CHA2DS2-VASc score as a predictor of clinical outcomes in hospitalized patients with and without chronic kidney disease.

BACKGROUND: High CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65-74 and Sex category) was associated with adverse clinical outcomes in different settings. The aim of the present study was to evaluate the association between CHA2DS2-VASc score and R2CHA2DS2-VASc score (which includes renal impairment) with in-hospital mortality and length of hospital stay in patients hospitalized in an internal medicine ward. METHODS: We enrolled 983 consecutive patients admitted during 3 years in an internal medicine ward. R2CHA2DS2-VASc score was calculated by adding 2 points to CHA2DS2-VASc for the presence of chronic kidney disease (CKD), defined according to K-DOQI. The primary outcome was a composite of all-cause mortality and length of hospital stay > 10 days. RESULTS: Patients with CKD stages 3-5 presented with increased CHA2DS2-VASc vs stages 1-2 (p < 0.001). The composite outcome occurred in 47.3% of inpatients. Multivariable linear logistic regression analyses adjusted for presence of infectious diseases and cancer, with the occurrence of composite outcome showed an adjusted OR of 1.349 (95% CI 1.248-1.462) and 1.254 (95% CI 1.179-1.336) for CHA2DS2-VASc and R2CHA2DS2-VASc scores, respectively. No differences were found in the association between CHA2DS2-VASc and R2CHA2DS2-VASc scores with the composite outcome (AUC 0.631 vs 0.630), and furthermore, adding the presence/absence of infectious diseases during hospitalization and positive cancer history to the models increased the AUC (0.667 and 0.663). CONCLUSIONS: Incrementally higher CHA2DS2-VASc score is associated with increased length of hospital stay and mortality in patients hospitalized in an internal medicine ward, regardless of the presence of CKD.

Fever and dyspnea after anti-Covid-19 vaccination: a challenging diagnosis.

There is still little information regarding the long-term safety of the vaccines. We report a case of new-onset adult-onset Still's disease (AOSD) that occurred following Covid-19 vaccination. This patient went to the emergency room with dyspnea from the last two weeks and bilateral swellings that occurred several weeks after the first vaccination. Based on the symptoms and laboratory results, we suspected AOSD. Considering the time relationship between Covid-19 vaccination and AOSD onset in our patient, and possible mechanisms linking vaccination with the onset of autoimmune disorders, physicians should consider adverse events from Covid-19 vaccination and assess the benefits and risks of vaccination for each patient.

Complete blood count alterations in COVID-19 patients: A narrative review.

Coronavirus disease 2019 (COVID-19) pandemic represents a scientific and social crisis. One of the main unmet needs for coronavirus disease 2019 is its unpredictable clinical course, which can rapidly change in an irreversible outcome. COVID-19 patients can be classified into mild, moderate, and severe. Several haematological parameters, such as platelets, white blood cell total count, lymphocytes, neutrophils, (together with neutrophil-lymphocyte and platelet-lymphocyte ratio), and haemoglobin were described to be associated with COVID-19 infection and severity. The purpose of these review is to describe the current state of the art about complete blood count alterations during COVID-19 infection, and to summarize the crucial role of some haematological parameters during the course of the disease. Decreased platelet, lymphocyte, haemoglobin, eosinophil, and basophil count, increased neutrophil count and neutrophil-lymphocyte and platelet-lymphocyte ratio have been associated with COVID-19 infection and a worse clinical outcome. Our study adds some novelty about the identification of effective biomarkers of progressive disease, and might be helpful for diagnosis, prevention of complications, and effective therapy.

