Statins and aspirin in the prevention of cardiovascular disease among HIV-positive patients between controversies and unmet needs: Review of the literature and suggestions for a friendly use

Background: As in non-infected subjects, statins and aspirin have a pivotal preventive role in reducing the cardiovascular related morbidity and mortality in HIV infected patients. The persistence of immune activation in these subjects, could contribute to accelerate atherosclerosis, therefore, these treatments that reduce inflammation could provide additional cardiovascular protection. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. Aim of the present position paper is to provide recommendations aimed to overcome the actual differences and limitations among the current ones and to adapt them to the needs of HIV infected patients. Results: We propose to adopt the new ACC/AHA guidelines, simple to use and cost effective, to use the ASCVD score that seems to estimate more accurately the cardiovascular risk among these patients. We suggest to start statin therapy in all patients with a calculated 10-year risk of a cardiovascular event of 10% or greater. Rosuvastatin and atorvastatin should be preferred. LDL-C target may be adopted. Aspirin should be always associated with a statin, in secondary prevention, while in primary prevention it should be reserved only to patients with 65 20% 10-year risk particularly adherent to treatments, and with low risk of bleeding. We suggest to start with a dose of 100 mg/day. Finally, management of antiplatelet agents or novel oral anticoagulants may include selecting antiretrovirals with a lower potential for drug interactions or choosing agents least likely to interact with antiretrovirals. Conclusions: As demonstrated in surveys, HIV physicians are generally highly committed regarding CVD and autonomous in prescribing statins and ASA. Consequently, in the light of the previously discussed discrepancies among the different guidelines and of the incomplete indications regarding HIV-positive persons, the present suggestions could overcome the actual differences and limitations among the current ones

High Altitude test of RPCs for the ARGO-YBJ experiment

A 50 m**2 RPC carpet was operated at the YangBaJing Cosmic Ray Laboratory (Tibet) located 4300 m a.s.l. The performance of RPCs in detecting Extensive Air Showers was studied. Efficiency and time resolution measurements at the pressure and temperature conditions typical of high mountain laboratories, are reported.Comment: 16 pages, 10 figures, submitted to Nucl. Instr. Met

Observation of TeV gamma-rays from the unidentified source HESS J1841-055 with the ARGO-YBJ experiment

We report the observation of a very high energy \gamma-ray source, whose position is coincident with HESS J1841-055. This source has been observed for 4.5 years by the ARGO-YBJ experiment from November 2007 to July 2012. Its emission is detected with a statistical significance of 5.3 standard deviations. Parameterizing the source shape with a two-dimensional Gaussian function we estimate an extension \sigma=(0.40(+0.32,-0.22}) degree, consistent with the HESS measurement. The observed energy spectrum is dN/dE =(9.0-+1.6) x 10^{-13}(E/5 TeV)^{-2.32-+0.23} photons cm^{-2} s^{-1} TeV^{-1}, in the energy range 0.9-50 TeV. The integral \gamma-ray flux above 1 TeV is 1.3-+0.4 Crab units, which is 3.2-+1.0 times the flux derived by HESS. The differences in the flux determination between HESS and ARGO-YBJ, and possible counterparts at other wavelengths are discussed.Comment: 17 pages, 4 figures, have been accepted for publication in Ap

Ex vivo Drug Sensitivity Imaging-based Platform for Primary Acute Lymphoblastic Leukemia Cells

