan treatment. Observed haematological benefits were maintained longer than the 13-week study period, throughout the study extension, including seven patients who stopped concomitant standard-of-care treatment and continued iptacopan as monotherapy. There were no deaths or treatment-related serious adverse events during the study period. Of three non-related serious adverse events, two occurred in the same patient (one during run-in and before exposure to iptacopan).Iptacopan at a chronic dose of 200 mg twice daily was well tolerated without any major drug-related safety findings and shows lactate dehydrogenase reduction and haemoglobin normalisation in most patients with paroxysmal nocturnal haemoglobinuria at week 13 and beyond, even in monotherapy. On the basis of these data, iptacopan will be tested as monotherapy in pivotal trials investigating its haematological benefit in a broader paroxysmal nocturnal haemoglobinuria population.Novartis Institutes for Biomedical Research.

Donor selection contributes to improve clinical outcomes of T-cell–replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

La presente publicación es producto de las investigaciones finalizadas en el marco de la Cátedra Unesco “Derechos Humanos y violencia: gobierno y gobernanza”, de la Universidad Externado de Colombia. Está compuesta por nueve capítulos que abordan temáticas relevantes como la justicia, el medio ambiente, la educación, el turismo y la memoria histórica, como medios para la restauración de los vínculos rotos de la sociedad colombiana. Este libro busca que se escuchen las voces de las personas que han sido víctimas del desplazamiento forzado o que están en condiciones de vulnerabilidad. A partir de las diferentes experiencias de agenciamiento se quiere contribuir a la construcción de instrumentos normativos y de política pública que permitan ampliar las definiciones sobre verdad, justicia, reparación y garantías de no repetición, bajo una perspectiva restaurativa. Esta perspectiva restaurativa permite visibilizar los diálogos que se han llevado a cabo entre los distintos participantes e identifica puntos en consenso entre las necesidades y las expectativas de la población en condiciones de vulnerabilidad y las expectativas institucionales y normativas. En este sentido, se resalta la necesidad de reconocimiento de las capacidades y recursos que desarrolla esta población desde sus entornos para avanzar hacia la transformación social, la garantía de derechos y la construcción de paz.

Esta propuesta parte de ejercicios prácticos de estudiantes de vii semestre de Psicología de la Universidad Externado de Colombia, que se desarrollaron entre 2015 y 2018 en el municipio de Soacha, y que establecen un puente entre las dinámicas intersubjetivas de la población de tres colegios del municipio, incluyendo 3.407 niños entre los 11 y los 16 años, 33 maestros, 127 estudiantes universitarios y nosotras, sus docentes. El objetivo general de esta investigación fue explorar desde la psicología cultural y la metodología de la investigación-acción en educación de qué manera se expresan y potencian los saberes de cada uno de los agentes involucrados alrededor de los procesos formativos en el aula, como escenarios de reconocimiento del otro, de sus trayectorias, territorios y de sus singularidades y potencialidades para conocer y transformar sus espacios vitales. Los resultados de esta indagación dan cuenta de una oportunidad para el trabajo de restitución de vínculos desde una perspectiva que recupere la vida cotidiana y el territorio como escenarios para la construcción de aprendizajes significativos, transformadores de dinámicas marcadas por la carencia, el sin sentido y la violencia. Esto requiere de una mirada sobre la diversidad/singularidad capaz de dialogar con las experiencias de los sujetos más allá del enfoque diferencial privilegiado en los últimos tiempos, que, aunque ha permitido grandes avances, ahora corre el peligro de reducirse a un lugar común. This proposal is based on practical experiences of 7th-semester students enrolled in the Psychology Degree Program of the Universidad Externado de Colombia. Those exercises were developed from 2015 to 2018 in Soacha, Cundinamarca and focused on establishing bridges between the intersubjective dynamics of three public school’s population, the students above mentioned, and us, the professors. Overall, 3407 school students aged between II and 16 years old, participated. Also, 33 schoolteachers, 127 university students and two university professors were involved in the experience during the period indicated. The exploration realized was guided by the contributions of Cultural Psychology and Investigation-Action methodologies in the educational field. Based on learnings and the results achieved, this research aimed to explore how the knowledge of each agent is expressed and enhanced along the learning processes in the schoolroom in a way it can become a scenario in which every-one is recognized as a significant part. Likewise, the personal life trajectories, the territories, the singularities and potentialities that appears in the classroom, are considered elements with an important role in the reflective processes knowledge and transforming vital spaces. The results presented show an opportunity to work on bond restitution from points of view able to assume everyday life, centered on territorial practices, as a scenario for the construction of significant learning. Together, they should represent spaces where it is possible to transform social dynamics marked by shortage, meaninglessness and violence. That also requires a critical look of the indivisible relationship between diversity and singularity that leads to an experiential dialogue with subjects beyond the privileged and recent “differential approach”. Although this has generated some progress, now is in risk to reduce the difference to a commonplace.

