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To evaluate the neurovascular bundle preservation grades during robotic-assisted radical prostatectomy and compared to the trifecta combined outcome (oncologic control, continence, and sexual function) twelve months after the surgery.Cohort of patients who underwent nerve-sparing robotic-assisted radical prostatectomy had the neurovascular bundle preservation retrospectively graded from 0 to 8 according to the Hopkins subjective visual classification. Patients then were divided into two groups, according to the median of nerve-sparing grading: those with score six or high and those with score less than six. Main outcome was the trifecta combined outcome and secondary outcomes was the individual trifecta criteria (prospective analysis). A secondary analysis with groups divided according to pre-operatory SHIM score was made.One hundred robotic-assisted nerve-sparing radical prostatectomy were performed, of which 83 were included. There were 53 patients with grading greater than or equal to six (group 1) and 30 patients less than six (group 2). 66.6% patients (35/53) in group 1 had a trifecta combined outcome of compared to 33.3% (10/30) in group 2 (p = 0.017). Individually, the erectile function was higher in group 1 (73.6%) compared to group 2 (46.7%) (p = 0.014). Both the results of the combined endpoint trifecta and erection were also maintained in the group with preoperative SHIM ≥ 17.The grading of preservation of the neurovascular bundle in radical prostatectomy is related to a better combined trifecta outcome one year after surgery.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

INTRODUCTION: Rheumatic heart disease with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires long-life anticoagulation and managing this can be challenging.METHODS AND RESULTS: We report data of a prospective observational study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum, by Emergency, an Italian Non-Governmental Organization, to evaluate the quality of anticoagulation control and the risk of thrombotic complications.RESULTS: We studied 3647 patients (median age 25.1 years; 53.9 % female). Median Time in Therapeutic Range (TTR) was 53 % (interquartile range 37 % to 67 %) and 70 thrombotic events (rate 1.8 × 100 pt-years [95 % CI 1.38-2.23]) were recorded. Among patients in the first quartile of TTR (≤37 %), we recorded 34/70 (48.6 %) of all thrombotic events (rate 3.7 × 100 pt-years [95 % CI 2.5-5.1]), with a high mortality rate (2.2 × 100 pt-years [95 % CI 1.3-3.3]). In patients with guideline-recommended TTR (≥65 %) the event rate was 0.8 × 100 pt-years for thrombotic events [95 % CI 0.3-1.5] and 0.4 × 100 pt-years for mortality [95 % CI 0.1-0.9]. Multivariable analysis showed that having a TTR in the lowest quartile (≤37 %) and being noncompliant are significantly associated with increased thrombotic risk. Aspirin use or different valve type did not influence the thrombotic risk. Almost 40 % of all thromboembolic complications could have been potentially prevented by further improving VKA management to obtain a TTR > 37 %.CONCLUSION: The thrombotic risk of MHV patients on VKAs living in a low-income country like Sudan is associated with low quality of anticoagulation control. Efforts should be made to decrease the number of non-compliant patients and to reach a guideline-recommended TTR of ≥65 %.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

Background: Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports. Objective: The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs. Methods: A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes. Results: Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound. Conclusion: The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation. RESUMO: Contexto: Os inibidores da bomba de prótons (IBPs) são um dos medicamentos mais prescritos no mundo. O uso frequente e a manutenção a longo prazo dessas drogas chamaram a atenção dos pesquisadores devido aos relatos esporádicos de efeitos adversos. Objetivo: Esta revisão narrativa tem o objetivo de discutir os dados e a causalidade relacionada a esses eventos adversos e o uso de IBPs. Métodos: Uma revisão narrativa foi conduzida através da sistematização das informações sobre segurança e eventos adversos de IBPs de 2015 a 2020. Uma busca estruturada na base de dados PubMed foi realizada visando identificar revisões sistemáticas e meta-análises investigando as situações a seguir: a) câncer gástrico; b) deficiência de microelementos; c) acidez de rebote; d) infecções; e) fraturas; f) demência; g) doença renal; e h) morte súbita e alterações cardiovasculares. Resultados: Estudos recentes têm potencialmente associado IBPs a alguns eventos adversos, como fraturas relacionadas à osteoporose. Também há relatos de infecções intestinais, incluindo Clostridium difficile, além de má absorção de vitaminas e minerais como vitamina B12, magnésio e ferro. Além disso, há alguns relatos de demência, pneumonia, doença renal, infarto do miocárdio e acidente vascular cerebral. Na doença renal, os estudos sugerem consistentemente que o uso de IBPs pode estar associado a um risco aumentado de eventos renais adversos, especialmente em idosos, com o uso de IBPs a longo prazo e doença renal preexistente. Outra questão adicional é se o uso crônico de IBPs também levaria ao aparecimento de câncer gástrico. A descontinuação abrupta de IBPs também está relacionada ao aumento da produção de ácido gástrico acima dos níveis de tratamento pré-IBPs; este fenômeno é conhecido como rebote ácido. Conclusão: A chave para mitigar esses efeitos adversos é o uso racional de IBPs na menor dose efetiva e com a menor duração possível. Embora esses efeitos adversos tenham um impacto clínico potencial, sua associação causal ainda está pendente de uma validação.

