Non-exposed Patients Research Articles

MicroRNA-98 is a prognostic factor for asbestos-induced mesothelioma

ABSTRACTMalignant pleural mesothelioma (MPM) is a type of cancer characterized by a short survival time and poor prognosis. Malignant pleural mesothelioma is most frequently associated with exposure to asbestos and other elongated mineral fibers. The aim of this study was to examine molecular differences between asbestos-exposed and non-exposed MPM patients and assess prognostic significances of molecular factors. Clinical and genetic data were downloaded from Cancer Genome Atlas. To identify the molecular differences, Significant Analysis of Microarray method was used. Prognostic significances of differentially expressed genes were confirmed by using Kaplan–Meier curve with the Log-Rank test. Although mRNAs did not exhibit any significant differences between the two patient groups, nine miRNAs were found to be down-regulated in the asbestos-exposed group. The top five pathways most relevant to the selected miRNAs were extracted through pathway enrichment analysis. Survival analysis revealed that high expression of only hsa-miR-98 was significantly associated with poor prognosis in patients with asbestos-exposed MPM. Evidence suggests that management of the aggressiveness and progression of asbestos-induced MPM may require high levels of hsa-miR-98 due to its tumor-suppressive role. This study might be helpful in enhancing our understanding of the biological mechanisms underlying asbestos-induced MPM and for acquiring greater insights into targeted therapy.Abbreviations: FDR: false discovery rate; MM: malignant mesothelioma; MPM: malignant pleural mesothelioma; mRNA: messenger RNA; miRNA: microRNA; SAM: significance analysis of microarrays; TCGA: the cancer genome atlas

Does Isoniazid Preventive Therapy Provide Better Treatment Outcomes in HIV-Infected Individuals in Northern Ethiopia? A Retrospective Cohort Study.

Objectives Early antiretroviral therapy (ART), isoniazid preventive therapy (IPT), and isoniazid-rifapentine (3HP) are effective strategies for preventing tuberculosis (TB) among people living with HIV (PLHIV). The study aimed to determine the effect of IPT on the TB incidence, follow-up CD4+ T cells, and all-cause mortality rate. Participants. Eligible patients on ART (n = 1, 863) were categorized into one-to-two ratios of exposed groups to IPT (n = 621) and nonexposed groups to IPT (n = 1, 242). Exposed groups entered the cohort at their first prescription of IPT, and unexposed groups entered into the study at the first prescription of ART and then followed until the occurrence of the outcome or date of administrative censoring (June 30, 2017). The outcome endpoints were TB incidence, follow-up CD4+ T cells, and all-cause mortality rate. Results The follow-up CD4+ T cells for the exposed and nonexposed groups were 405.74 and 366.95 cells/mm (World Health Organization (WHO), 2017), respectively, a statistically significant finding (t1861 = −3.770, p < 0.0001; Cohen's d = 0.186). Nine percent of the exposed patients (620 incidence of TB per 100,000 person-years (PYs)) and 21.9% of the nonexposed patients (3160 incidence of TB per 100,000 PYs) developed TB. Mortality rate (per 100,000 PYs) was 440 for the exposed and 1490 for the unexposed patients. Statistically significant determinants of the all-cause mortality were unscheduled follow-up (AHR = 1.601; 95% CI: 1.154–2.222) and unable to work properly (AHR = 2.324; 95% CI: 1.643–3.288). Conclusion This study demonstrates the effect of IPT in reducing incidence of TB and all-cause mortality rate and improving follow-up CD4+ T cells. Promoting IPT use can help to achieve the TB eradicating national agenda in Ethiopia.

Delayed effects of sulfur mustard on autophagy suppression in chemically-injured lung tissue

