Cause specific mortality in an Italian pool of asbestos workers cohorts.

BACKGROUND: Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS: Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS: The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS: Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.

Longitudinal monitoring of SARS-CoV-2 viral load in self-collected saliva from health care workers during breakthrough infections to spare working days.

IMPORTANCE: Real-time quantitative PCR (RT-qPCR) on nasopharyngeal swabs (NPS) has been used as the standard method for detecting and monitoring SARS-CoV-2 infection during the pandemic. However, NPS collection often causes discomfort and poses a higher risk of transmission to health care workers (HCW). Furthermore, RT-qPCR only provides relative quantification and does not allow distinguishing those samples with residual, no longer active infection, whereas droplet digital PCR (ddPCR) allows for precise quantification of viral load, offering greater sensitivity and reproducibility. This study highlights the effectiveness of using self-collected saliva as a convenient and reliable sampling method. By utilizing ddPCR to measure the SARS-CoV-2 viral load in saliva samples, individuals with low or undetectable viral loads can be quickly identified. This approach is particularly advantageous for surveillance programs targeting HCW, as it enables the early identification and release of uninfected personnel, minimizing lost workdays. Additionally, analyzing viral load in saliva samples by ddPCR is valuable in determining virus shedding duration across different SARS-CoV-2 variants, informing transmission and disease control. Finally, testing saliva could overcome the detection of historic cases due to prolonged RNA swabbing past-infection and the unnecessary exclusion of those individuals from the workplace.

Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.

Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0-T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0-T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials.

Role of Diacylglycerol Kinases in Acute Myeloid Leukemia.

Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability.

Mammary nodules as incidental findings on chest computed tomography: a retrospective analysis on their frequency and predictive value.

PURPOSE: To evaluate the frequency of mammary nodules as incidental findings on chest CT scans and to determine a correlation between semiological features and mammographic and histopathological outcomes. METHODS: A total of 42,864 chest CT scans performed on patients with breast-unrelated working diagnoses by the Radiology Department at AOU Maggiore della Carità, between 1st January 2016 and 30th April 2022, were analysed. Sixty-eight patients (3 males and 65 females) with mammary nodule CT detection were selected and subjected to mammography, mammary ultrasound and, eventually, biopsy. RESULTS: Thirty-five of the 68 patients received a histopathological confirmation of malignancy. According to Pearson's Chi-square test, the CT features most likely associated with BI-RADS 5 following mammography were post-contrast enhancement (p = 0.001), margin irregularity (p = 0.0001), nipple retraction (p = 0.001), skin thickening (p = 0.024), and the presence of structurally atypical lymph nodes suspicious for metastatic involvement (p = 0.0001). The CT features predictive of a biopsy positive for malignancy were post-contrast enhancement (p = 0.0001), margin irregularity (p = 0.0001), and the presence of suspicious lymph nodes (p = 0.011). Finally, 63.4% of patients with a working diagnosis related to cancer were diagnosed with breast cancer. CONCLUSION: Chest CT incidental findings of mammary nodules had a 0.21% incidence rate. The accurate description of some CT scan features, such as post-contrast enhancement, margin irregularity, nipple retraction, skin thickening and the presence of structurally atypical lymph nodes, may help to establish a radiological suspicion of malignancy, especially if these characteristics are supported by a working diagnosis of cancer.

UPO Biobank: The Challenge of Integrating Biobanking into the Academic Environment to Support Translational Research.

Biobanks are driving motors of precision and personalized medicine by providing high-quality biological material/data through the standardization and harmonization of their collection, preservation, and distribution. UPO Biobank was established in 2020 as an institutional, disease, and population biobank within the University of Piemonte Orientale (UPO) for the promotion and support of high-quality, multidisciplinary studies. UPO Biobank collaborates with UPO researchers, sustaining academic translational research, and supports the Novara Cohort Study, a longitudinal cohort study involving the population in the Novara area that will collect data and biological specimens that will be available for epidemiological, public health, and biological studies on aging. UPO Biobank has been developed by implementing the quality standards for the field and the ethical and legal issues and normative about privacy protection, data collection, and sharing. As a member of the "Biobanking and Biomolecular Resources Research Infrastructure" (BBMRI) network, UPO Biobank aims to expand its activity worldwide and launch cooperation with new national and international partners and researchers. The objective of this manuscript is to report an institutional and operational experience through the description of the technical and procedural solutions and ethical and scientific implications associated with the establishment of this university research biobank.