BACKGROUND Infection is an important complication of epidermolysis bullosa (EB), and Staphylococcus aureus has been pointed out as the most common pathogen among this population. The objective of this study was to investigate the prevalence and antimicrobial resistance profile of S. aureus colonizing EB patients in Brazil. METHODS This cross-sectional multicenter study was conducted between December 2015 and December 2017. We included a total of 89 individuals with EB from medical centers across Brazil. Data were obtained through clinical and bacteriological investigation. S. aureus were identified by biochemical tests. The nuc and mecA genes were confirmed by PCR assay. Antimicrobial susceptibility was investigated by disk diffusion method. RESULTS The overall prevalence of S. aureus was 51.7% (46/89). Methicillin-resistant S. aureus (MRSA) was detected in 24.7% (19/77) of all S. aureus isolates, colonizing 15.7% (14/89) of all patients. Community-associated (CA)-MRSA strains were resistant against sulfamethoxazole/trimethoprim and levofloxacin (P

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 12 recommendations and outlined future research priorities. Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.

Background and Aims Inflammatory bowel diseases [IBD], comprising Crohn’s disease [CD] and ulcerative colitis [UC], are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural killer [NK] cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion, and killing capacity of human NK cells during active IBD. Methods Peripheral blood mononuclear cells were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, and proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. The metabolic profile was analyzed by an extracellular flux analyzer. Results NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo, but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine-stimulated cells. Conclusions Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.

Background Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. Aim Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. Methods We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17–.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21–.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12–59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25–.46; very low certainty evidence). Conclusion VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.

How to prevent recurrences after a first venous thromboembolic (VTE) event in elderly patients is still an open issue, especially because of the high bleeding risk of anticoagulation in these patients. The placebo-controlled “Jason” study aims at assessing the efficacy and safety for secondary VTE prevention in elderly patients of oral Sulodexide (Vessel®) administration, a mixture of glycosaminoglycans (Alfasigma, Bologna, Italy) which proved effective against recurrences in a general population (SURVET study) without major bleeding (MB) complications. 1450 patients, aged ≥ 75 years, after at least 3 months of anticoagulation treatment for a first VTE episode, are double-blind randomized to receive for 12 months either sulodexide 500 lipasemic units (LSUs) twice daily, or sulodexide 250 LSU twice daily + indistinguishable placebo, or indistinguishable placebo. Primary outcomes for efficacy are the composite of death for VTE and recurrent VTE, and occurrence of MB for safety. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, and MB + clinically relevant non-MB. The first patient is scheduled to be randomized in May 2020. The study protocol has been approved by AIFA (Agenzia Italiana del Farmaco) and the Ethics Committee of the coordinating center. Written informed consent will be obtained from all patients prior to study participation. Jason study is an investigator-initiated trial, promoted by “Arianna Anticoagulazione” Foundation, Bologna, Italy, and supported by Alfasigma, Bologna, Italy. Study findings will be disseminated to participant centers, at research conferences and in peer-reviewed journals. Trial registration numbers NCT 04257487; EudraCT (2019–000570-33). Electronic supplementary material The online version of this article (10.1007/s11739-020-02381-5) contains supplementary material, which is available to authorized users.

Introduction Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half‐life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. Aim Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. Methods Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII 80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0‐11 years) undergoing minor surgeries received 20‐75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). Results pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1‐6. No safety concerns or inhibitors were identified. Forty‐five minor surgeries in 23 children were performed without complications. Conclusion Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

HLA-DR, an MHC class II molecule that mediates antigen presentation, is a favourable prognostic indicator in colorectal cancer (CRC). However, the dynamics and location of HLA-DR expression during CRC development are unclear. We aimed to define HLA-DR expression by immunohistochemistry in colorectal epithelium and stromal tissue at different stages of cancer development, assessing non-neoplastic colorectal adenocarcinoma–adjacent tissue, adenomas and carcinoma tissues, and to associate HLA-DR levels with clinical outcomes. Patients with higher than median HLA-DR expression survived at least twice as long as patients with lower expression. This association was significant for HLA-DR staining in the colorectal carcinoma epithelium (n = 152, p = 0.011, HR 1.9, 95% CI 1.15–3.15) and adjacent non-neoplastic epithelium (n = 152, p n = 63, p = 0.015, HR 3.6, 95% CI 1.279–10.25) and stroma (n = 63, p = 0.018, HR 5.07, 95% CI 1.32–19.49). HLA-DR was lower in carcinoma tissue compared to matched adenomas (n = 35), in epithelium (p p n = 101) compared to early stage (n = 105), in epithelium (p p p

Background\ud \ud Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag.\ud \ud \ud \ud Objective\ud \ud To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity.\ud \ud \ud \ud Methods\ud \ud European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients’ diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman’s rank correlation.\ud \ud \ud \ud Results\ud \ud Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2–2.7; P = .016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0–4.2; P = .054]). FVIII:C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r = .024; P = .778).\ud \ud \ud \ud Conclusions\ud \ud An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non–SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36.

