Employment in the Ecuadorian cut-flower industry and the risk of spontaneous abortion

<p>Abstract</p> <p>Background</p> <p>Research on the potentially adverse effects of occupational pesticide exposure on risk of spontaneous abortion (SAB) is limited, particularly among female agricultural workers residing in developing countries.</p> <p>Methods</p> <p>Reproductive histories were obtained from 217 Ecuadorian mothers participating in a study focusing on occupational pesticide exposure and children's neurobehavioral development. Only women with 2+ pregnancies were included in this study (n = 153). Gravidity, parity and frequency of SAB were compared between women with and without a history of working in the cut-flower industry in the previous 6 years. Logistic regression analysis was conducted to assess the relation between SAB and employment in the flower industry adjusting for maternal age.</p> <p>Results</p> <p>In comparison to women not working in the flower industry, women working in the flower industry were significantly younger (27 versus 32 years) and of lower gravidity (3.3 versus 4.5) and reported more pregnancy losses. A 2.6 (95% CI: 1.03-6.7) fold increase in the odds of pregnancy loss among exposed women was observed after adjusting for age. Odds of reporting an SAB increased with duration of flower employment, increasing to 3.4 (95% CI: 1.3, 8.8) among women working 4 to 6 years in the flower industry compared to women who did not work in the flower industry.</p> <p>Conclusion</p> <p>This exploratory analysis suggests a potential adverse association between employment in the cut-flower industry and SAB. Study limitations include the absence of a temporal relation between exposure and SAB, no quantification of specific pesticides, and residual confounding such as physical stressors (i.e., standing). Considering that approximately half of the Ecuadorian flower laborers are women, our results emphasize the need for an evaluating the reproductive health effects of employment in the flower industry on reproductive health in this population.</p

A core outcome set for pre-eclampsia research : an international consensus development study

Objective: To develop a core outcome set for pre-eclampsia. Design: Consensus development study. Setting: International. Population: Two hundred and eight-one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. Methods: Modified Delphi method and Modified Nominal Group Technique. Results: A long-list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre-eclampsia trials with those derived from thematic analysis of 30 in-depth interviews of women with lived experience of pre-eclampsia. Forty-seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small-for-gestational-age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. Conclusions: The core outcome set for pre-eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies. Tweetable abstract: 281 healthcare professionals, 41 researchers and 110 women have developed #preeclampsia core outcomes @HOPEoutcomes @jamesmnduffy. [Correction added on 29 June 2020, after first online publication: the order has been corrected.]

Environmentalism, pre-environmentalism, and public policy

In the last decade, thousands of new grassroots groups have formed to oppose environmental pollution on the basis that it endangers their health. These groups have revitalized the environmental movement and enlarged its membership well beyond the middle class. Scientists, however, have been unable to corroborate these groups' claims that exposure to pollutants has caused their diseases. For policy analysts this situation appears to pose a choice between democracy and science. It needn't. Instead of evaluating the grassroots groups from the perspective of science, it is possible to evaluate science from the perspective of environmentalism. This paper argues that environmental epidemiology reflects ‘pre-environmentalist’ assumptions about nature and that new ideas about nature advanced by the environmental movement could change the way scientists collect and interpret data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45449/1/11077_2005_Article_BF01006494.pd

Multiparameter Flow Cytometry (MFC) of Cerebrospinal Fluid (CSF) from Adults Receiving Hypercvad for Acute Lymphoblastic Leukemia/Lymphoma (ALL) Identifies Patients at Higher Risk of Central Nervous System (CNS) Relapse: A Single-Center Retrospective Analysis