BackgroundAutophagy is an intracellular hemostasis mechanism, responding to extracellular or intracellular stresses. Sulfur mustard (SM) induces cellular stress. Iranian soldiers exposed to SM gas, during the Iraq-Iran war, suffer from delayed complications even 30 years after exposure. In this study, for exploring the SM effect on autophagy pathway, gene and protein expression of autophagy markers are evaluated in the lung of SM-exposed people. Methods52 FFPE lung tissues of SM-exposed people and 33 lung paraffin blocks of non-exposed patients to SM were selected. LC3 and Beclin-1 mRNA expressions were evaluated by QRT-PCR. LC3-B protein and LC3II/LC3I proteins ratio were detected by Immunohistochemistry and immunoblotting method. The collected data were analyzed in SPSS, and P value ≤ 0.05 was considered significant. ResultsLC3 gene expression in SM-exposed subjects (median CT value = 4.97) increased about 4 fold compared with the control group (median CT value = 0.46, P = 0.025). Beclin-1 mRNA expression had not significant difference between two groups. After adjusting the confounding variables such as drug usage, LC3-B protein (P = 0.041) and LC3II/LC3I ratio (P = 0.044) were found significantly lower in the lung cells of SM-exposed group. ConclusionUpon exposure to SM gas, the lung cells are affected by acute cellular stress such as oxidative stress. The study results show that LC3 mRNA level increases in these patients, but, surprisingly, LC3-B protein via unknown mechanism has been down-regulated. N-acetyl cysteine and salbutamol drugs could induce the autophagy, and help to reduce the SM effects and improve the clinical condition of SM-injured patients.

Some aspects of thyroid neoplasia after chernobyl

Significant increase in thyroid carcinoma (TC) incidence was registered after the Chernobyl accident among people exposed as children and adolescents. The quantity of radiogenic cases and dose-effect correlations have been overestimated due the screening-effect, improved medical surveillance after the accident, overdiagnosis, recall bias, dose-dependent selection and self-selection. Besides, some non-exposed patients were counted among Chernobyl victims. Before the accident, the registered incidence of paediatric TC was lower in the USSR compared to other industrialised countries. The screening found not only small nodules but also late-stage TC interpreted as rapidly growing radiogenic cancers developing after a short latent period. Some supposed markers of radiogenic malignancy were in fact associated with a later stage of neoplastic progression. In conclusion, the overestimation of Chernobyl consequences may lead to a biased concept about carcinogenicity of low-dose low-rate exposures, especially from radioiodine.

Anti-citrullinated peptide antibodies in rheumatoid arthritis patients exposed to wood smoke

&lt;abstract&gt;&lt;sec&gt; &lt;title&gt;Background and Aims&lt;/title&gt; &lt;p&gt;Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease with an unknown etiology, which attacks the synovial tissue more than any other organ. Citrulline has been observed in the joints of RA patients. Anti-citrullinated peptide antibodies (ACPAs), which are recognized as the most specific serologic markers of RA, are synthesized against unusual citrullinated peptides during the disease. There is little information about the increased production of antibodies against citrullinated peptides in RA patients exposed to wood smoke. Therefore, in this study, we aimed to compare the serum level of ACPA in two groups of exposed and non-exposed RA patients to wood smoke.&lt;/p&gt; &lt;/sec&gt;&lt;sec&gt; &lt;title&gt;Materials and Methods&lt;/title&gt; &lt;p&gt;A total of 110 RA patients, including 55 exposed patients to wood smoke and 55 non-exposed patients, were enrolled in this study. The serum level of ACPA, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and disease activity (based on the 28-joint Disease Activity Score) were determined in patients and compared between the two groups.&lt;/p&gt; &lt;/sec&gt;&lt;sec&gt; &lt;title&gt;Results&lt;/title&gt; &lt;p&gt;In this study, there was no significant difference in the serum level of ACPA between the exposed and non-exposed groups (P = 0.73). On the other hand, RF (P = 0.03), ESR (P = 0.007), and disease activity index (P = 0.01) were significantly higher in the exposed group, compared to the non-exposed group.&lt;/p&gt; &lt;/sec&gt;&lt;sec&gt; &lt;title&gt;Conclusion&lt;/title&gt; &lt;p&gt;According to the results of the current study, pollutants from wood smoke significantly increased the RF, ESR, and disease activity index in RA patients. Nonetheless, there was no significant difference in the serum level of ACPA between the two groups.&lt;/p&gt; &lt;/sec&gt;&lt;/abstract&gt;

Association of air pollutants, airborne occupational exposures, and chronic rhinosinusitis disease severity

