Systematic review of clinical practice guidelines for adults with fractures: identification of best evidence for rehabilitation to develop the WHO’s Package of Interventions for Rehabilitation

Background The identification of existing rehabilitation interventions and related evidence represents a crucial step along the development of the World Health Organization’s (WHO) Package of Interventions for Rehabilitation (PIR). The methods for such identification have been developed by the WHO Rehabilitation Programme and Cochrane Rehabilitation under the guidance of the WHO’s Guideline Review Committee secretariat. The aim of this paper is to report on the results of the systematic search for clinical practice guidelines (CPGs) relevant to the rehabilitation of adults with fractures and to present the current state of evidence available from the identified CPGs. Methods This paper is part of the Best Evidence for Rehabilitation (be4rehab) series, developed according to the methodology presented in the World Health Organization’s (WHO) Package of Interventions for Rehabilitation (PIR) introductory paper. It is a systematic review of existing CPGs on fractures in adult population published from 2009 to 2019. Results We identified 23 relevant CPGs after title and abstract screening. According to inclusion/exclusion criteria, we selected 13 CPGs. After checking for quality, publication time, multiprofessionality, and comprehensiveness, we finally included five CPGs dealing with rehabilitative management of fractures in adult population, two CPGs addressing treatment of distal radius fracture and three the treatment of femoral/hip fracture. Conclusion The selected CPGs on management of distal radius and femoral/hip fracture include few recommendations regarding rehabilitation, with overall low to very low quality of evidence and weak/conditional strength of recommendation. Moreover, several gaps in specific rehabilitative topics occur. Further high-quality trials are required to upgrade the quality of the available evidence

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3. 10.1093/brain/awy039-video1 awy039media1 574205353400

Erratum to: Portal vein thrombosis relevance on liver cirrhosis: Italian Venous Thrombotic Events Registry (Intern Emerg Med, 10.1007/s11739-016-1416-8)

In the original publication, the second author name was incorrectly published as Roberto Gino Corazza. The correct name should read as \u201cGino Roberto Corazza\u201d. Also, the PRO-LIVER Study Collaborator, Dr. Gabriella Carnevale Maff\ue8 has not been included in the Appendix by mistake. The name of Dr. Carnevale Maffe` should read in the Appendix as follows: Bergamaschi Gaetano, Carnevale Maff\ue8 Gabriella, Masotti Michela, Costanzo Filippo (I\ub0 Clinica Medica, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy)

Incidence and Recurrence of Portal Vein Thrombosis in Cirrhotic Patients

Cirrhosis has been long considered a risk factor for bleeding due to the co-existence of the so-called \u2018coagulopathy\u2019. More recently, however, compelling evidences have been provided on the occurrence of thrombotic events in the portal and systemic circulation.3\u20135 Portal vein thrombosis (PVT) is predominantly observed in patients with moderate to severe liver failure with a variable prevalence ranging from 0.6 to 25%. Only fewstudies have provided a longitudinal assessment of the PVT incidence and its sequelae, including recurrence and survival.9\u201314 Due to the variability of PVT incidence and the paucity of data regarding recurrence and survival,15\u201320 we prospectively analysed the incidence and the recurrence of PVT in the population of Portal vein thrombosis Relevance On Liver cirrhosis: ItalianVenous thromboticEventsRegistry (PROLIVER), a multi-centre study,8 which involved 43 enrolling centres in Italy (ClinicalTrials.gov Identifier: NCT01470547)

Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients

Asthma in patients admitted to emergency department for COVID-19: prevalence and risk of hospitalization

Non

Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER Study

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of \ue2\u88\ubc4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64\uc2\ub137 years; 47% Child\ue2\u80\u93Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800\ue2\u80\u931,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count \ue2\u89\ua450\uc3\u97103/\uce\ubcl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11\ue2\u80\u933.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16\ue2\u80\u933.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients