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Background It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations. The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations. Methods 914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and

Background Carpal tunnel syndrome (CTS) is a socially and economically relevant disease caused by compression or entrapment of the median nerve within the carpal tunnel. This population-based case-control study aims to investigate occupational/non-occupational risk factors for surgically treated CTS. Methods Cases (n = 220) aged 18-65 years were randomly drawn from 13 administrative databases of citizens who were surgically treated with carpal tunnel release during 2001. Controls (n = 356) were randomly sampled from National Health Service registry records and were frequency matched by age-gender-specific CTS hospitalization rates. Results At multivariate analysis, risk factors were blue-collar/housewife status, BMI ≥ 30 kg/m2, sibling history of CTS and coexistence of trigger finger. Being relatively tall (cut-offs based on tertiles: women ≥165 cm; men ≥175 cm) was associated with lower risk. Blue-collar work was a moderate/strong risk factor in both sexes. Raised risks were apparent for combinations of biomechanical risk factors that included frequent repetitivity and sustained force. Conclusion This study strongly underlines the relevance of biomechanical exposures in both non-industrial and industrial work as risk factors for surgically treated CTS.

Tumors undergo dynamic immunoediting as part of a process that balances immunologic sensing of emerging neoantigens and evasion from immune responses. Tumor-infiltrating lymphocytes (TIL) comprise heterogeneous subsets of peripheral T cells characterized by diverse functional differentiation states and dependence on T-cell receptor (TCR) specificity gained through recombination events during their development. We hypothesized that within the tumor microenvironment (TME), an antigenic milieu and immunologic interface, tumor-infiltrating peripheral T cells could reexpress key elements of the TCR recombination machinery, namely, Rag1 and Rag2 recombinases and Tdt polymerase, as a potential mechanism involved in the revision of TCR specificity. Using two syngeneic invasive breast cancer transplantable models, 4T1 and TS/A, we observed that Rag1, Rag2, and Dntt in situ mRNA expression characterized rare tumor-infiltrating T cells. In situ expression of the transcripts was increased in coisogenic Mlh1-deficient tumors, characterized by genomic overinstability, and was also modulated by PD-1 immune-checkpoint blockade. Through immunolocalization and mRNA hybridization analyses, we detected the presence of rare TDT+RAG1/2+ cells populating primary tumors and draining lymph nodes in human invasive breast cancer. Analysis of harmonized single-cell RNA-sequencing data sets of human cancers identified a very small fraction of tumor-associated T cells, characterized by the expression of recombination/revision machinery transcripts, which on pseudotemporal ordering corresponded to differentiated effector T cells. We offer thought-provoking evidence of a TIL microniche marked by rare transcripts involved in TCR shaping.

Background: Workplace physical aggressions determine severe consequences for people and organizations. Previous studies reported their spread in organizations and described factors related to their occurrence (e.g. aggressor within/ outside the organization, type of activity, etc.). However, such data are not available in the Italian work contexts, limiting the possibility of intervention. Objectives: This study aims to provide a description of workplace physical aggressions in the Italian context and the Emilia-Romagna region, considering the main variables described in the literature. Methods: We used data available from the "Flussi informativi" database, containing national data provided by INAIL (National Institute for Insurance against Accidents at Work), which concern all injuries, occupational illness and insured companies’ information, from 2000 to 2018. Information about aggressions in the workplace in Italy and Emilia-Romagna are derived from a subset of these data, coded according to ESAW (European Statistics for Accidents at Work) requirements. The number of events per year per 100,000 estimated insured employees by INAIL is considered as an indicator. Results: In the period 2014-2018, 23,084 injures from aggression were registered in Italy (an average of 28.7 events per 100,000 employees) and 2,308 in Emilia Romagna (30.2). Aggressions by people outside the organization accounted for 85.14 % in Italy and 87.87 % in Emilia-Romagna region. “Health and social services”, “Offices and other activities” and “Transportation” were the sectors that showed the highest numbers of events and rates. Furthermore, we reported detailed results about the variation of the events between professions, the site and nature of the lesion and gravity of events. Discussion: The study provides a description of workplace physical aggressions in the Italian context and we discuss the implication of these results for primary, secondary and tertiary prevention strategies of intervention.

Background Intra-tumour heterogeneity in lymphoid malignancies encompasses selection of genetic events and epigenetic regulation of transcriptional programs. Clonal-related neoplastic cell populations are unsteadily subjected to immune editing and metabolic adaptations within different tissue microenvironments. How tissue-specific mesenchymal cells impact on the diversification of aggressive lymphoma clones is still unknown. Methods Combining in situ quantitative immunophenotypical analyses and RNA sequencing we investigated the intra-tumour heterogeneity and the specific mesenchymal modifications that are associated with A20 diffuse large B-cell lymphoma (DLBCL) cells seeding of different tissue microenvironments. Furthermore, we characterized features of lymphoma-associated stromatogenesis in human DLBCL samples using Digital Spatial Profiling, and established their relationship with prognostically relevant variables, such as MYC. Findings We found that the tissue microenvironment casts a relevant influence over A20 transcriptional landscape also impacting on Myc and DNA damage response programs. Extending the investigation to mice deficient for the matricellular protein SPARC, a stromal prognostic factor in human DLBCL, we demonstrated a different immune imprint on A20 cells according to stromal Sparc proficiency. Through Digital Spatial Profiling of 87 immune and stromal genes on human nodal DLBCL regions characterized by different mesenchymal composition, we demonstrate intra-lesional heterogeneity arising from diversified mesenchymal contextures and impacting on the stromal and immune milieu. Interpretation Our study provides experimental evidence that stromal microenvironment generates topological determinants of intra-tumour heterogeneity in DLBCL involving key transcriptional pathways such as Myc expression, damage response programs and immune checkpoints. Funding This study has been supported by the Italian Foundation for Cancer Research (AIRC) (grants 15999 and 22145 to C. Tripodo) and by the University of Palermo.

Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds.

Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival1-3, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival4-7. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies8,9. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3ß) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3ß activity and are rescued from their competitive growth disadvantage by GSK3ß inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3ß activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells.

Objective In response to a request for a medicolegal opinion from an orthopaedic technician with pacinian neuroma of the hand, we conducted a systematic review of reported cases designed to assess whether this rare disease could be considered to be work-related. Methods We used Medline, Embase, Google Scholar, Google, and a manual search to identify reports of histologically confirmed pacinian neuroma of the hand manifesting after 15 years of age. Cases with available information (from article/authors) on personal history were considered eligible. We tabulated information on age/gender; localization and histopathologic features; signs/symptoms; history of local trauma; occupation, sports/hobbies or other physical exposures; right- or left-handedness; and outcome. Results We found 44 eligible cases (including the present referral). Of these, 21 (48%) followed a trauma [

Objective To compare the yield of hand-searching with optimised electronic search strategies in retrieving occupational health (OH) intervention studies published in a language other than English. Methods The authors systematically hand-searched and screened reports of OH intervention studies published in Italian in peer-reviewed scientific journals between 1990 and 2008. The authors evaluated how many of them met the Cochrane Occupational Safety and Health Review Groups (OSHRG) definition of being an OH intervention study and how many potentially relevant studies retrieved by hand-searching would not be found by PubMed alone using the OSHRG's most specific and most sensitive search strings. Results Hand-searching retrieved 25 articles (reporting 27 studies), including nine not indexed in MEDLINE. Most studies (81%, 22/27) had a before-after design and only one was a randomised trial. The OSHRG's most sensitive search string retrieved all 16 articles published in the Italian language journals that were indexed in MEDLINE, while the most specific search strategy retrieved nine articles (56%, 9/16). The most specific search string showed a lower 'number needed to read' value than the most sensitive one (60 vs 132). Conclusions These findings suggest that a sensitive electronic search strategy may be able to find most of the OH interventions published in languages other than English that are indexed in MEDLINE. Hand-searching of important national journals not indexed in MEDLINE should be considered when conducting particularly in-depth research.