Distinct Signatures of Tumor-Associated Microbiota and Metabolome in Low-Grade vs. High-Grade Dysplastic Colon Polyps: Inference of Their Role in Tumor Initiation and Progression.

According to the driver-passenger model for colorectal cancer (CRC), the tumor-associated microbiota is a dynamic ecosystem of bacterial species where bacteria with carcinogenic features linked to CRC initiation are defined as "drivers", while opportunistic bacteria colonizing more advanced tumor stages are known as "passengers". We reasoned that also gut microbiota-associated metabolites may be differentially enriched according to tumor stage, and be potential determinants of CRC development. Thus, we characterized the mucosa- and lumen-associated microbiota (MAM and LAM, respectively) and mucosa-associated metabolites in low- vs. high-grade dysplastic colon polyps from 78 patients. We show that MAM, obtained with a new biopsy-preserving approach, and LAM differ in composition and α/ß-diversity. By stratifying patients for polyp histology, we found that bacteria proposed as passengers by previous studies colonized high-grade dysplastic adenomas, whereas driver taxa were enriched in low-grade polyps. Furthermore, we report altered "mucosa-associated metabolite" levels in low- vs. high-grade groups. Integrated microbiota-metabolome analysis suggests the involvement of the gut microbiota in the production and consumption of these metabolites. Altogether, our findings support the involvement of bacterial species and associated metabolites in CRC mucosal homeostasis in a tumor-stage-specific manner. These distinct signatures may be used to distinguish low-grade from high-grade dysplastic polyps.

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry.

BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

The Italian Experience in the Development of Mesothelioma Registries: A Pathway for Other Countries to Address the Negative Legacy of Asbestos.

Asbestos (all forms, including chrysotile, crocidolite, amosite, tremolite, actinolite, and anthophyllite) is carcinogenic to humans and causally associated with mesothelioma and cancer of the lung, larynx, and ovary. It is one of the carcinogens most diffuse in the world, in workplaces, but also in the environment and is responsible for a very high global cancer burden. A large number of countries, mostly with high-income economies, has banned the use of asbestos which, however, is still widespread in low- and middle-income countries. It remains, thus, one of the most common occupational and environmental carcinogens worldwide. Italy issued an asbestos ban in 1992, following the dramatic observation of a large increase in mortality from mesothelioma and other asbestos-related diseases in exposed workers and also in subjects with non-occupational exposure. A mesothelioma registry was also organized and still monitors the occurrence of mesothelioma cases, conducting a case-by-case evaluation of asbestos exposure. In this report, we describe two Italian communities, Casale Monferrato and Broni, that faced an epidemic of mesothelioma resulting from the production of asbestos cement and the diffuse environmental exposure; we present the activity and results of the Italian mesothelioma registry (ReNaM), describe the risk-communication activities at the local and national level with a focus on international cooperation and also describe the interaction between mesothelioma registration and medical services specialized in mesothelioma diagnosis and treatment in an area at high risk of mesothelioma. Finally, we assess the potential application of the solutions and methods already developed in Italy in a city in Colombia with high mesothelioma incidence associated with the production of asbestos-cement materials and the presence of diffuse environmental asbestos pollution.

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.

INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

Long-Term Survival among Patients Hospitalized for COVID-19 during the First Three Epidemic Waves: An Observational Study in a Northern Italy Hospital.

The mortality rate of hospitalized COVID-19 patients differed strongly between the first three pandemic waves. Nevertheless, their long-term survival has been poorly assessed. The aim of this study was to compare the clinical characteristics and mortality rates of 825 patients with coronavirus disease 2019 (COVID-19) infection who were hospitalized at the Alessandria hub hospital, in Northern Italy, during the first fifty days of the first three pandemic waves. Each subject was followed in terms of vital status for six months from the date of hospital admission or until deceased. Patients admitted during the three waves differed in age (p = 0.03), disease severity (p < 0.0001), Charlson comorbidity index (p = 0.0002), oxygen therapy (p = 0.002), and invasive mechanical ventilation (p < 0.0001). By the end of follow-up, 309 deaths (38.7%) were observed, of which 186 occurred during hub hospitalization (22.5%). Deaths were distributed differently among the waves (p < 0.0001), resulting in being higher amongst those subjects admitted during the first wave. The COVID-19 infection was reported as the main cause of death and patients with a higher mortality risk were those aged ≥65 years [adjusted HR = 3.40 (95% CI 2.20-5.24)], with a higher disease severity [adjusted HR = 1.87 (95%CI 1.43-2.45)], and those requiring oxygen therapy [adjusted HR = 2.30 (95%CI 1.61-3.30)]. In conclusion, COVID-19 patients admitted to our hub hospital during the second and the third waves had a lower risk of long-term mortality than those admitted during the first. Older age, more severe disease, and the need for oxygen therapy were among the strongest risk factors for poor prognosis.