© 2022 British Society for Haematology and John Wiley & Sons Ltd., The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I2 = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2 = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2 = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Background and Aims Evidence suggests patients with inflammatory bowel disease [IBD] receiving TNF antagonists have attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and of various medications for treatment of IBD on antibody responses to vaccination against COVID-19. Methods Patients with IBD [n = 270] and healthy controls [HC, n = 116] were recruited prospectively, and quantitative antibody responses were assessed following COVID-19 vaccination. The impact of IBD and of medications for treatment of IBD on vaccine response rates was investigated. Results Of HC, 100% seroconverted following complete vaccination with two vaccine doses; 2% of patients with IBD failed to seroconvert. Median anti-spike protein [SP] immunoglobulin [Ig]G levels following complete vaccination in our IBD cohort was significantly lower than among HC [2613 AU/mL versus 6871 AU/mL, p ≤0.001]. A diagnosis of IBD was independently associated with lower anti-SP IgG levels [β coefficient -0.2, p = 0.001]. Use of mRNA vaccines was independently associated with higher anti-SP IgG levels [β coefficient 0.25, p ≤0.001]. Patients with IBD receiving TNF inhibitors had significantly lower anti-SP IgG levels [2445 AU/mL] than IBD patients not receiving TNF inhibitors [3868 AU/mL, p ≤0.001]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared with HC [3868 AU/mL versus 8747 AU/mL, p = 0.001]. Conclusions Patients with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy negatively affects anti-SP IgG levels further. Patients who do not seroconvert following vaccination are a particularly vulnerable cohort. Impaired responses to vaccination in our study highlight the importance of booster vaccination programmes for patients with IBD.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary “anticoagulation team” with the aim to define the optimal perioperative management of anticoagulation.

Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study). Objectives: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients. Methods: Patients with IPD, type 1 VWD (VWD-1) and age- and sex-matched healthy controls enrolled in the BAT-VAL study were prospectively followed-up for 2years and bleeding episodes requiring treatment were recorded. Results: Of the 1098 subjects initially enrolled, 955 were followed-up and 124 suffered hemorrhages during follow-up, 60% of whom had inherited platelet function disorders (IPFD). Total number of events was significantly higher in IPFD (n=235) than VWD-1 (n=52) or inherited thrombocytopenia (IT; n=20). Events requiring transfusions were 66% in IPFD, 5.7% in VWD-1, and 3% in IT. Baseline BS was significantly higher in IPFD patients with a bleeding event at follow-up than in those without (p&nbsp

Background: Trial of Rivaroxaban in AntiPhospholipid Syndrome was a prospective randomized, open-label, noninferiority study conducted in 14 centers in Italy. Rivaroxaban was compared with warfarin for the prevention of thromboembolic events, major bleeding, and vascular death in high-risk, triple-positive patients with antiphospholipid syndrome. Objective: The aim of this paper is to report the events during the 2-year follow-up after the study closure. Methods: On January 28, 2018, the trial was prematurely stopped by adjudication and safety committee for an excess of events in the rivaroxaban group. Randomized patients were advised on trial results and those randomized to rivaroxaban were solicited to switch to warfarin. All 14 participating centers were asked and accepted to follow their patients for clinical events. This report describes the rate of events that occurred between January 28, 2018, and January 28, 2020. Results: Of 120 randomized patients, 115 were available for follow-up. Outcome events were two in six (33.3%) patients who remained on direct oral anticoagulants (DOACs) and six in 109 (5.7%) patients on warfarin (hazard ratio [HR] 6.9; 95% confidence interval [CI] 1.4-34.5, P=.018). The two patients on DOACs (one taking dabigatran and one taking rivaroxaban) suffered from thromboembolic events, whereas of the six patients with composite outcomes on warfarin, three had thromboembolic events (HR for thrombosis 13.3; 95% CI 2.2-79.9, P=.005). Conclusion: These data further support the use of warfarin in high-risk patients with antiphospholipid syndrome.

Shark bites on humans are rare but are sufficiently frequent to generate substantial public concern, which typically leads to measures to reduce their frequency. Unfortunately, we understand little about why sharks bite humans. One theory for bites occurring at the surface, e.g. on surfers, is that of mistaken identity, whereby sharks mistake humans for their typical prey (pinnipeds in the case of white sharks). This study tests the mistaken identity theory by comparing video footage of pinnipeds, humans swimming and humans paddling surfboards, from the perspective of a white shark viewing these objects from below. Videos were processed to reflect how a shark's retina would detect the visual motion and shape cues. Motion cues of humans swimming, humans paddling surfboards and pinnipeds swimming did not differ significantly. The shape of paddled surfboards and human swimmers was also similar to that of pinnipeds with their flippers abducted. The difference in shape between pinnipeds with abducted versus adducted flippers was bigger than between pinnipeds with flippers abducted and surfboards or human swimmers. From the perspective of a white shark, therefore, neither visual motion nor shape cues allow an unequivocal visual distinction between pinnipeds and humans, supporting the mistaken identity theory behind some bites.