Diverticulitis is the most severe form of Diverticular disease (DD). An effective treatment strategy for its prevention has not yet been defined. This review aimed to provide a viewpoint on the role of mesalazine, also note as 5-aminosalicylic acid (5-ASA), in the prevention of diverticulitis. A systematic electronic search of relevant articles was performed using PubMed, Embase, Scopus, and Cochrane. Randomized controlled trials (RCTs), open trials, and retrospective studies, published between January 1999 and January 2020, were identified. Twelve eligible studies that analyzed primary or secondary outcomes of diverticulitis were included. The population included patients with symptomatic uncomplicated diverticular disease (SUDD), or patients with a history of diverticulitis. All studies compared 5-ASA to placebo, rifaximin, or other treatments. Two studies, including 359 patients, assessed the efficacy of 5-ASA in preventing the first appearance of diverticulitis in patients with SUDD. Of these, one showed that 5-ASA was effective, and one did not. Ten studies, including 2.995 patients, assessed the efficacy of 5-ASA treatment in preventing the recurrence of diverticulitis in patients with a history of diverticulitis. Four studies showed that 5-ASA had a certain degree of efficacy. All four RCTs demonstrated that 5-ASA did not significantly reduce the rate of diverticulitis recurrence. In a retrospective trial, 5-ASA was less effective than rifaximin in preventing diverticulitis recurrence. In an open trial, there was no difference between 5-ASA and probiotic treatment. Overall, there is currently conflicting evidence regarding the efficacy of 5-ASA treatment in the prevention of diverticulitis and further RCTs are needed.

Background and objectives: Electrocardiograph abnormalities (i.e., QT interval prolongation) have been described in inflammatory bowel diseases (IBD). We aimed to measure the QT interval in a cohort of patients with IBD and to analyze its relationship with clinical and inflammatory activity. Materials and Methods: We performed a cross-sectional study that included 38 IBD outpatients and 38 &ldquo, age- and sex-matched&rdquo, healthy controls. Nine patients had active IBD, and 29 were in clinical remission. Among the latter, 10 patients had sustained (lasting &gt, 1 year) and 19 had short-term remission (&le, 1 year). Corrected QT (QTc) interval was measured on standard 12-lead electrocardiograph. A systematic review of the literature on studies investigating the QT interval in patients with IBD was also performed. Results: QTc interval values were similar between IBD patients and healthy controls (417.58 &plusmn, 22.05 ms vs. 409.13 &plusmn, 19.61 ms, respectively, p: 0.479). Patients with active IBD had significantly higher QTc values (435.11 &plusmn, 27.31 ms) than both controls (409.13 &plusmn, 19.61 ms) and patients in remission (412.14 &plusmn, 17.33 ms) (p: 0.031). Post hoc analysis showed that the difference in QTc values between active IBD and remission was attributable to the group of patients with sustained remission (p &lt, 0.05). Lastly, a significant correlation between QTc interval and C-reactive protein (CRP) values was observed (Spearman test: r = 0.563, p: 0.0005). Conclusions: Our study demonstrates an association between QTc duration and both clinical and inflammatory activity in patients with IBD. The higher the CRP value, the longer is the QTc duration. For practical purposes, all patients with active IBD should undergo a standard ECG. Prescription of drugs able to modify the QT interval should be avoided in patients with active IBD. The systematic review of the literature indicated that this is the first published study demonstrating an association between the QTc duration and CRP values in patients with IBD.

