The Effects of Air Pollution on COVID-19 Related Mortality in Northern Italy.

Long-term exposure to ambient air pollutant concentrations is known to cause chronic lung inflammation, a condition that may promote increased severity of COVID-19 syndrome caused by the novel coronavirus (SARS-CoV-2). In this paper, we empirically investigate the ecologic association between long-term concentrations of area-level fine particulate matter (PM2.5) and excess deaths in the first quarter of 2020 in municipalities of Northern Italy. The study accounts for potentially spatial confounding factors related to urbanization that may have influenced the spreading of SARS-CoV-2 and related COVID-19 mortality. Our epidemiological analysis uses geographical information (e.g., municipalities) and negative binomial regression to assess whether both ambient PM2.5 concentration and excess mortality have a similar spatial distribution. Our analysis suggests a positive association of ambient PM2.5 concentration on excess mortality in Northern Italy related to the COVID-19 epidemic. Our estimates suggest that a one-unit increase in PM2.5 concentration (µg/m3) is associated with a 9% (95% confidence interval: 6-12%) increase in COVID-19 related mortality.

γ-Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down-regulation.

γ-Secretase inhibitors (GSIs) have been proposed for combined therapies of malignancies with a dysregulated Notch signaling. GSI I (Z-Leu-Leu-Nle-CHO) induces apoptosis of some tumor cells by inhibiting proteasome and Notch activity. Alterations in these two cell survival regulators contribute to apoptosis resistance of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the mechanisms whereby GSI I increases apoptosis of primary CLL cells. Time-course studies indicate that initial apoptotic events are inhibition of proteasome activity, concomitant with an increased endoplasmic reticulum (ER) stress apoptotic signaling, and a consistent Noxa protein up-regulation. These events precede, and some of them contribute to, mitochondrial alterations, which occur notwithstanding Mcl-1 accumulation induced by GSI I. In CLL cells, GSI I inhibits Notch1 and Notch2 activation only in the late apoptotic phases, suggesting that this event does not initiate CLL cell apoptosis. However, Notch inhibition may contribute to amplify GSI I-induced CLL cell apoptosis, given that Notch activation sustains the survival of these cells, as demonstrated by the evidence that both Notch1 and Notch2 down-regulation by small-interfering RNA accelerates spontaneous CLL cell apoptosis. Overall, our results show that GSI I triggers CLL cell apoptosis by inhibiting proteasome activity and enhancing ER stress, and amplifies it by blocking Notch activation. These findings suggest the potential relevance of simultaneously targeting these three important apoptosis regulators as a novel therapeutic strategy for CLL.

T regulatory cell separation for clinical application.

We selected T regulatory cells (Tregs) from standard leukapheresis using double-negative selection (anti-CD8 and anti-CD19) followed by positive selection (anti-CD25) and 72 procedures were performed. A median of 263×10(6)cells (range 143-470×10(6)) were recovered with a mean of CD4(+)/CD25(+) cells of 94.5±2.4% (36.5±18.6% CD4(+)/CD25(+hi)). FoxP3(+) cells were equal to 79.8%±22.2. CD127(+) cells were 12.5%±8.2. The inhibition assay showed an inhibition rate of 67±22. Cells isolated by means of this approach can be used in allogeneic hematopoietic stem cell transplantation to reduce the incidence and severity of GvHD without bystander inhibition of general immunity.

Pharmaceutical companies and Italian Regional Governments: managing relationships in an increasing institutional complexity.

In Italy, the process of power decentralization to Regional Governments has particularly affected pharmaceutical care policies. Regions are experimenting with various strategies to govern drugs utilization and expenditure, and differentiating their approaches, leading to an ever-changing and complex institutional scenario. Pharmaceutical companies have created new professional roles, the Regional Affairs Managers (RAM), with the mandate to monitor the different regional contexts and measures, and to establish relationships with the public actors in charge of pharmaceutical policies. This analysis shows how public affairs/lobbying actions at regional level and the creation of a solid political competence within companies are still in an early phase. The activities carried out by RAMs remain limited to an exchange of information and only rarely are perceived by Regional public servants (RRs) as giving support to their work or influence decisions. The interaction with RAMs is often seen as little relevant and still too concentrated on products and a marketing/commercial approach rather than on broader issues of interest to RRs who need to manage the pharmaceutical care system at large. The level of acceptance of this type of activity is also variable and RRs' attitudes alternate between diffidence, polite tolerance, and openness to a constructive dialogue about pharmaceuticals and their management in a regional healthcare system.