Male patients, especially the young, are at a higher risk of recurrent venous thromboembolism (RVTE) than females. Recent scientific reports show the use of D-dimer does not help predict RVTE risk in males. In the present report, we reviewed the data obtained in the DULCIS study (main report published in Blood 2014), focusing on D-dimer results recorded in non-elderly patients of both genders included in the study, and their relationship with RVTE events occurring during follow-up. Using specifically designed cutoff values for positive/negative interpretation, serial D-dimer measurements (performed during warfarin treatment and up to 3 months after discontinuation of anticoagulation) in 475 patients (males 57.3%) aged ≤ 65 years were obtained. D-dimer resulted positive in 46.3% and 30.5% of males and females, respectively (p = 0.001). Following management procedure, anticoagulation was stopped in 53.7% of males and 69.5% of females, who had persistently negative D-dimer results. The rate of subsequent recurrent events was 1.7% (95% CI 0.5–4.5%) and 0.4% (95% CI 0–2.5%) patient-years in males and females, respectively, with upper limits of confidence intervals always below the level of risk considered acceptable by international scientific societies for stopping anticoagulation (

Background Thrombocytopenia is associated with increased mortality in the general population, but few data exist in patients with atrial fibrillation ( AF ) taking oral anticoagulants. We investigated factor determinants of thrombocytopenia in a large cohort of patients affected by AF and its association with total mortality. Methods and Results Multicenter prospective cohort study, including 5215 patients with AF from the START (Survey on Anticoagulated Patients Register) registry, 3877 (74.3%) and 1338 (25.7%) on vitamin K or non–vitamin K antagonist oral anticoagulants, respectively. Thrombocytopenia was defined by a platelet count 9 /L. Determinants of thrombocytopenia were investigated, and all‐cause mortality was the primary survival end point of the study. Thrombocytopenia was present in 592 patients (11.4%). At multivariable logistic regression analysis, chronic kidney disease (odds ratio [ OR], 1.257; P =0.030), active cancer ( OR, 2.065; P =0.001), liver cirrhosis ( OR, 7.635; P OR, 1.234; P =0.046) were positively associated with thrombocytopenia, whereas female sex ( OR, 0.387; P OR, 0.787; P =0.032) were negatively associated. During a median follow‐up of 19.2 months (9942 patient‐years), 391 deaths occurred (rate, 3.93%/year). Mortality rate increased from 3.8%/year to 9.9%/year in patients with normal platelet count and in those with moderate‐severe thrombocytopenia, respectively (log‐rank test, P =0.009). The association between moderate‐severe thrombocytopenia and mortality persisted after adjustment for CHA 2 DS 2 VAS c score (hazard ratio, 2.431; 95% CI, 1.254–4.713; P =0.009), but not in the fully adjusted multivariable Cox regression analysis model. Conclusions Thrombocytopenia is common in patients with AF . Despite an increased incidence of mortality, thrombocytopenia was not associated with mortality at multivariable analysis. Thrombocytopenia may reflect the presence of comorbidities associated with poor survival in AF .

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once-daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once- vs. twice- or three-times daily low-dose aspirin in inhibiting platelet thromboxane (TX) A2 production, as reflected by serum (s) TXB2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once-daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P

The primary study objective is to compare the outcomes of patients taking oral anticoagulant medications in two distinct populations treated according to different management models (comprehensive vs. usual care). (Design: regional prospective cohort study; setting: hospital admission data from two regions). Eligible partecipants were patients taking oral anticoagulant drugs (vitamin K antagonist or direct oral anticoagulants), residents in the Vicenza and Cremona districts from February 1st, 2016 to June 30th, 2017. Patients were identified by accessing the administrative databases of patient drug prescriptions. The primary study outcome was admission to the Emergency Department for stroke, systemic arterial embolism, recurrence of venous thromboembolism or major bleeding. The study evaluated outcomes in 14,226 patients taking oral anticoagulants, of whom 6725 being followed in Cremona with a comprehensive management model. There were 19 and 45 thromboembolic events over 6205 and 6530 patient-years in the Cremona and Vicenza cohort, respectively (IRR 0.44, 95% CI 0.24-0.77). The reduction of events in the Cremona cohort was almost entirely explained by a decrease of events in patients taking VKA (IRR 0.41, 95% CI 0.20-0.78) but not DOACs (IRR 1.08, 95% CI 0.25-5.24). The rate of major bleeding was non-significantly higher in Cremona than in Vicenza (IRI 1.32; 95% CI 0.74-2.40). Across the two cohorts, the risk of bleeding was lower in patients being treated with DOACs rather than warfarin (10/4574 vs. 42/8161 event/person-years, respectively, IRR 0.42 95% CI 0.19-0.86). We conclude that a comprehensive management model providing centralized dose prescription and follow-up may significantly reduce the rate of thromboembolic complications, without substantially increasing the number of bleeding complications. Patients treated with direct oral anticoagulants appear to have a rate of thromboembolic complications comparable to VKA patients under the best management model, with a reduction of major bleeding.