Time to hospitalisation, CT pulmonary involvement and in-hospital death in COVID-19 patients in an Emergency Medicine Unit.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) are often treated at home given the limited healthcare resources. Many patients may have sudden clinical worsening and may be already compromised at hospitalisation. We investigated the burden of lung involvement according to the time to hospitalisation. METHODS: In this observational cohort study, 55 consecutive COVID-19-related pneumonia patients were admitted to the Emergency Medicine Unit. Groups of lung involvement at computed tomography were classified as follows: 0 (<5%), 1 (5%-25%), 2 (26%-50%), 3 (51%-75%) and 4 (>75%). We also investigated in-hospital death and the predictive value of Yan-XGBoost model and PREDI-CO scores for death. RESULTS: The median age was 74 years and 34 were men. Time to admission increased from 2 days in group 0 to 8.5-9 days in groups 3 and 4. A progressive increase in LDH, CRP and d-dimer was found across groups, while a decrease of lymphocytes paO2 /FiO2 ratio and SpO2 was found. Ten (18.2%) patients died during the in-hospital staying. Patients who died were older, with a trend to lower lymphocytes, a higher d-dimer, creatine phosphokinase and troponin T. The Yan-XGBoost model did not accurately predict in-hospital death with an AUC of 0.57 (95% confidence interval [CI] 0.37-0.76), which improved after the addition of the lung involvement groups (AUC 0.68, 95%CI 0.45-0.90). Conversely, a good predictive value was found for the original PREDI-CO score with an AUC of 0.76 (95% CI 0.58-0.93) which remained similar after the addition of the lung involvement (AUC 0.76, 95% CI 0.57-0.94). CONCLUSION: We found that delayed hospital admission is associated with higher lung involvement. Hence, our data suggest that patients at risk for more severe disease, such as those with high LDH, CRP and d-dimer, should be promptly referred to hospital care.

Sonic hedgehog therapy in a mouse model of age-associated impairment of skeletal muscle regeneration.

Sonic hedgehog (Shh) is a morphogen regulating muscle development during embryogenesis. We have shown that the Shh pathway is postnatally recapitulated after injury and during regeneration of the adult skeletal muscle and regulates angiogenesis and myogenesis after muscle injury. Here, we demonstrate that in 18-month-old mice, there is a significant impairment of the upregulation of the Shh pathway that physiologically occurs in the young skeletal muscle after injury. Such impairment is even more pronounced in 24-month-old mice. In old animals, intramuscular therapy with a plasmid encoding the human Shh gene increases the regenerative capacities of the injured muscle, in terms of Myf5-positive cells, regenerating myofibers, and fibrosis. At the molecular level, Shh treatment increases the upregulation of the prototypical growth factors, insulin-like growth factor-1 and vascular endothelial growth factor. These data demonstrate that Shh increases regeneration after injury in the muscle of 24-month-old mice and suggest that the manipulation of the Shh pathway may be useful for the treatment of muscular diseases associated with aging.

Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy.

OBJECTIVE: Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs. APPROACH AND RESULTS: We isolated vascular ECs from mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, and wild-type controls, and we found that mdx-derived ECs have impaired angiogenic properties, in terms of migration, proliferation, and tube formation. They also undergo increased apoptosis in vitro compared with wild-type cells and have increased senescence-associated ß-galactosidase activity. Mdx-derived ECs also display reduced ability to support myoblast proliferation when cocultured with satellite cell-derived primary myoblasts. These endothelial defects are mirrored by systemic impairment of angiogenesis in vivo, both on induction of ischemia, stimulation with growth factors in the corneal model and matrigel plug assays, and tumor growth. We also found that dystrophin forms a complex with endothelial NO synthase and caveolin-1 in ECs, and that NO production and cGMP formation are compromised in ECs isolated from mdx mice. Interestingly, treatment with aspirin enhances production of both cGMP and NO in dystrophic ECs, whereas low-dose aspirin improves the dystrophic phenotype of mdx mice in vivo, in terms of resistance to physical exercise, muscle fiber permeability, and capillary density. CONCLUSIONS: These findings demonstrate that impaired angiogenesis is a novel player and potential therapeutic target in Duchenne muscular dystrophy.