Resistance of acute lymphoblastic leukemia (ALL) cells to chemotherapy, whether present at diagnosis or acquired during treatment, is a major cause of treatment failure. Primary ALL cells are accessible for drug sensitivity testing at the time of new diagnosis or at relapse, but there are major limitations with current methods for determining drug sensitivity ex vivo. Here, we describe a functional precision medicine method using a fluorescence imaging platform to test drug sensitivity profiles of primary ALL cells. Leukemia cells are co-cultured with mesenchymal stromal cells and tested with a panel of 40 anti-leukemia drugs to determine individual patterns of drug resistance and sensitivity ("pharmacotype"). This imaging-based pharmacotyping assay addresses the limitations of prior ex vivo drug sensitivity methods by automating data analysis to produce high-throughput data while requiring fewer cells and significantly decreasing the labor-intensive time required to conduct the assay. The integration of drug sensitivity data with genomic profiling provides a basis for rational genomics-guided precision medicine. Key features Analysis of primary acute lymphoblastic leukemia (ALL) blasts obtained at diagnosis from bone marrow aspirate or peripheral blood. Experiments are performed ex vivo with mesenchymal stromal cell co-culture and require four days to complete. This fluorescence imaging-based protocol enhances previous ex vivo drug sensitivity assays and improves efficiency by requiring fewer primary cells while increasing the number of drugs tested to 40. It takes approximately 2-3 h for sample preparation and processing and a 1.5-hour imaging time. Graphical overview

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study

BACKGROUND: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe. METHODS: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing. FINDINGS: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57–77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19–0·61) and 28 days (0·34 [0·16–0·79]), complications due to COVID-19 (0·26 [0·17–0·46]), and hospitalisation due to COVID-19 (0·17 [0·09–0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15–0·34]) and oxygen therapy (0·24 [0·14–0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase. INTERPRETATION: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19. FUNDING: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust

Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective

Background: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. Methods: From the OnCovid repository (N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT− not referred). Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more ‘Do not attempt cardio-pulmonary resuscitation’ orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p < 0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% versus 22.1%, p < 0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% versus 0%, p < 0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control. Conclusion: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population

Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study

Background: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. Methods: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients’ death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. Findings: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4–57·8) from cancer diagnosis and 44 days (28–329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113–148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio [HR] 1·80 [95% CI 1·18–2·75]) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 [95% CI 1·45–8·59]), but dose or regimen adjustments were not (0·84 [0·35–2·02]). Interpretation: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients. Funding: National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score

Background: Cancer patients are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and Covid-19. We investigated systemic inflammation as a driver of severity and mortality from Covid-19, evaluating the prognostic role of commonly utilized inflammatory indices in SARS-CoV-2-infected cancer patients accrued to the OnCovid study. Methods: In a multi-center cohort of SARS-CoV-2-infected cancer patients in Europe, we evaluated dynamic changes in neutrophil-lymphocyte ratio (NLR); platelet-lymphocyte ratio (PLR); prognostic nutritional index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow prognostic score (mGPS); and prognostic index (PI) in relationship to oncological and Covid-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results: We evaluated 1,071 eligible patients: 625 (58.3%) males, 420 with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) ≥1 Covid-19 complication. NLR, OIS, and mGPS worsened at Covid-19 diagnosis compared to pre-Covid-19 measurement (P<0.01), recovering in survivors to pre-Covid-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (P<0.001) and shorter median overall survival in the training and validation sets (P<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 – 4.20, P=0.001; adjusted C-index 0.611). Conclusions: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected cancer patients and can be utilized as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe Covid-19, supporting their use for risk stratification. Reversal of the Covid-19-induced pro-inflammatory state is a putative therapeutic strategy in patients with cancer

“Impaired adipokine profile in HIV positive patients without metabolic syndrome: the role of antiretroviral therapy.”

Adipose tissue secretes of a range of biologically active proteins called adipokines. Dysregulation of adipokines is implicated in the etiology of insulin resistance and metabolic syndrome, but the relation between adiponectin, leptin and antiretroviral therapy has been poorly studied and subject to controversy. This study investigated the relation between plasma adipokine levels and different antiretroviral drug exposure in HIV positive subjects with similar metabolic and anthropometric parameters and without metabolic syndrome. Our data show that antiretroviral drugs impair the adipokine and osteoprotegerin profiles in HIV positive patients without metabolic syndrome and in the absence of impaired glycemic and lipidic parameters