Background Partial nephrectomy (PN) is the preferred modality of treatment for small renal masses. Laparoscopic partial nephrectomy (LPN) has been adopted worldwide and a fundamental role is played by surgical skills. The need for skill instruction outside the operating room is well recognized in the modern models of surgery residency training. We aim to investigate the impact of residents’ laparoscopic surgical skills training on the successful implementation of LPN in a reference public teaching hospital in southern Brazil. Methods We accessed all patients undergoing LPN by senior's urology residents at Hospital de Clinicas de Porto Alegre. Patients were stratified in 2 periods of time named ‘LPN eras’ 1 and 2, to report the training impact on the outcome. LPN era 1 was from October 2012 to February 2017 and LPN era 2 from March 2017 to June 2019. All the senior residents of LPN era 2 followed a simulation training divided into 4 years with a total training time of 244 hours before performing the LPN. Residents from LPN era 1 did not have simulation training. Results 124 patients underwent LPN during the study period, 53 (42.7%) of those were performed in LPN era 1 and 71 (57.3%) in LPN era 2. Baseline characteristics of the patients in the two groups were similar. The training performed by LPN era 2 residents was able to significantly reduce estimated blood loss, ischemia time and LOS with p value respectively 0.007, 0.001 and 0.001. LPN era 2 group also reached Trifecta in 77.5% of patients, being significantly more than in the LPN era 1 (p = 0.007). Conclusions Simulation in residents surgical training was able to improve clinical outcomes in LPN. These data reinforce the fundamental importance of adequate residents training before performing surgery on a patient.

Vitamin K antagonists (VKA) are the most widely used anticoagulants in the world. An appropriate management of treated patients is crucial for their efficacy and safety. The prospective, observational, multicenter, inception-cohort FCSA-START Register, a branch of START Register (NCT02219984) included VKA-treated patients managed by centers of Italian Federation of anticoagulation clinics (AC). Baseline patient characteristics and data during treatment were analyzed and compared with those of ISCOAT study, performed by the Federation and published in 1996/7. 5707 naïve patients [53% males, mean age 73.0 years (28.1% >80 years)], 61.6% treated for atrial fibrillation (AF), and 28.0% for venous thromboembolism were included. During the 8906 patient-years (pt-yrs) of observation, 123 patients had major bleeding (MB) (1.38% pt-yrs; fatal: 0.11% pt-yrs), while non-major clinically relevant bleeds were 144 (1.62% pt-yrs). Bleeding was more frequent in elderly (≥70 years; p = 0.04), and during initial 3-month therapy (p = 0.02). Bleeding rate was 2.5% pt-yrs for temporally related INR results

Background: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. Objectives: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC). Patients/Methods: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. Results: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9

Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

The intensive use of pesticides in agriculture is associated with several negative externalities, which affect both the environment and public health. It is known that the number of records is lower than that of pesticide poisonings, and that underreporting occurs. Aiming to understand this underreporting, we analyzed the data from two information systems for notifications and health injuries and a case study was carried out with professionals from the 5th Regional Health Center and the health network of a municipality in the state of Paraná. It was concluded that underreporting occurs in the information systems, confirming the inconsistency of data and the lack of communication between them, making it difficult to understand the reality of poisonings. In the case study, the occurrence of prior underreporting was identified: when many workers do not seek health systems; the training of professionals is insufficient and neutralized by high turnover, especially among physicians; the diagnosis, conduct and treatment of pesticide poisoning are not part of the curriculum of many courses in the health area; the capacity of health services in many municipalities falls short of the demand, causing work overload to the professionals and the consequent underreporting.O uso intensivo de agrotóxicos na agricultura está associado a externalidades negativas, que afetam o meio ambiente e a saúde pública. Sabe-se que o número de registros é menor que os de intoxicações por pesticidas, ocorrendo subnotificações. Com o objetivo de compreender esse evento, analisou-se os dados de dois sistemas de informação de notificações e agravos à saúde e realizou-se estudo de caso com profissionais da 5ª Regional de Saúde e da rede de saúde de um município do Paraná. Confirmou-se que ocorrem as subnotificações nos sistemas de informações, a inconsistência de dados e a falta de comunicação entre eles, dificultando a compreensão da realidade das intoxicações. No estudo de caso identificou-se a ocorrência de subnotificação prévia: quando muitos trabalhadores não procuram os sistemas de saúde; as capacitações dos profissionais são insuficientes e neutralizadas pela grande rotatividade, especialmente de médicos; o diagnóstico, a conduta e o tratamento das intoxicações por agrotóxicos não fazem parte do currículo de muitos dos cursos da área de saúde; e a capacidade dos serviços de saúde de muitos municípios está aquém da demanda, ocasionando sobrecarga de trabalho aos profissionais e a consequente subnotificação.