Combined therapy with sonic hedgehog gene transfer and bone marrow-derived endothelial progenitor cells enhances angiogenesis and myogenesis in the ischemic skeletal muscle.

We have previously demonstrated that sonic hedgehog (Shh) gene transfer improves angiogenesis in the setting of ischemia by upregulating the expression of multiple growth factors and enhancing the incorporation of endogenous bone marrow (BM)-derived endothelial progenitor cells (EPCs). In this study, we hypothesized that combined therapy with Shh gene transfer and BM-derived EPCs is more effective than Shh gene therapy alone in an experimental model of peripheral limb ischemia. We used old mice, which have a significantly reduced angiogenic response to ischemia, and compared the ability of Shh gene transfer, exogenous EPCs, or both to improve regeneration after ischemia. We found a significantly higher capillary density in the Shh + EPC-treated muscles compared to the other experimental groups. We also found that Shh gene transfer increases the incorporation and survival of transplanted EPCs. Finally, we found a significantly higher number of regenerating myofibers in the ischemic muscles of mice receiving combined treatment with Shh and BM-derived EPCs. In summary, the combination of Shh gene transfer and BM-derived EPCs more effectively promotes angiogenesis and muscle regeneration than each treatment individually and merits further investigation for its potential beneficial effects in ischemic diseases.

Pleiotropic beneficial effects of sonic hedgehog gene therapy in an experimental model of peripheral limb ischemia.

We have previously shown that the signaling pathway of the embryonic morphogen Sonic hedgehog (Shh) is recapitulated in the postnatal skeletal muscle in response to ischemia. We have also demonstrated that Shh is an indirect angiogenic agent upregulating various families of angiogenic growth factors and that Shh gene therapy improves angiogenesis and heart function in experimental models of myocardial ischemia. Based on these findings, we hypothesized that Shh gene therapy is beneficial in an experimental model of peripheral ischemia. We found that intramuscular (i.m.) treatment with a plasmid encoding the Shh human gene (phShh) increased blood flow, capillary density, and arteriole density in mice in which peripheral circulation of the hindlimb was disrupted by removal of the common femoral artery. Shh gene therapy also enhanced vasculogenesis, by increasing the number of circulating bone marrow (BM)-derived endothelial precursors and improving the contribution of these cells to the process of neovascularization. Finally, phShh treatment induced upregulation of prototypical angiogenic, arteriogenic, and vasculogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin 1 (Ang-1), and stromal cell-derived factor-1 (SDF-1α). These data suggest that Shh gene therapy merits further investigation for its ability to trigger the expression of potent trophic factors and stimulate pleiotropic aspects of neovascularization in the setting of ischemia.

Low-dose valganciclovir as preemptive therapy for cytomegalovirus infection occurring in allogeneic stem cell transplant recipients.

Few data are available to date on the dose of oral valganciclovir as cytomegalovirus (CMV) preemptive therapy in stem cell transplantation patients. This study aimed to evaluate the efficacy and safety of low-dose valganciclovir (900 mg/day) as preemptive treatment in allotransplanted recipients. Valganciclovir was used in 34 patients who underwent allogeneic stem cell transplantation for hematological malignancies at the dose of 900 mg oral administration/day (12 patients, group 1) or 1,800 mg oral administration/day (22 patients, group 2). Thirty-two out of 34 patients (94%) obtained negativization of polymerase chain reaction for CMV at a median of 12.5 days from the beginning of valganciclovir administration (10/12 patients of group 1, 22/22 patients of group 2). We conclude that oral administration of valganciclovir can induce clearance of CMV viral load in about 2 weeks; moreover, lower-dose oral valganciclovir (900 mg/day) has a comparable efficacy to the proposed standard dose (1,800 mg/day).

MTHFR polymorphisms involved in vitamin B12 deficiency associated with atrophic gastritis.