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.

Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study.

BACKGROUND: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries. PATIENTS AND METHODS: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy. RESULTS: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively. CONCLUSIONS: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.

Depressão pós-parto: incidência e fatores de risco associados / Postpartum depression: incidence and risk factors associate

As doenças psiquiátricas do pós-parto foram reconhecidas como transtorno específico há pouco tempo. São, por isso, pouco pesquisadas e de escasso conhecimento. Contudo, mostram-se de identificação importante pela morbidade e frequência com que acometem as puérperas. A prevalência de depressão pós-parto (DPP) é de 10-15%, com estudos apontando para 22%. Sua etiologia é multifatorial e inclui fatores biológicos, psicológicos e sociais, podendo durar até um ano após o parto. Buscou-se avaliar a incidência de DPP em puérperas no primeiro ano de pós-parto na cidade de Curitiba – PR, tentando ainda identificar as mudanças de humor ocorridas no pós-parto e os principais fatores de risco associados ao desenvolvimento da DPP. Aplicaram-se dois questionários, com o perfil socioeconômico e a Escala de Depressão Pós-Parto de Edimburgo, visando rastrear mães com sintomas compatíveis com DPP. Pontuações maiores ou iguais a 10 foram consideradas positivas e encaminhadas para avaliação com profissional especializado. Os dados foram avaliados estatisticamente pelo programa SPSS 10.0. Analisaram se 146 mães, com média etária de 28,97 anos e período de pós-parto majoritário de 3-6 meses. Houve predomínio de mães casadas, com ensino superior e renda de 4-6 salários mínimos. Um total de 31,5% das mães apresentou escore compatível com DPP, sem pico de incidência em relação ao período de pósparto. Relacionamento insatisfatório mostrou-se como fator de risco para DPP e ajuda insatisfatória como possível fator. Idade e escolaridade maternas, estado civil e renda, não mostraram relevância estatística. Encontrou-se média de casos compatíveis com DPP acima da descrita na literatura, entretanto, tal média apresenta-se com grande variação, evidenciado o caráter cultural e ambiental do transtorno.

Postpartum psychiatric illnesses were recognized as specific disorder recently. Therefore, they are under-researched and there’s few knowledge about them. However, the diagnosis is important due to morbidity and frequency that affects the mothers. The prevalence of postpartum depression (PPD) is 10-15%, with studies pointing to 22%. Its etiology is multifactorial and includes biological, psychological and social factors, and may last up to one year after delivery. We sought to evaluate the incidence of PPD in mothers during the first year postpartum in Curitiba - PR, still trying to identify mood changes occurring in the postpartum period and the main risk factors associated with the development of PPD. We applied two questionnaires, the socioeconomic profile and Edinburgh Postnatal Depression Scale, aiming to track mothers with symptoms compatible with PPD. Scores greater than or equal to 10 were considered positive and referred for evaluation with a specialized professional. The data were statistically analyzed bySPSS 10.0. We analyzed 146 mothers with a mean age of 28.97 years and the postpartum period majority of 3-6 months. There was a predominance of married mothers with higher education and income of 6.4 minimum wages. A total of 31.5% of mothers had scores compatible with PPD, without peak regarding the period after delivery. Unsatisfactory relationship proved to be a risk factor for PPD and helps unsatisfactory as a possible factor. Age and maternal education, marital status and income showed no statistical significance. It’s was found an average of DPP compatible cases above the described in the literature, however,this average is presented with great variation, indicating the culturaland environmental character of the disorder.