Knowledge of the distribution of risk factors for superficial thrombosis (SVT) in low-risk population is fundamental to improve the prevention of the disease in each individual and high-risk settings of patients. Exact frequency data for the low-risk population are scarce, but could be useful for optimal use of prophylactic strategies against venous thrombosis. Blood donors represent a low-risk population, because are healthier than the general population. The objective of this study was to assess the prevalence of vein thrombosis, particularly SVT, and associated risk factors in a low-risk population such as blood donors. In this multicentre cross-sectional study, donors from six Italian blood banks responded to a self-administered questionnaire. The enrolment lasted from 1st June 2017 to 30th July 2018. History of vein thrombosis was referred by 89 (0.76%) individuals, (49 men) with an age-dependent effect. The prevalence reached 2.9% in women and 0.8% in men aged ≥ 49 years, with a significant difference only for women. After controlling for potential confounders, a significant and independent association was found between a history of vein thrombosis and age (OR: 1.03, 95%CI 1.01-1.05), varicose veins (OR: 15.8, 95%CI 7.7-32.6), plaster cast/bed rest (OR: 2.3, 95% CI 1.0-5.3) and transfusion (OR: 5.1, 95% CI 1.3-19.5). This study shows that low-risk individuals share the same risk factors for SVT as patients in secondary care. It also suggests that transfusion confers an increased risk of SVT in healthy population.

Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6β4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.

This study examined the effectiveness of a 10-wk intervention program based on occupational therapy principles on visual-motor integration skills and fine motor abilities in kindergartners and first graders. We recruited 55 students tested three times with the Visual-Motor Integration Test (VMI) and Movement Assessment Battery for Children-2 (MABC-2): before the intervention (T1), post-intervention (T2) and one month later (T3). Research findings: Significant improvements were found on VMI between T1 and T2, particularly for kindergartners. Neither group of children demonstrated changes on manual dexterity scores. The present study showed that the intervention program led to different changes in the at-risk of motor impairment group than in the not at-risk children. Results indicated that games and stimulation activities helped children below the 16th percentile over time in the manual dexterity domain. A gender effect was observed, with female children increasing their abilities over time more than male peers. Future research should concentrate on stimulating fine motor skills in hand manipulation and test how these abilities influence graphomotor skills and handwriting over time. Finally, more research is needed to determine the impact of activities and games carried out in educational settings.

Introduction The factor VIII (FVIII)-mimetic bispecific monoclonal antibody, emicizumab, previously approved for prophylaxis in haemophilia A with inhibitors, has been recently licensed in several countries also in patients with severe haemophilia A (PWSHA) without inhibitors. The introduction of this innovative agent requires the development of specific pathways at Haemophilia Treatment Centres (HTC), particularly regarding laboratory testing and treatment of breakthrough bleeds and invasive procedures/surgeries, even more critical when patients are managed by non-specialist professionals. Limited literature data and clinical experience in PWSHA without inhibitors on emicizumab are currently available. Aim To promote awareness and overcome these challenges, the Italian Association of Haemophilia Centres (AICE) issued a guidance on the management of PWSHA without inhibitors on emicizumab prophylaxis, focused on emergency and shared with other National Scientific Societies in the field. Methods The document, drafted by an AICE expert panel and approved through online consultation, was further revised by a multidisciplinary working group, including members of 5 haemostasis, laboratory and emergency scientific societies. The final version was approved by the Council of each society. Results General recommendations about use of FVIII concentrates for the treatment of bleeding or haemostatic coverage of invasive procedures/surgeries and laboratory monitoring in PWSHA without inhibitors on emicizumab are provided. Specific issues of the management in the emergency room are focused, highlighting the need for direct involvement or formalized supervision by specialist HTC physicians. Conclusions This guidance provides a reference pathway to be implemented in the different healthcare organizations, especially for the challenging emergency management in this setting.

ObjectiveThe proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.DesignA prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed.SettingAbout 60 Italian anticoagulation and thrombosis centres participated in the observational START2-RegisterParticipants2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment.InterventionsPatients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE.Outcomes measuresEfficacy: rate of VTE recurrence (all thrombotic complications were also recorded). Safety: the rate of major and clinically relevant non-major bleeding events.ResultsAlmost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was >180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14–4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, pConclusionItalian centres treat most patients with VTE with DOACs and prefer VKA for those with more serious clinical conditions. Recurrences were significantly more frequent in DOAC-treated patients due to increased incidence after 180 days of treatment, probably due to reduced adherence to treatment. These results underline the importance of structured surveillance of DOAC-treated patients with VTE to strengthen treatment adherence during extended therapy.