Previous work has shown that chronic rhinosinusitis (CRS) severity may be associated with particulate matter 2.5 (PM2.5 ) and black carbon (BC) in CRS patients without nasal polyps (CRSsNP). Data regarding occupational exposures, however, are lacking. We assessed the impact of PM2.5 , BC, as well as occupational airborne exposure on CRS disease severity. Patients with CRS with nasal polyps (CRSwNP), CRSsNP, and aspirin-exacerbated respiratory disease (AERD) were identified from an institutionwide database. Spatial modeling from 37 pollutant monitoring sites in Allegheny County was used to estimate exposures. Patient occupations using the 2010 Standard Occupation Classification (SOC10) and airborne occupation exposures to vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) or diesel fumes were recorded. Disease severity was measured by modified Lund-Mackay score (LMS), systemic corticosteroid therapy, and incidence of functional endoscopic sinus surgery (FESS). Two hundred thirty-four patients were included (CRSwNP, n = 113; CRSsNP, n = 96; AERD, n = 25). The prevalence ofAERDamong those with CRSwNP was 18%. Patients exposed to VGDFFiM or diesel fumes required higher steroid doses vs nonexposed patients (p = 0.015 and p = 0.03, respectively); patients with VGDFFiM levels >5% were more likely to undergo FESS vs nonexposed patients (p = 0.0378). There was no difference in PM2.5 and BC with regard to disease severity and FESS between CRSwNP, CRSsNP, and AERD patients. Steroid use was significantly higher in CRSwNP and AERD vs CRSsNP (p = 0.001). LMS was significantly higher in AERD as compared with CRSwNP and CRSsNP (p = 0.001). Occupational airborne exposure to VGDFFiM correlated with increased prevalence of FESS and need for corticosteroids in CRS patients. There was no difference in PM2.5 and BC levels and disease severity outcome measures between CRS subtypes in this subset.

Atypical, Non-V600 BRAF Mutations as a Potential Mechanism of Resistance to EGFR Inhibition in Metastatic Colorectal Cancer.

Atypical, non-V600 BRAF (aBRAF) mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize aBRAF mutations into class II (intermediate to high levels of kinase activity, RAS independent) and III (low kinase activity level, RAS dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown. Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided. BRAF mutations were harbored by 257 patients, including 36 with aBRAF mutations: 22 class III, 10 class II, four unclassified. For patients with aBRAF mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with BRAFV600E mCRC. In contrast to right-sided predominance of tumors with BRAFV600E mutation, 53% of patients with aBRAF mCRC had left-sided primary tumors. Concurrent RAS mutations were noted in 33% of patients with aBRAF mCRC, and 67% of patients had microsatellite stable disease. Among patients with aBRAF RAS wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III aBRAF mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of aBRAF mutations and subclonal aBRAF mutations (P < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients. Efficacy of anti-EGFR therapy is limited in class II and III aBRAF mCRC. Detection of aBRAF mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.

Association of Occupational Pesticide Exposure With Immunochemotherapy Response and Survival Among Patients With Diffuse Large B-Cell Lymphoma

Professional use of pesticides is a risk factor for non-Hodgkin lymphoma. The main biological mechanisms of pesticides and chemotherapy are genotoxicity and reactive oxygen species generation. Cellular adaptation among patients exposed to low doses of genotoxic and oxidative compounds might hinder chemotherapy efficiency in patients with lymphoma. To examine the association of occupational exposure to pesticides with immunochemotherapy response and survival among patients treated for diffuse large B-cell lymphoma. This retrospective cohort study assessed patients treated from July 1, 2010, to May 31, 2015, for diffuse large B-cell lymphoma, with a 2-year follow-up. The study took place at 6 university and nonuniversity hospitals in Languedoc-Roussillon, France. A total of 404 patients with newly diagnosed diffuse large B-cell lymphoma treated with anthracycline-based immunochemotherapy were included before the study began. Occupational history was reconstructed for 244 patients and analyzed with the PESTIPOP French job-exposure matrix to determine likelihood of occupational exposure to pesticides. Analysis of the data was performed from July 15, 2017, to July 15, 2018. Treatment failure (ie, partial response, stable disease, disease progression, or interruption for toxic effects) rate, 2-year event-free survival, and overall survival between exposed and nonexposed patients after adjustment for confounding factors. A total of 244 patients (mean [SD] age, 61.3 [15.2] years; 153 [62.7%] male) had complete occupational data. Of these patients, 67 (27.4%) had occupational exposure to pesticides, with 38 exposed through agricultural occupations. Occupational exposure was not associated with clinical and biological characteristics at diagnosis. Occupationally exposed patients had a significantly higher treatment failure rate (22.4% vs 11.3%; P = .03; adjusted odds ratio [AOR] for confounding factors, 3.0; 95% CI, 1.3-6.9); this difference was higher among patients with exposing agricultural occupations compared with other patients (29.0% vs 11.7%; AOR, 5.1; 95% CI, 2.0-12.8). Two-year event-free survival was 70% in the occupationally exposed group vs 82% in the unexposed group (adjusted hazard ratio [AHR] for confounding factors, 2.2; 95% CI, 1.3-3.9). Among patients with exposing agricultural occupations compared with other patients, the difference was more pronounced (2-year event-free survival, 56% vs 83%; AHR, 3.5; 95% CI, 1.9-6.5). Similarly, 2-year overall survival was lower in the group of patients with exposing agricultural occupations compared with other patients (81% vs 92%; AHR, 3.9; 95% CI, 1.5-10.0). This retrospective study showed that agricultural occupational exposure to pesticides was associated with treatment failure, event-free survival, and overall survival among patients with diffuse large B-cell lymphoma.

Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers.

Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy. Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test. Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis. In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

Anesthesia for non-obstetric surgery during pregnancy in a tertiary referral center: a 16-year retrospective, matched case-control, cohort study

IntroductionThis retrospective, matched case-control cohort study describes the incidence, indications, anesthesia techniques and outcomes of pregnancies complicated by surgery in a single tertiary-referral hospital. MethodsRetrospective review of the hospital records of 171 patients who had non-obstetric surgery in the current pregnancy, between 2001 and 2016. Pregnancy outcomes of these women were firstly compared with all contemporary non-exposed patients (n=35 411), and secondly with 684 non-exposed control patients, matched for age, time of delivery and parity. ResultsThe incidence of non-obstetric surgery during pregnancy was 0.48%, mostly performed during the second trimester (44%) and under general anesthesia (81%). Intra-abdominal surgery (44%) was the most commonly performed procedure, predominantly using laparoscopy (79%). Women undergoing surgery delivered earlier and more frequently preterm (25% vs. 17%, P=0.018); and birth weight was significantly lower [median (95% CI) 3.16 (3.06 to 3.26) vs. 3.27 (3.22 to 3.32) kg, P=0.044]. When surgery was performed under general anesthesia, low birth weight was more frequent (22% vs 6%, P=0.046). Overall pregnancy outcomes were neither influenced by trimester nor location (intra- vs extra-abdominal) of surgery. However, preterm birth rate secondary to surgery was higher for interventions during the third trimester, compared with other trimesters (10% vs 0, P <0.001). ConclusionPregnant women who underwent surgery delivered preterm more frequently and their babies had lower birth weights. Laparoscopic surgery did not increase the incidence of adverse pregnancy outcomes. General anesthesia was associated with low birth weight. Whether these associations suggest causation or reflect the severity of the underlying condition remains speculative.

Long-term Follow-up of Autologous Fat Transfer vs Conventional Breast Reconstruction and Association With Cancer Relapse in Patients With Breast Cancer

Autologous fat transfer (AFT or fat grafting) has become an invaluable tool for the correction of disfiguring deformities after breast cancer surgery. However, clinical and animal studies have shown conflicting results regarding its oncologic safety. To determine whether exposure to AFT vs conventional breast reconstruction is associated with increased rates of cancer relapse in patients with breast cancer. This matched cohort study involved retrospective medical record review to identify all patients in a local patient database receiving AFT between 2006 and 2014. Each AFT case was matched with a nonexposed control patient with similar baseline characteristics. The mean (SD) follow-up of patients receiving AFT was 9.3 (4.9) years including 5.0 (1.7) years following AFT. Control patients were followed up for a mean (SD) of 8.6 (1.8) years from the primary surgery. Patients were identified through the local patient database of the Tergooi Hospital in Hilversum, the Netherlands. A total of 287 patients with breast cancer (300 affected breasts) who received AFT for breast reconstruction after cancer were included in the intervention group. Each AFT case was matched with a respective control patient based on age, type of oncologic surgery, tumor invasiveness, and disease stage. In addition, individual AFT-control pairs were selected to have the same locoregional recurrence-free interval at baseline. Data were analyzed between 2016 and 2017. Reconstruction with AFT vs conventional breast reconstruction or none. Primary end points were the cumulative incidences of oncologic events in AFT and control patients and their respective hazard ratios. Of the 587 total patients, all were women and the mean age was 48.1 years for the patients undergoing AFT and 49.4 years for the control patients. Eight locoregional recurrences were observed in the treatment group (287 patients) and 11 among the control group (300 patients), leading to an unadjusted hazard ratio of 0.63 (95% CI, 0.25-1.60; P = .33). No increased locoregional recurrence rates were seen in relevant subgroups based on the type of oncological surgery, tumor invasiveness, or pathological stage. In addition, no increased risks with AFT were detected with respect to distant recurrences or breast cancer-specific mortality. No significant differences in the locoregional recurrence rates between the AFT and control groups were observed after 5 years of follow-up. These findings confirm the results of previous studies; therefore, clinical evidence suggesting that AFT is associated with increased risk for cancer relapse is still lacking.

Frequency and Associations of Prescription Nonsteroidal Anti-inflammatory Drug Use Among Patients With a Musculoskeletal Disorder and Hypertension, Heart Failure, or Chronic Kidney Disease

International nephrology societies advise against nonsteroidal anti-inflammatory drug (NSAID) use in patients with hypertension, heart failure, or chronic kidney disease (CKD); however, recent studies have not investigated the frequency or associations of use in these patients. To estimate the frequency of and variation in prescription NSAID use among high-risk patients, to identify characteristics associated with prescription NSAID use, and to investigate whether use is associated with short-term, safety-related outcomes. In this retrospective cohort study, administrative claims databases were linked to create a cohort of primary care visits for a musculoskeletal disorder involving patients 65 years and older with a history of hypertension, heart failure, or CKD between April 1, 2012, and March 31, 2016, in Ontario, Canada. Prescription NSAID use was defined as at least 1 patient-level Ontario Drug Benefit claim for a prescription NSAID dispensing within 7 days after a visit. Multiple cardiovascular and renal safety-related outcomes were observed between 8 and 37 days after each visit, including cardiac complications (any emergency department visit or hospitalization for cardiovascular disease), renal complications (any hospitalization for hyperkalemia, acute kidney injury, or dialysis), and death. The study identified 2 415 291 musculoskeletal-related primary care visits by 814 049 older adults (mean [SD] age, 75.3 [4.0] years; 61.1% female) with hypertension, heart failure, or CKD, of which 224 825 (9.3%) were followed by prescription NSAID use. The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%-16.7%) among 7365 primary care physicians. Within a sample of 35 552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, -0.001 to 0.002; P = .74). While prescription NSAID use in primary care was frequent among high-risk patients, with widespread physician-level variation, use was not associated with increased risk of short-term, safety-related outcomes.

Movement Disorders After Exposure to Antipsychotic Drugs in Patients With Depressive Disorders.

The aims of the study were to explore the frequency of movement disorders (MDs) in depressive patients exposed to antipsychotic drugs (APDs) and to compare it with nonexposed depressive patients and APDs-treated schizophrenic patients. Four hundred fifty-two depressive patients not exposed to APDs (group A), 156 depressives exposed to APDs (group B), and 75 patients with schizophrenia on APDs (group C) were recruited. Presence of MDs was explored by the Simpson-Angus and UKU scales (Registration: NCT02409823). Movement disorders were observed in 5%, 9%, and 13% of patients in groups A to C, respectively (P < 0.001, χ for linear trend). A logistic multivariate analysis revealed that male sex (odds ratio = 2.26, 95% confidence interval = 1.13-4.49, P < 0.01), exposure to first-generation (vs second-generation) APDs (odds ratio = 5.71, 95% confidence interval = 2.08-15.66, P < 0.01), and exposure to lithium (odds ratio = 3.99, 95% confidence interval = 1.74-9.14, P < 0.01) were independently and significantly associated with MDs. Male sex, use first-generation APDs, and exposure to lithium were associated with MDs in depression. Therefore, caution is advised with the use of these drugs in depressive patients. Prospective studies are needed to confirm these results.

Prognosis of diffuse large B cell lymphoma related to occupational exposure to pesticides: A cohort study