Genetic polymorphisms affecting methylentetrahydrofolate reductase (MTHFR) activity may influence hematological and neurological dysfunction in cobalamin-deficient patients. We studied the prevalence of C677T and A1298C polymorphisms by analyzing genomic DNA in 30 cobalamin-deficient patients. No significant difference was found in 677 and 1298 genotype distribution with respect to hematological parameters, B12 and folate levels, and neurological symptoms. The two MTHFR polymorphisms were not protective against anemia or neurological dysfunction in patients with cobalamin deficiency; however, we found evidence of a significant increase in atrophic gastritis in the 677TT group (P = 0.009) but not for the 1298CC genotype. Based on observations that inadequate cobalamin intake and reduced MTHFR activity might be significant risk factors for gastric cancer, and the increased risk of gastric cancer shown in patients affected by atrophic gastritis, we speculate that concomitant atrophic gastritis and impaired MTHFR function could have a role in the development of gastric cancer.

Severe veno-occlusive disease after autologous peripheral blood stem cell transplantation for high-grade non-Hodgkin lymphoma: report of a successfully managed case and a literature review of veno-occlusive disease.

Veno-occlusive disease (VOD) of the liver is a severe complication of high-dose chemotherapy and allogeneic or autologous stem cell transplantation with potential fatal outcome. We report a case of severe VOD in a patient with a high-grade B-cell lymphoma. Liver-venule occlusion was confirmed by liver biopsy. Supportive care, fibrinolytic treatment with recombinant tissue plasminogen activator and defibrotide maintenance therapy led to complete resolution of VOD demonstrated at liver biopsy and with a follow-up of 44 months after autologous peripheral blood stem cell transplantation. The literature on VOD has been reviewed.

MTHFR polymorphisms' influence on outcome and toxicity in acute lymphoblastic leukemia patients.

Recently the influence of polymorphisms of different genes involved in metabolism of chemoterapic agents have been studied especially in childhood acute lymphoblastic leukemia (ALL). We evaluated the influence of C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms on time to relapse and survival and on methotrexate (MTX) toxicity in 82 ALL adult patients. Relapse free survival and event free survival between homozygous wild-type and variant patients in both polymorphisms were not significantly different. However, we observed an association between 677TT variant and survival in a subset of ALL patients homogenously treated with MTX-based maintenance (p=0.02). In the same subgroup we confirmed the role of 677TT variant on toxicity during MTX treatment (p=0.003).

Analysis of MTHFR polymorphisms and P16 methylation and their correlation with clinical-biological features of multiple myeloma.

BACKGROUND: Low folate intake and changes in folate metabolism due to polymorphisms in the methylentetrahydrofolate reductase (MTHFR) gene have been associated with myelomagenesis. However, controversial data have been published regarding a protective role of variant alleles of MTHFR on MM. PATIENTS AND METHODS: To investigate the influence of two common polymorphisms of MTHFR C677T and A1298C on the risk of multiple myeloma (MM), we performed a matched case-control study. The methylation status pattern of p16 was also addressed. RESULTS: The frequency each of 677 CC, 677CT, and 677TT was 31, 44, and 25%, respectively, whereas, the frequency each of 1298 AA, AC, CC was 48, 44, and 8% in MM patients. In the control group, the frequency each of 677CC, 677CT, and 677TT was 36, 45, and 19%, respectively, while the frequency each of 1298 AA, AC, CC was 37, 50, and 13%, respectively. No significant association between susceptibility to MM, 677, and 1298 MTHFR variants was detected. As regards p16 methylation, we confirmed a high prevalence of p16 methylation (40%) in patients affected by MM and demonstrated that MTHFR 677CC is associated with a higher prevalence of p16 hypermethylation. CONCLUSIONS: Our data demonstrated that variant alleles did not play a key role neither in protection nor in increased risk for MM, suggesting that the effect of MTHFR on folate metabolism might be modified by diet intake. Moreover, our findings demonstrated that p16 hypermethylation might be a frequent genetic aberration in MM and may contribute with other molecular aberrations in the pathogenesis of this malignant disorder.