Major surgery is associated with an increased risk of venous thromboembolism, thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of venous thromboembolism in patients with inherited platelet disorders undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in inherited platelet disorders patients undergoing surgery at venous thromboembolism-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of inherited platelet disorders (venous thromboembolism-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to venous thromboembolism-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest venous thromboembolism-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions. Two thromboembolic events were registered, both occurring after high venous thromboembolism-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that venous thromboembolism incidence is low in patients with inherited platelet disorders undergoing surgery at venous thromboembolism-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with inherited platelet disorders undergoing invasive procedures at venous thromboembolism-risk and low-molecular-weight-heparin should be considered for major surgery. Fil: Paciullo, Francesco. Università di Perugia; Italia Fil: Bury, Loredana. Università di Perugia; Italia Fil: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia Fil: Falcinelli, Emanuela. Università di Perugia; Italia Fil: Melazzini, Federica. Universita Degli Studi Di Pavia.; Italia Fil: Orsini, Sara. Università di Perugia; Italia Fil: Zaninetti, Carlo. Universita Degli Studi Di Pavia.; Italia Fil: Abdul Kadir, Rezan. Haemophilia Centre And Haemostasis Unit, Royal Free Fou; Reino Unido Fil: Obeng Tuudah, Deborah. Haemophilia Centre And Haemostasis Unit, Royal Free Fou; Reino Unido Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fabris, Fabrizio. Università di Padova; Italia Fil: Rivera, Jose. Universidad de Murcia; España Fil: Lozano, Maria Luisa. Universidad de Murcia; España Fil: Butta, Nora. Hospital Universitario la Paz; España Fil: Favier, Remi. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Cid, Ana Rosa. Hospital Universitario y Politecnico la Fe; España Fil: Fouassier, Marc. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Podda, Gian Marco. Università degli Studi di Milano; Italia Fil: Santoro, Cristina. Università degli studi di Roma "La Sapienza"; Italia Fil: Grandone, Elvira. Casa Sollievo Della Sofferenza,s.giovanni Rotondo; Italia Fil: Henskens, Yvonne. Maastricht University Medical Centre; Países Bajos Fil: Nurden, Paquita. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Zieger, Barbara. Albert Ludwigs University of Freiburg; Alemania Fil: Cuker, Adam. University of Pennsylvania; Estados Unidos Fil: Devreese, Katrien. University of Ghent; Bélgica Fil: Tosetto, Alberto. Hospital San Bortolo; Italia Fil: De Candia, Erica. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia Fil: Dupuis, Arnaud. French Reference Centre For Inherited Platelet Disorder; Francia Fil: Miyazaki, Koji. Kitasato University School Of Medicine; Japón Fil: Othman, Maha. Queens University; Canadá Fil: Gresele, Paolo. Università di Perugia; Italia

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. Summary Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 μg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 μg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

In the D-dimer and ULtrasonography in Combination Italian Study (DULCIS), serial D-dimer measurement in combination with assessment of residual thrombosis (in patients with deep vein thrombosis (DVT)) identified patients who safely discontinued anticoagulation after an unprovoked venous thromboembolism (VTE).In this subgroup analysis, the value of D-dimer tests was assessed in patients with isolated pulmonary embolism (PE) compared with those with DVT, with or without PE (DVT/PE). The DULCIS database was reanalysed in relation to this target.26.8% of the DULCIS patients had isolated PE as the index event; this was more prevalent in females (34.1%) than in males (21.1%; pversus 3.8% ppy; nonsignificant) who stopped anticoagulation for negative D-dimer, but it was markedly high (11.2% ppy; pversus two (7.4%) out of 27; p=0.0085).Serial D-dimer assessment can inform on the risk of recurrent VTE and help determine the duration of anticoagulation in patients with isolated PE.

Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. Summary: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a ‘low-risk’ (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51–1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.