Summary Importance Professional use of pesticides is a risk factor for non-Hodgkin lymphoma. The main biological mechanisms of both pesticides and chemotherapy are genotoxicity and reactive oxygen species generation. Cellular adaptation among patients exposed to low doses of genotoxic and oxidative compounds may hinder chemotherapy efficiency in lymphoma patients. Objective We aim to determine the influence of occupational exposure to pesticides on response to immuno-chemotherapy and survival of patients treated for Diffuse Large B Cell Lymphoma (DLBCL). Design The ProLyPhy study is a retrospective cohort of patients treated between 2010 and mid-2015, for DLBCL, with a least 2-year follow-up. Setting The study took place in six hospitals of central southern France (Languedoc-Roussillon district): two university hospitals, three general hospitals, and one private hospital. Participants We pre-included 404 patients with newly-diagnosed DLBCL treated with anthracycline-based immuno-chemotherapy (R-CHOP like). Occupational history was reconstructed for 244 patients. Occupational data were analysed with the Pestipop French job-exposure matrix to determine probability of occupational exposure to pesticides, and with the Pestimat French crop exposure matrix for farming activities to characterise the probability of using specific compounds. Main outcome and measure We have compared complete response (CR), 2-year event-free survival (EFS) and overall survival (OS) of exposed and non-exposed patients, after adjustment on confounding factors. Results Average age was 61.3 years (range 19–90), 62.7% of patients were male, 67 had occupational exposure to pesticides, of which 38 from farming activities. Occupational exposure did not impact clinical and biological characteristics at diagnostic. We observed that exposed patients had significantly lower CR rate: 77.6% versus 88.7% (P = 0.027), OR = 0.31 (0.55–0.09, P = 0.007); this difference was higher among farmers: 68.6% CR versus 87.2%, P = 0.005, OR = 0.22 (0.56–0.09, P = 0.001). Two-year EFS was 70% in the occupationally-exposed group versus 82%, HR = 2.1 (95% CI: 1.2–3.6, P = 0.008). Among farmers, the difference was more pronounced: 2-year EFS was 56% versus 83%, HR = 3.1 (95% CI: 1.7–5.6, P Conclusion and relevance This retrospective study suggests that agricultural occupational exposure to pesticides is an independent risk factor for treatment failure, EFS and OS in DLBCL. Trial registration The study was registered in ClinicalTrials.gov ( NCT02898870 ).

A genomic copy number signature predicts radiation exposure in post-Chernobyl breast cancer.

Breast cancer is the second leading cause of cancer death among women worldwide and besides life style, age and genetic risk factors, exposure to ionizing radiation is known to increase the risk for breast cancer. Further, DNA copy number alterations (CNAs), which can result from radiation-induced double-strand breaks, are frequently occurring in breast cancer cells. We set out to identify a signature of CNAs discriminating breast cancers from radiation-exposed and non-exposed female patients. We analyzed resected breast cancer tissues from 68 exposed female Chernobyl clean-up workers and evacuees and 68 matched non-exposed control patients for CNAs by array comparative genomic hybridization analysis (aCGH). Using a stepwise forward-backward selection approach a non-complex CNA signature, that is, less than ten features, was identified in the training data set, which could be subsequently validated in the validation data set (p value < 0.05). The signature consisted of nine copy number regions located on chromosomal bands 7q11.22-11.23, 7q21.3, 16q24.3, 17q21.31, 20p11.23-11.21, 1p21.1, 2q35, 2q35, 6p22.2. The signature was independent of any clinical characteristics of the patients. In all, we identified a CNA signature that has the potential to allow identification of radiation-associated breast cancer at the individual level.

Sulfur mustard triggers oxidative stress through glutathione depletion and altered expression of glutathione-related enzymes in human airways

Context: Sulfur mustard (SM) is a lipophilic and reactive chemical compound that targets human airway system.Objective: Glutathione (GSH) depletion, oxidative stress (OS) status, and changes in expression of GSH-dependent antioxidant enzymes were considered in human mustard lungs.Materials and methods: Lung biopsies and bronchoalveolar lavage (BAL) were collected from non-exposed (n = 10) individuals and SM-exposed patients (n = 12). Alterations in expression of GSH-dependent enzymes were studied using RT2 Profiler™ PCR array. OS was evaluated by determining BAL fluid levels of total antioxidant capacity (TAC), malondialdehyde (MDA), and GSH.Results: Mean TAC (0.142 ± 0.027 µmol/l) and GSH (4.98 ± 1.02 nmol/l) in BAL fluids of control group was significantly higher (p < .05) than those in SM-exposed patients (TAC = 0.095 ± 0.018 µmol/l and GSH= 3.09 ± 1.02 nmol/l), while MDA level in BAL fluids of these patients (0.71 ± 0.06 nmol/l) was significantly (p = .001) higher than that in controls (0.49 ± 0.048 nmol/l). Glutathione peroxidases (GPXs), glutathione-s-transferases (GSTs), and glutathione synthetase (GSS) enzymes were overexpressed in mustard lung biopsies, while glutathione reductase (GSR) was significantly downregulated (14.95-fold).Conclusions: GSH depletion induced by GSR downregulation may be a major mechanism of SM toxicity on human lung. Despite overexpression of GSTs and GPXs genes, GSH depletion may decline the productivity of these enzymes and total antioxidants capacity, which is associated with OS.