Background: to explore explanations for elevated mortality from diabetes among male garment manufacturers and repairers in England and Wales during 1979-1990, analysis was extended by 10 years, looking also at other textile workers and at deaths from ischaemic heart disease (IHD).Methods: data on some 3.5 million deaths were used to compute proportional mortality ratios (PMRs) for diabetes and IHD, standardised for age and social class, in 10 textile-associated job groups, with additional analyses by place of birth for 1993–2000.Results: male mortality from diabetes was elevated in nine of the 10 textile jobs, with overall PMRs of 147 (95% CI 131 to 165) during 1979–90 and 170 (95% CI 144 to 199) during 1991–2000. Proportional mortality from IHD was also consistently high. Female mortality from both diseases was close to that for other occupations. In both sexes, mortality from diabetes and IHD was increased among people born in the Indian subcontinent (PMRs 353 and 139 in men; 262 and 130 in women). In men, the proportion of deceased textile workers born in the Indian subcontinent (11.4%) was much higher than for all occupations (1.8%), but not in women (1.1% vs 0.7%). PMRs for male textile workers standardised for place of birth were lower but still significantly elevated (133, 95% CI 110 to 159 for diabetes; 109, 95% CI 105 to 114 for IHD).Conclusions: no obvious occupational hazard explains the increased risk specific to men across a wide range of textile occupations. One possible explanation is uncontrolled residual confounding related to place of birth. This could be tested through suitably designed morbidity surveys

Objective: To identify efficient PubMed search strategies to retrieve articles regarding putative occupational determinants of conditions not generally considered to be work related. Methods: Based on MeSH definitions and expert knowledge, we selected as candidate search terms the four MeSH terms describing 'occupational disease', 'occupational exposure', 'occupational health' and 'occupational medicine' (DEHM) alongside 22 other promising terms. We first explored overlaps between the candidate terms in PubMed. Using random samples of abstracts retrieved by each term, we estimated the proportions of articles containing potentially pertinent information regarding occupational aetiology in order to formulate two search strategies (one more 'specific', one more 'sensitive'). We applied these strategies to retrieve information on the possible occupational aetiology of meningioma, pancreatitis and atrial fibrillation. Results: Only 20.3% of abstracts were retrieved by more than one DEHM term. The more 'specific' search string was based on the combination of terms that yielded the highest proportion (40%) of potentially pertinent abstracts. The more 'sensitive' string was based on the use of broader search fields and additional coverage provided by other search terms under study. Using the specific string, the numbers of abstracts needed to read to find one potentially pertinent article were 1.2 for meningioma, 1.9 for pancreatitis and 1.8 for atrial fibrillation. Using the sensitive strategy, the numbers needed to read were 4.4 for meningioma, 8.9 for pancreatitis and 10.5 for atrial fibrillation. Conclusions: The proposed strings could help health care professionals explore putative occupational aetiology for diseases that are not generally thought to be work related.

OBJECTIVES: Rates of surgically treated carpal tunnel syndrome (CTS) among blue- and white-collar workers and housewives in the general population were compared. METHODS: Surgically treated cases of idiopathic CTS were investigated among 25-59-year-old residents of Tuscany, Italy, during 1997-2000, based on obligatory discharge records from all Italian public/private hospitals, archived according to residence on Tuscany's regional database. Population data were extracted from the 2001 census. RESULTS: After excluding repeat admissions, 8801 eligible cases were identified. Age-standardised rates (per 100 000 person-years) of surgical CTS were: "blue-collar women", 367.8; "white-collar women", 88.1; "housewives", 334.5; "blue-collar men", 73.5; and "white-collar men", 15.3. Compared with reference categories (same-sex white-collar workers): female blue-collar workers experienced a 4.2-fold higher standardised rate; housewives, a 3.8-fold excess; and male blue-collar workers, a 4.8-fold excess (all p