Zateyshchikov, Dmitry A/0000-0001-7065-2045; Vyshnyvetskyy, Ivan/0000-0001-7228-3052; Bustillo, Sonia Ruiz/0000-0002-6074-914X; Maslovskyi, Valentyn/0000-0001-5184-1799; Ruzic, Alen/0000-0001-5031-2975; Nikolaev, Konstantin/0000-0003-4601-6203; Musial, Jacek/0000-0002-8994-0036; Malynovsky, Yaroslav V/0000-0002-9118-1104; Tsivgoulis, Georgios/0000-0002-0640-3797; Maslovskyi, Valentyn/0000-0001-5184-1799; Grinshtein, Yury/0000-0001-8847-235X; Shpagina, Lyubov/0000-0003-0871-7551; Yildiz, Oznur/0000-0002-5379-6829; Marchev, Sotir/0000-0001-9250-510X; Weitz, Jeffrey/0000-0002-1092-7550; Apartsin, Konstantin A/0000-0003-0577-9001; Reis, Gilmar/0000-0002-4847-1034; Baker, Ross/0000-0002-2728-6788; Koziolkin, Olexandr/0000-0001-9878-5798; Barbarash, Olga/0000-0002-4642-3610; Sala-Llinas, Ernest/0000-0002-6499-1638; Gallus, Alexander/0000-0001-7347-9989; lodigiani, corrado/0000-0002-9152-9385; Kosmacheva, Elena/0000-0001-8600-0199; Ramacciotti, Eduardo/0000-0002-5735-1333; Khorana, Alok/0000-0002-9509-0998; Giorgi-Pierfranceschi, Matteo/0000-0002-7988-9652; Torbicki, Adam/0000-0003-3475-8832; Abragamovic, Orest/0000-0001-6862-6809; Jara-Palomares, Luis/0000-0002-4125-3376; Prozesky, Hans/0000-0001-9715-3449; Andreev, Denis/0000-0002-0276-7374; Cuervas-Mons Martinez, Valentin/0000-0003-3086-9463; Apostolovic, Svetlana/0000-0001-9015-297X; Gregorio, Tiago/0000-0002-0131-9430; Sanchez Martinez, Rosario/0000-0003-0408-3029; Antonicelli, Roberto/0000-0002-5921-1828; Konstantinides, Stavros/0000-0001-6359-7279; Karapanayiotides, Theodoros/0000-0002-2357-7967; Repin, Alexey/0000-0001-7123-0645 WOS: 000445020900006 PubMed: 30145946 BACKGROUND Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma n-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. Janssen Research and Development; Daiichi SankyoDaiichi Sankyo Company Limited; Portola; Boehringer IngelheimBoehringer Ingelheim; JanssenJohnson & Johnson USAJanssen Biotech Inc; BayerBayer AG; BMS PfizerPfizer; Aspen; Sanofi; University of Cincinnati and Spectrum Health; PfizerPfizer; ATLAS Group (Colorado Prevention Center); Johnson JohnsonJohnson & Johnson USA; Ortho-McNeil-JanssenJohnson & Johnson USAJanssen Biotech Inc; Bayer/JanssenJohnson & Johnson USAJanssen Biotech IncBayer AG; MerckMerck & Company; AmgenAmgen Supported by Janssen Research and Development.r Dr. Spyropoulos reports receiving advisory board fees from Daiichi Sankyo and Portola, grant support, consulting fees, and advisory board fees from Boehringer Ingelheim and Janssen, consulting fees and advisory board fees from Bayer, and a stipend from ATLAS Group (Colorado Prevention Center); Dr. Ageno, receiving grant support and advisory board fees from Bayer and BMS Pfizer and advisory board fees from Portola, Daiichi Sankyo, Aspen, Boehringer Ingelheim, and Sanofi; Dr. Albers, receiving consulting fees from Bayer; Dr. Elliott, receiving fees for serving on a steering committee from Bayer and lecture fees from the University of Cincinnati and Spectrum Health; Dr. Halperin, receiving consulting fees from Boehringer Ingelheim, Daiichi Sankyo, Pfizer, ATLAS Group (Colorado Prevention Center), Johnson & Johnson, and Ortho-McNeil-Janssen; Dr. Hiatt, receiving grant support from Janssen and Bayer; Dr. Steg, receiving grant support and fees for serving on a steering committee from Bayer/Janssen, grant support and lecture fees from Merck, grant support, consulting fees, lecture fees, and fees for serving as cochair of the ODYSSEY outcomes trial and the SCORED trial from Sanofi, grant support and fees for serving as chair of the CLARIFY registry from Servier, consulting fees and fees for serving on the executive steering committee for the REDUCE IT trial from Amarin, consulting fees and lecture fees from Amgen, consulting fees, lecture fees, and fees for critical event committee work from Bristol-Myers Squibb, fees for serving on the executive steering committee of the REDUAL PCI trial from Boehringer Ingelheim, fees for critical event committee work from Pfizer, consulting fees and fees for serving on the executive steering committee for the PARADISE MI trial from Novartis, consulting fees from Regeneron and Lilly, and consulting fees and fees for serving as cochair of the THEMIS trial from AstraZeneca; Dr. Weitz, receiving consulting fees and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer and Portola; Dr. Suh and Dr. Barnathan, being employed by Janssen Research and Development and owning stock in Johnson & Johnson; Dr. Spiro, being employed by and owning shares in Bayer U.S.; and Dr. Raskob, receiving consulting fees from Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Portola, and Novartis and consulting fees and honoraria from Daiichi Sankyo and Pfizer. No other potential conflict of interest relevant to this article was reported.

This study aims to evaluate the impact of 5-alpha-reductase inhibitors (5ARI) for prostate cancer (PCa) primary prevention on specific and overall mortality (primary outcomes), the incidence of PCa diagnosis and disease aggressiveness (secondary outcomes). We searched MEDLINE, EMBASE, Cochrane, ClinicalTrials and BVS through April 2018 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement to identify randomized clinical trials (RCT) and cohort studies (CS). We included articles with data on mortality or PCa incidence for men using 5ARI previously to PCa diagnosis. Regarding the included studies, nine had data on mortality, 16 on PCa incidence and 12 on Gleason scores (GS). We found that the use of 5ARI had no impact on overall mortality (RR 0.93 95% CI 0.78–1.11) and PCa-related mortality (RR 1.35 95% CI 0.50–3.94), nor on high-grade PCa diagnosis (RR 1.06 95% CI 0.72–1.56). We identified a relative risk reduction of 24% in moderate-grade PCa diagnosis (RR 0.76 95% CI 0.59–0.98) and low-grade PCa diagnosis (RR 0.76 95% CI 0.59–0.97) Also, a reduction of 26% in overall PCa diagnosis was observed in the RCT subgroup analysis (RR 0.74 95% CI 0.65–0.84). 5ARI significantly reduced the risk of being diagnosed with PCa, not increasing high-grade disease, overall or cancer-specific mortality. Due to the relatively short mean follow-up of most studies, the mortality analysis is limited.