Cluster Headache Clinical Phenotypes: Tobacco Nonexposed (Never Smoker and No Parental Secondary Smoke Exposure as a Child) versus Tobacco-Exposed: Results from the United States Cluster Headache Survey.

To present results from the United States Cluster Headache Survey comparing the clinical presentation of tobacco nonexposed and tobacco-exposed cluster headache patients. Cluster headache is uniquely tied to a personal history of tobacco usage/cigarette smoking and, if the individual cluster headache sufferer did not smoke, it has been shown that their parent(s) typically did and that individual had significant secondary smoke exposure as a child. The true nontobacco exposed (no personal or secondary exposure) cluster headache sufferer has never been fully studied. The United States Cluster Headache Survey consisted of 187 multiple choice questions related to cluster headache including: patient demographics, clinical headache characteristics, family history, triggers, smoking history (personal and secondary), and headache-related disability. The survey was placed on a website from October through December 2008. One thousand one hundred thirty-four individuals completed the survey. One hundred thirty-three subjects or 12% of the surveyed population had no personal smoking/tobacco use history and no secondary smoke exposure as an infant/child, thus a nontobacco exposed population. In the nonexposed population, there were 87 males and 46 females with a gender ratio of 1.9:1. Episodic cluster headache occurred in 80% of nonexposed subjects. One thousand and one survey responders or 88% were tobacco-exposed (729 males and 272 females) with a gender ratio of 2.7:1. Eighty-three percent had a personal smoking history, while only 17% just had parents who smoked with secondary smoke exposure. Eighty-five percent of smokers had double exposure with a personal smoking history and secondary exposure as a child. Nonexposed cluster headache subjects are significantly more likely to develop cluster headache at ages 40 years and younger, while the exposed sufferers are significantly more likely to develop cluster headache at 40 years of age and older. Nonexposed patients have a statistically significant higher frequency of a migraine family history. The exposed population is statistically significantly more likely to have a history of head trauma 19% vs the nonexposed population 10% (P = .02). Tobacco exposed are significantly more likely to transition from episodic to chronic cluster headache (23% vs 14%, P = .02). Cranial autonomic symptoms as well as agitation are more common in tobacco exposed. Nonexposed are less likely to have specific cluster headache triggers. Exposed are significantly more likely to be triggered by alcohol. Tobacco exposed are significantly heavier caffeine users than nonexposed. Nonexposed are significantly more likely to have cluster headache cycles that vary throughout the year than exposed (52% vs 40%, P = .02). Exposed are much more likely to develop cluster headache from 12 am to 6 am than non exposed. Exposed experience significantly more frequent attacks per day and longer duration cycles than nonexposed. A significantly larger percent of the exposed population (57%) has suicidal ideations with their syndrome than nonexposed (43%) (P = .003). In regard to disability, both subtypes are disabled by their headaches, but exposed have more work related disability and lost home-days from headache. Both subgroups have a poor overall response to preventive and abortive medication outside of inhaled oxygen and injectable sumatriptan. Cluster headache sufferers who were never exposed to tobacco (personal or secondary as a child) appear to present uniquely compared to the tobacco exposed subgroup. The tobacco exposed clinical phenotype appears to have a more severe syndrome based on attack frequency, cycle duration, and headache related disability. Tobacco exposure is associated with cluster headache chronification. The nonexposed subtype appears to have an earlier age of onset, higher rate of familial migraine, and less circadian periodicity and daytime entrainment, suggesting a possible different underlying pathology than in the tobacco exposed sub-form.

Opioid Prescribing Practices by Orthopaedic Trauma Surgeons After Isolated Femur Fractures.

The purpose of this retrospective study was to identify opioid prescribing practices, determine the number of morphine milliequivalents (MMEs) prescribed by orthopaedic/nonorthopaedic members to narcotic naive and previously exposed patients, and provide narcotic prescribing recommendations. Patients older than 18 years with an isolated femur fracture sustained between 2013 and 2015 were identified using the CPT code 27506. Prescribing information was obtained from the State Controlled Substance Monitoring Database. Descriptive analysis of MMEs was then performed. Outliers and patients without prescriptions from orthopaedic providers were excluded to eliminate skewing of data. Mean and standard deviations were then calculated for patients without a history of opiates prescribed within 1 year of injury and for patients with a history of opiates prescribed within 1 year before the injury. Forty-five percent (40/88) of patients were opiate exposed at the time of injury. Previously exposed patients received 1491 MMEs (SD, 1044; median, 1350; range, 210-5140) and nonexposed patients received 1363 MMEs (SD, 977.2; median, 1260; range, 105-4935) from orthopaedic providers (P = 0.1473). Nonorthopedists prescribed 530 MMEs (SD, 780.7; median, 140; range, 0-3515) to previously exposed patients and 175 MMEs (SD, 393; median, 140; range, 0-1890) to patients without exposure (P < 0.0001). Patients with prior exposure are more likely to be prescribed more opiates after femoral shaft fracture treatment. We recommend a protocol of prescribing half the mean of MMEs currently prescribed by orthopedists equating to 47 (711 MMEs) pills of oxycodone 10 mg in up to 3 prescriptions.