Steroid-refractory graft versus host disease (GVHD) represents a fearsome complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective study on outcomes and risk factors associated with acute and chronic steroid-refractory GVHD in a large cohort of 1207 patients receiving HSCT in Saint Louis Hospital between 2007 and 2017. Among patients who developed an acute and/or a chronic GVHD, the cumulative incidences of acute and chronic steroid-refractory disease were 31% and 48%, respectively, at day +100 and 1-year post-HSCT. Through a multivariable analysis we selected several risk factors associated with the development of a steroid-refractory disease. For acute GVHD steroid refractoriness, we identified (1) a very high disease risk index, (2) an unrelated donor, (3) the absence of in vivo T-depletion as GVHD prophylaxis, and (4) a reduced intensity conditioning regimen. For chronic GVHD, (1) the use of peripheral blood stem cells, (2) unrelated donors, and (3) absence of in vivo T-depletion were more likely associated with a steroid-refractory disease. After the construction of a multistate dynamic model, we found that the probability of being alive without relapse after the resolution of all GVHD episodes was about 36% in the long term.

Context: The Global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has resulted in explosive patterns of transmission in most countries. Nasopharyngeal swabs were the specimen’s collection tools recommended for the diagnosis of SARS-CoV-2 infection, and for monitoring infection outbreaks in communities. Our objective was to report the quality and efficacy of unsupervised self-collected mid turbinate “dry FLOQSwabs” (MT FLOQSwabs) (56380CS01, Copan). There were 111 specimens collected for the study: 36 by health care personnel, from themselves, to verify the quality and efficacy of mid-turbinate swabs, 75 to compare and assess the diagnostic performance, among health care personnel, of nasopharyngeal swabs and self-collected mid-turbinate FLOQSwabs. A collection of 51 specimens was enrolled to define the efficacy of the Testami program (validation). Our analyses demonstrate that self-collected mid-turbinate dry swabs ensure an accuracy of 97.3%, as compared to the standard nasopharyngeal swabs collected by health care workers. Furthermore, the mid-turbinate FLOQSwabs can be stored without medium for six days at room temperature without affecting the molecular diagnosis of the SARS-CoV-2 virus infection. Self-collection of diagnostic specimens at home could offer an avenue to increase testing availability for SARS-CoV-2 infection without asking people to travel to a clinic or a laboratory, thus reducing people’s exposure to infection. Our findings demonstrate that unsupervised self-collection swabs, transported dry, are sensitive, practical and easy-to-use tools and should be considered for diagnosis of SARS-COV-2 and coronavirus disease 2019 (COVID-19) surveillance.

Background: The purpose of the study was to identify homogenous subgroups, based upon achievement of two functional milestones (marriage and employment) and Global Assessment of Functioning (GAF) score in a sample of 848 acute patients admitted to the Psychiatric Emergency Service (PES) of the Città della Salute e della Scienza di Torino, during a 24-months period. Subjects and methods: A two-step cluster-analysis, using GAF total score and the achievements in the two milestones as input data was performed. In order to examine whether the identified subgroups differed in external variables that were not included in the clustering process, and consequently to validate the found functional profiles, chi-square tests for categorical variables and analyses of variance (ANOVA) for continuous variables were performed. Results: Five clusters were found. Employed patients (Clusters 4 and 5) had more years of education, less illness chronicity (shorter duration of illness and lower proportion of previous voluntary hospitalizations), lower use of mental health resources in the last year yet higher treatment adherence, larger network size, and higher ordinary discharge. Married inpatients (Clusters 3 and 5) had lower frequencies of substance abuse. Conclusions: The remarkably high rate of unemployment in this inpatients’ sample, and the evidence of associations between unemployment and poorer functioning, argue for further research and development of evidence-based supported employment programs, that put forth diligent effort in helping people obtain work quickly and sustain; they may also help to reduce health care service use among that clientele.