Public Attitude towards Biobanking: An Italian University Survey.

Biobanks have established a critical role in biomedical research by collecting, preserving, organizing, and disseminating biospecimens and related health data, contributing to precision medicine development. Participation in biobanks is influenced by several factors, such as trust in institutions and scientists, knowledge about biobanking, and the consideration of benefit sharing. Understanding public attitudes, fears, and concerns toward biobanking is fundamental to designing targeted interventions to increase trust towards biobanks. The aim of our study was to investigate the level of knowledge and perception of biobanks in students and personnel of the University of Piemonte Orientale. An online questionnaire was designed and administered via e-mail. A total of 17,758 UPO personnel and students were invited to participate in the survey, and 1521 (9.3%) subjects completed the survey. The results showed that 65.0% of the participants were aware of the term "biobank" and knew what the activity of a biobank was, and 76.3% of subjects were willing to provide biospecimens to a research biobank, whereas 67.3% of the respondents were willing to contribute, in addition to biospecimens, their health and lifestyle data. Concerns were raised about the confidentiality of the information (25.6%) and the commercial use of the samples (25.0%). In conclusion, participants were aware of the role that biobanks play in research and were eager to participate for the sake of furthering scientific research. Still, several concerns need to be addressed regarding the confidentiality of the data along with the commercial use of the samples and associated data.

Misophonia: Analysis of the neuroanatomic patterns at the basis of psychiatric symptoms and changes of the orthosympathetic/ parasympathetic balance.

Background/Aim: Misophonia is a disorder characterized by reduced tolerance to specific sounds or stimuli known as "triggers," which tend to evoke negative emotional, physiological, and behavioral responses. In this study, we aimed to better characterize participants with misophonia through the evaluation of the response of the autonomic nervous system to "trigger sounds," a psychometric assessment, and the analysis of the neurological pathways. Materials and methods: Participants included 11 adults presenting with misophonic disturbance and 44 sex-matched healthy controls (HCs). Following recently proposed diagnostic criteria, the participants listened to six "trigger sounds" and a "general annoyance" sound (baby crying) during a series of physiological tests. The effects were examined through functional magnetic resonance imaging (fMRI), the analysis of heart rate variability (HRV), and of galvanic skin conductance (GSC). The fMRI was performed on a 3T Scanner. The HRV was obtained through the analysis of electrocardiogram, whereas the GSC was examined through the positioning of silver-chloride electrodes on fingers. Furthermore, the psychometric assessment included questionnaires focused on misophonia, psychopathology, resilience, anger, and motivation. Results: Participants with misophonia showed patterns of increased sympathetic activation in response to trigger sounds and a general annoyance sound, the low frequency (LF) component of HRV, the sympathetic index, and the number of significant GSC over the threshold, where the amplitude/phasic response of GSC was higher. The fMRI analysis provided evidence for the activation of the temporal cortex, the limbic area, the ventromedial prefrontal/premotor/cingulate cortex, and the cerebellum in participants with misophonia. In addition, the psychometric assessment seemed to differentiate misophonia as a construct independent from general psychopathology. Conclusion: These results suggest the activation of a specific auditory-insula-limbic pathway at the basis of the sympathetic activation observed in participants with misophonia in response to "trigger and general annoyance sounds." Further studies should disentangle the complex issue of whether misophonia represents a new clinical disorder or a non-pathological condition. These results could help to build diagnostic tests to recognize and better classify this disorder. The relevance of this question goes beyond purely theoretical issues, as in the first case, participants with misophonia should receive a diagnosis and a targeted treatment, while in the second case, they should not.

Parental occupational exposure to combustion products, metals, silica and asbestos and risk of childhood leukaemia: Findings from the Childhood Cancer and Leukaemia International Consortium (CLIC).