High prevalence of occupational exposure to solvents or silica in male systemic sclerosis patients: a Belgian cohort analysis.

Increasing evidence supports a relation of some occupational exposures to systemic sclerosis pathogenesis. We aimed to evaluate occupational exposure and clinical characteristics in male patients with systemic sclerosis followed in two Belgian academic hospitals. One hundred and three male patients, included in the Belgian Systemic Sclerosis Cohort, were identified. An expert in occupational medicine reviewed the occupational history and allocated the patients to one of the following groups: probable exposure to crystalline silica, probable exposure to solvents, probable exposure to other toxins, or no suspected occupational exposure. Clinical characteristics were extracted from the Belgian Systemic Sclerosis Cohort database. Sufficient data were available for 96/103 patients. Most of these male patients (70/96, 72.9%) had a history of occupational exposure, 55 patients were likely exposed to crystalline silica, 11 patients to solvents, 2 patients to both silica and solvents, and 2 patients to asbestos. Only 26 patients had no suspected occupational exposure (27.1%). We noticed a significant difference in smoking status between exposed and non-exposed patients, with the highest percentage of ever smokers in the group with solvent exposure (p = 0.011). We found no significant differences in disease phenotype between exposed and non-exposed patients. However, we noted a trend to a higher prevalence of anti-Scl70 antibodies, cardiac dysfunction, and higher disease activity score in patients with occupational exposure. We observed a strikingly high prevalence of occupational exposure to both silica and solvents in male systemic sclerosis patients. Occupational exposure to silica or solvents is highly prevalent in male systemic sclerosis patients.

Effect of outpatient antibiotics for urinary tract infections on antimicrobial resistance among commensal Enterobacteriaceae: a multinational prospective cohort study

ObjectivesWe quantified the impact of antibiotics prescribed in primary care for urinary tract infections (UTIs) on intestinal colonization by ciprofloxacin-resistant (CIP-RE) and extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), while accounting for household clustering. MethodsProspective cohort study from January 2011 to August 2013 at primary care sites in Belgium, Poland and Switzerland. We recruited outpatients requiring antibiotics for suspected UTIs or asymptomatic bacteriuria (exposed patients), outpatients not requiring antibiotics (non-exposed patients), and one to three household contacts for each patient. Faecal samples were tested for CIP-RE, ESBL-PE, nitrofurantoin-resistant Enterobacteriaceae (NIT-RE) and any Enterobacteriaceae at baseline (S1), end of antibiotics (S2) and 28 days after S2 (S3). ResultsWe included 300 households (205 exposed, 95 non-exposed) with 716 participants. Most exposed patients received nitrofurans (86; 42%) or fluoroquinolones (76; 37%). CIP-RE were identified in 16% (328/2033) of samples from 202 (28%) participants. Fluoroquinolone treatment caused transient suppression of Enterobacteriaceae (S2) and subsequent two-fold increase in CIP-RE prevalence at S3 (adjusted prevalence ratio (aPR) 2.0, 95% CI 1.2–3.4), with corresponding number-needed-to-harm of 12. Nitrofurans had no impact on CIP-RE (aPR 1.0, 95% CI 0.5–1.8) or NIT-RE. ESBL-PE were identified in 5% (107/2058) of samples from 71 (10%) participants, with colonization not associated with antibiotic exposure. Household exposure to CIP-RE or ESBL-PE was associated with increased individual risk of colonization: aPR 1.8 (95% CI 1.3–2.5) and 3.4 (95% CI 1.3–9.0), respectively. ConclusionsThese findings support avoidance of fluoroquinolones for first-line UTI therapy in primary care, and suggest potential for interventions that interrupt household circulation of resistant Enterobacteriaceae.