Developing approaches to control SARS-CoV-2 in a public hospital

The Territorial Public Health Care Company (in Italian, ASST) of the Saints Paolo e Carlo of Milano includes two large public hospitals, and several outpatients and territorial healthcare services. It employs 5642 workers. The outbreak of novel coronavirus disease 2019 (COVID-19) reached our ASST in the last week of February when a doctor in the Intensive Care Unit of the San Paolo Hospital was diagnosed with COVID-19. Our Occupational Health Unit immediately introduced measures to control the epidemic. Our approach was based on contact tracing and isolation of asymptomatic infected workers. A \u2018close contact\u2019 was defined as a person who had face-to-face contact or spent at least 15 min in an indoor environment with a positive subject (patient, colleague or relative) without any protective equipment (surgical mask). From 27 February to 23 April we tested 2907 workers (51% of the total workforce) with nasopharyngeal swabs (NPS) using rtPCR for SARS-CoV-2 detection [1,2], with positive results in 152 hospital and 33 territorial workers (3% of the total workforce). All the infected workers were asked to fill in a daily electronic data collection form for the duration of the infection. About 50% remained substantially asymptomatic for the quarantine period, which ended when the workers underwent two NPS on two consecutive days with a negative result. The time to recovery took from 12\u201347 days, with a median duration of about 30 days, which is longer than normally expected. Symptomatic workers showed only very mild symptoms; mainly loss/change of smell and taste. Four were hospitalized but none had severe or life-threatening infection. The data suggest that the \u2018active search approach\u2019 is more effective in closed communities such as groups of healthcare workers than generalized testing. We have started a retrospective survey of 100 positive workers studying symptoms, source of exposure and co-morbidities using a modified version of the \u2018WHO novel coronavirus acute respiratory infection clinical characterization data tool\u2019, administered by telephone interview. Finally, in order to prepare for future outbreaks, we are testing a novel telemedicine approach enabling us to follow quarantined workers with a digital platform with a mobile phone app that provides remote video examinations and online symptoms and health parameter checking (body temperature, oxygen saturation, etc.). The platform facilitates rapid intervention. Using this approach, we can follow a large cohort of workers with continuous monitoring. The tool may also be able to reduce the rate of patients\u2019 hospitalization. We are also comparing those with positive and negative swabs using a rapid immunochromatographic assay for the detection of IgG and IgM antibodies to SARS-CoV-2 virus in whole blood to assess potential immunity. Preliminary results are promising for IgG, even though the protective capacity of this immunoglobulin is still unknown

Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: Study design, and baseline urinary, bowel and sexual function and quality of life

Objectives: To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations. Materials and Methods: A total of 1643 randomized men, aged 50-69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999-2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men's age at biopsy and PSA testing time points for selected measures. Results: A total of 1438 participants completed biopsy questionnaires (88%) and 77-88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65-70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49-54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments. Conclusion: The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer

A General Definition and Nomenclature for Alternative Splicing Events

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells is one of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenon contributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora of different transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify the different types of reflected splicing variation. In this work, we present a general definition of the AS event along with a notation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assigns a specific “AS code” to every possible pattern of splicing variation. On the basis of this definition and the corresponding codes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of AS events in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversity across genes, chromosomes, and species. Our analysis reveals that a substantial part—in human more than a quarter—of the observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate and to compare the AS landscape of different reference annotation sets in human and in other metazoan species and found that proportions of AS events change substantially depending on the annotation protocol, species-specific attributes, and coding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conduct specific studies investigating the occurrence, impact, and regulation of AS

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer

Abstract: Background: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer. Methods: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years’ median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk. Results: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups. Conclusions: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man’s lifetime. Trial registration: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014)

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

A prospective cohort and extended comprehensive-cohort design provided insights about the generalizability of a pragmatic trial:the ProtecT prostate cancer trial

Objectives Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability. Study Design and Setting Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct. Results The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa. Conclusion The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Aging and work in Italy : Under the project Epsilon - European Partnership for preventions and Social Innovation through training and science, founded under the operational program Human Resources Development

Aging is the one of the most relevant phenomenon affecting nowadays the population of the economically developed countries, including Europe, but the same concept of "aged worker" can have several different meanings depending on the context. In ltaly, the elderly workers pose specific problems, due to the reduction of fitness tor specific jobs and the increase in the presence of chronic diseases. The health of elderly is in charge of the ltalian National Health Care System (INHS), but the specific health problems of the elderly are dealt also at the workplace both during the usual activities of health surveillance of workers and through specific health promotion programs not always developed. In Italy, for example, several companies, under the guidance of their occupational physicians, carry out such programs, even though very seldom they are specifically targeted at aging. More often specific age related actions are part of a broader health surveillance activity addressed at work related disorders, cancer prevention or lifestyle improvement. Available data demonstrate that several jobs well suit for aged workers. Therefore, creating sound occupational options for the elderly who, for their experience, knowledge and capacity are a fundamental resource, is an important task for occupational medicine, together with the development of training and educational activities addressed at promoting their resilience

Messa a punto di protocolli per la sorveglianza sanitaria dei lavoratori agricoli lombardi

This paper describes a project addressed at improving the activities of health surveillance of agricultural workers carried out in the Region of Lombardy. The main objectives of the project are the definition of specific protocols specifically addressed at specific exposure and risk groups and at harmonizing the approach carried out by different occupational health physicians in different rural enterprises. To this aim, we have defined the following main types of working tasks, with a particular attention to occupational exposures and risk assessment outcomes: farmer engaged only in crop growing (different kinds of crops, including greenhouses); public and private gardens maintenance; animal breeding (different kinds of animals); fish breeders; worker engaged in rural tourist enterprises. The final objective of this project is enlarging the number of agricultural workers provided with health surveillance at the workplace, based only to evidence of exposure to risk factors and independently from the type of engagement in the enterprises. Health surveillance is provided directly at the workplace. We have pointed out an approach based on a common panel of medical, laboratory and instrumental investigations, accompanied with specific examinations addressed at specific risk groups. The main results of this project, together with its criticisms, will yearly checked, up while the future periodicity of examination will be defined based on the statistical elaboration of the data and the results of risk assessment activities. The main risk factors that we have considered are: biological risk; chemical risk; noise and vibrations; muscle and skeletal risks, climatic conditions (particularly, heat exposition); exposure to allergens. This harmonized approach will pose the basis for a sound data collection and elaboration, with the possibility of producing sound epidemiological data on the agricultural workers of our Region