Parental occupational exposures around conception (father) or during pregnancy (mother) have been hypothesized as potential predisposing factors for childhood leukaemia. We investigated parental exposure to several known occupational carcinogens and childhood leukaemia risk. We conducted a pooled analysis using case-control data from four European countries (3362 childhood leukemia cases and 6268 controls). Parental occupational exposures to polycyclic aromatic hydrocarbons (PAH), diesel engine exhaust (DEE), chromium, nickel, crystalline silica, and asbestos were assessed by a general population job-exposure matrix. We estimated odd ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models for all childhood leukaemia combined, by leukaemia type (ALL and AML) and by ALL subtype (B-lineage and T-lineage). We found an association between high paternal occupational exposure to crystalline silica and childhood ALL (OR 2.20, CI 1.60-3.01) with increasing trend from no exposure to high exposure (P = <0.001), and also for AML (OR 2.03, CI 1.04-3.97; P for trend = 0.008). ORs were similar for B- and T-lineage ALL. For ALL, ORs were also slightly elevated with wide confidence intervals for high paternal occupational exposure to chromium (OR 1.23, CI 0.77-1.96), and DEE (OR 1.21, CI 0.82-1.77). No associations were observed for paternal exposures to nickel, PAH and asbestos. For maternal occupational exposure we found several slightly elevated odds ratios but mostly with very wide confidence intervals due to low numbers of exposed mothers. This is a first study suggesting an association between fathers' occupational exposure to crystalline silica and an increased risk of childhood leukaemia in their offspring. As this association was driven by certain occupations (field crop farmers and miners) where other potentially relevant exposures like pesticides and radon may also occur, more research is needed to confirm our findings of an association with crystalline silica, and if so, mechanistic studies to understand the pathways.

One-Year Follow up of Noninvasive Respiratory Support in General Wards.

BACKGROUND: Noninvasive respiratory support (NRS) has been used to treat acute respiratory failure outside the ICU, but existing data have left many knowledge gaps for managing NRS in general wards. The primary objective of this study was to describe indications, duration of treatment, and outcomes of subjects treated with NRS outside the ICU. The secondary objective was to compare outcomes based on age < 80 or ≥ 80 y. METHODS: This retrospective observational study was conducted at Maggiore della Carità University Hospital in Novara, Italy, and included all patients treated with noninvasive ventilation (NIV) or CPAP outside the ICU from November 2017 to October 2018, with 1 year of follow-up. RESULTS: Of the 570 treatments performed, 383 subjects were analyzed, 136 NIV and 247 CPAP. Subjects' median (interquartile range [IQR]) age was 79 (72-85) y, and the main diagnoses of respiratory failure were cardiogenic pulmonary edema in 128 subjects (33%), pneumonia in 99 (26%), and COPD exacerbation in 52 (14%), with a median (IQR) treatment duration of 38 (16-74) h. Rapid response team visits lasted a median (IQR) 3 (2-6) d. Interface-related pressure lesions occurred in 13% of the subjects, in no case leading to definitive treatment discontinuation. Compared with the subjects ≥ 80 y old, the younger subjects had a median (IQR) longer hospitalization (16 [10-24] d vs 13 [9-20] d; P = .003) but slightly decreased in-hospital mortality (21% vs 30%; P = .061) and a decreased post-discharged 1-year mortality in hospital survivors (25% vs 41%; P = .002), differences observed only in the subjects treated with NIV. CONCLUSIONS: In a real-life setting outside the ICU, NIV and CPAP managed by a rapid response team with a daily visit in collaboration with ward staff highly experienced in NRS allowed us to treat the subjects without major complications. Post-discharge 1-year mortality was higher in the subjects ≥ 80 y old treated with NIV for acute hypercapnic respiratory failure.

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

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.

Time-Trends of Drug-Drug Interactions among Elderly Outpatients in the Piedmont Region (Italy): A Population-Based Study.

Adverse drug reactions (ADRs) are a major health problem in the primary care setting, particularly among the elderly population. While the high frequency of ADRs in the elderly has several causes, a major and common determinant is polypharmacy, which can in turn increase the risk of drug-drug interactions (DDIs). In this paper, we analyzed the drugs prescriptions dispensed to elderly outpatients, to assess changes in the prevalence of selected DDIs in the period 2013−2019. Overall, about 15% of the patients aged >65 years were poly-treated. Among them, a decreasing trend in prevalence was observed for the majority of DDIs during the study period. This trend was particularly noticeable for DDIs involving fluoroquinolones and vitamin K antagonists, where a sharp reduction of over 40% was observed. On the opposite, a small increase in prevalence was observed for the association of antidiabetics and beta-blocking agents and for that of clopidogrel and PPIs. While the occurrence of most of the considered DDIs among poly-treated elderly decreased over time, the prevalence of some of them is still worrying. The complexity of the national drug formularies, as well as the increased number of prescribing actors that are involved, further urges the update of DDI lists to be used to monitor drug appropriateness and reduce avoidable ADRs.