Background Carpal tunnel syndrome (CTS) is a socially relevant condition associated with biomechanical risk factors. We evaluated age-sex-specific incidence rates of in-hospital cases of CTS in central/northern Italy and explored relations with marital status. Methods Seven regions were considered (overall population, 14.9 million) over 3–6-year periods between 1997 and 2002 (when out-of-hospital CTS surgery was extremely rare). Incidence rates of in-hospital cases of CTS were estimated based on 1) codified demographic, diagnostic and intervention data in obligatory discharge records from all Italian public/private hospitals, archived (according to residence) on regional databases; 2) demographic general population data for each region. We compared (using the χscore test) age-sex-specific rates between married, unmarried, divorced and widowed subsets of the general population. We calculated standardized incidence ratios (SIRs) for married/unmarried men and women. Results Age-standardized incidence rates (per 100,000 person-years) of in-hospital cases of CTS were 166 in women and 44 in men (106 overall). Married subjects of both sexes showed higher age-specific rates with respect to unmarried men/women. SIRs were calculated comparing married vs unmarried rates of both sexes: 1.59 (95% confidence interval [95% CI], 1.57–1.60) in women, and 1.42 (95% CI, 1.40–1.45) in men. As compared with married women/men, widows/widowers both showed 2–3-fold higher incidence peaks during the fourth decade of life (beyond 50 years of age, widowed subjects showed similar trends to unmarried counterparts). Conclusion This large population-based study illustrates distinct age-related trends in men and women, and also raises the question whether marital status could be associated with CTS in the general population.

People with myopia (near sightedness) are at increased risk for retinal detachment. We explored other factors that may be associated with retinal detachment within this high-risk group.We conducted a case-control study comprising 61 cases with retinal detachment and myopia and 99 hospital controls who also had myopia. Cases were recruited from a general hospital, and controls from ophthalmologic clinics. Participants compiled a questionnaire including details of past and current occupational lifting tasks to explore Valsalva maneuver as a possible risk factor. We devised a cumulative lifting index to distinguish light and heavy lifting.After adjusting for potential confounders, we found strong associations of retinal detachment with eye surgery, eye or head trauma, severe myopia (all known risk factors), and heavy lifting (vs. no lifting, odds ratio = 4.4 [95% confidence interval = 1.5-13]) and high body mass index (or=25.5 kg/m, 6.8 [1.6-29]).Heavy occupational lifting and being overweight may be important risk factors for retinal detachment among people with myopia. The role of these risk factors in the etiology of retinal detachment deserves to be explored in more general populations.

Objective: To assess risks associated with work-related biomechanical overloads in onset/course of carpal tunnel syndrome. Methods: Workgroups with job tasks spanning different biomechanical exposures were evaluated at baseline in terms of American Conference of Governmental Industrial Hygienists hand-activity/peak force action limit and threshold limit values (TLV). Exposures of interest were “unacceptable” (hand-activity above TLV) and “borderline” (between action limit and TLV) overloads. Clinical/individual data were collected at baseline and 12 months. Results: One-year incidence of “classic/possible” carpal tunnel syndrome symptoms as defined by consensus criteria was 7.3% (153 of 2092). “Unacceptable” overload was associated with a 3-fold increased risk of onset with respect to “acceptable” load. At ordered logistic regression analysis of symptom-status variations, increased risks were recorded for “unacceptable” and “borderline” overloads. Conclusions: Effectiveness of encouraging workplace adherence to the American Conference of Governmental Industrial Hygienists recommendations deserves investigation as a possible key to wide-scale prevention.

INTRODUCTION: Evidence-based prevention (EBP) is gaining the growing interest of the scientific community in Occupational Health (OH). To highlight the Italian contribution to EBP, a systematic review was performed, on the main OH-journals publishing in Italian language. METHODS: Studies that have evaluated interventions carried out to improve workers' health were found out from the articles published in the period 1990-2006, by means of hand-searching. The selected articles were classified on occupational health topics as health intervention, study design, risk factor, authors affiliation. RESULTS: 16 publications were selected, which represent less than 0.5% of all papers published on the 8 Italian journals examined. The most frequent study-design is the pre-post intervention evaluation; 2 out of 16 (25%) studies are randomized trial. The interventions are directed mainly to control the effects of noise and biomechanical overload; textile, health-care and energy production are the most frequent industrial settings. We did not found researches aimed to evaluate the effectiveness of interventions performed in the metalware industry or addressed to injuries prevention. DISCUSSION: The systematic approach of EBP can be applied to most of the occupational health interventions and effectiveness evaluation should represent a challenge for the occupational health field. The results of the hand searching among publication in Italian could raise interesting debate about methodology and outcomes in the scientific community.