BACKGROUND: CNS directed chemotherapy (chemo) reduces the risk of CNS relapse of ALL, but the optimal way to measure baseline CNS involvement is controversial. Baseline CSF testing can provide risk stratification and often dictates CNS prophylaxis (ppx) during initial treatment. Despite advances, up to 10% of adults still suffer CNS relapse (Blood 2008;112:1646, Cancer 2014;120:3660). Testing typically focuses on conventional cytospin (CC) of CSF, but CC is limited by interobserver variability and insensitivity (Blood 2014;124:3799). Alternatively, MFC is more sensitive (ASH 2018, #658). A previous study in children with ALL found leukemia detection in the CNS by CC or MFC at diagnosis to be associated with an increased risk of both isolated bone marrow and any CNS relapse (ASH 2018, #657). To our knowledge, this use of MFC has not specifically been studied in hyperCVAD, a commonly used chemotherapy regimen for the initial treatment of adult ALL. We hypothesized that baseline lymphoblast detection in the CSF by MFC is predictive of CNS relapse. METHODS: We included data collected from 11/6/07 to 6/22/20. Patients (pts) ≥18 years old who received ≥4 cycles (equivalent of cycle 2B) of hyperCVAD as first-line therapy were eligible. Pts must have had MFC done on CSF at baseline. Pts with mixed phenotype or insufficient follow-up data were excluded. CNS ppx with hyperCVAD historically uses intra-CSF (ie, intrathecal or intraventricular) methotrexate 12 mg on day 2 and cytarabine 100 mg on day 8 of each cycle for 6-12 doses without cranial radiation, though all patients were treated per physician discretion. CC and MFC results were taken from clinical reports and verified by an independent hematopathologist (Dr. Cherian). Baseline CSF positivity (CSF+) and negativity (CSF-) were defined by MFC, with any percentage of lymphoblasts considered CSF+. COG definitions of CNS status by CC were also used (J Clin Oncol 2016;34:2380). Univariate Cox models evaluated associations to CNS relapse. Kaplan-Meier curves were used to estimate the probabilities of overall survival (OS) and cumulative incidence of CNS relapse. RESULTS: We identified 92 eligible pts. Disease and treatment characteristics are summarized in Table 1, and results of initial CSF testing are shown in Table 2. Twenty-one pts were CSF+ by MFC at baseline: by CC, 6 of these were positive, 6 were negative, 7 were equivocal (ie, morphologic review was unable to rule out blasts), and 2 did not have baseline CC. None were positive by CC but negative by MFC. Eight of 29 (38%) with circulating blasts had a traumatic (&amp;gt;10 RBC/uL of CSF) first lumbar puncture (LP). Of these 8, 4 (50%) were CSF+. Five (5%) pts had an Ommaya reservoir placed during treatment. Pts received a median of 8 doses of intra-CSF chemo (range, 5-52). All but 7 pts (8%) received a combination of methotrexate and cytarabine like above. Twenty CSF+ pts (95%) achieved CSF- after a median of 1 dose of intra-CSF chemo (range, 1-5). Out of the 71 CSF- pts, none became CSF+ during initial treatment despite being tested a median of 5 times (range, 2-10). Eight pts (9%) had CNS relapse (3 isolated, 5 concurrent medullary relapse). Comparisons between baseline CSF testing, intra-CSF treatment, and CNS relapse are shown in Table 2. CSF+ pts received significantly greater doses of intra-CSF chemo. Of the 21 CSF+ pts, 5 (24%) had CNS relapse (2 isolated, 3 concurrent), and out of the 71 CSF- pts, 3 (4%) had CNS relapse (1 isolated, 2 concurrent; p=0.014). Among univariate models of CSF+ vs -, traumatic LP vs not, B vs T lineage, LDH, and WBC, only CSF+ was significantly associated with CNS relapse (hazard ratio 4.8, 95% confidence interval [CI] 1.2-20, p=0.031). Estimated 3-year cumulative incidence of CNS relapse for CSF+ was 15% vs 3.3% for CSF- (Figure 1). Median OS for the whole cohort was not reached, with estimated 3-year OS of 74% (95% CI, 65%-84%). CONCLUSIONS: MFC of CSF is more predictive of CNS relapse risk than CC in the context of front-line hyperCVAD, questioning the use of CC if MFC is performed. Further, CNS relapses were significantly more frequent when CSF+ despite administration of significantly more intra-CSF chemo. Traumatic LP per se did not increase risk of CNS relapse if CSF- by MFC. Surveillance during treatment by MFC in CSF- pts identified no cases of occult CNS relapse, arguing against this routine practice. Future studies should consider incorporating MFC of CSF into risk-adapted CNS-directed treatment strategies. Disclosures Shustov: Seattle Genetics: Research Funding. Becker:Accordant Health Services/Caremark: Membership on an entity's Board of Directors or advisory committees; Cardiff Oncology: Research Funding; SecuraBio: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; JW Pharmaceutical: Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Invivoscribe: Research Funding. Oehler:Takeda: Consultancy; BMS: Consultancy; Pfizer, Inc: Research Funding. Halpern:Bayer: Other; Novartis: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Amgen: Consultancy, Research Funding; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding; StemLine: Research Funding; Selvita: Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding. </jats:sec

A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Abstract Background: In a prior single-institution trial, CLAG-M resulted in high rates of measurable residual disease (MRD)-negative remissions for adults with previously untreated AML or high-grade myeloid neoplasms (HG-MN) with ≥10% blasts in bone marrow and/or blood (Halpern et al. Leukemia 2018;32:2352-62). The CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), reduces relapse and improves survival when added to other intensive chemotherapy regimens, prompting this phase 1/2 study (NCT03531918) combining GO with CLAG-M as initial therapy for fit adults with newly diagnosed AML or HG-MN. Patients and Methods: Adults ≥18 years were eligible if they had LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal, and treatment-related mortality (TRM) score of ≤13.1, previously corresponding to &amp;lt;13.1% risk of 28-day mortality (Walter et al. J Clin Oncol 2011;29:4417-23). Patients with APL, CML in blast crisis, other illness with expected survival &amp;lt;1 year, or uncontrolled infection were excluded. Phase 1 tested two dose levels of GO in combination with CLAG-M: "GO1": 3 mg/m 2 on day 1 and "GO3": 3 mg/m 2 on days 1, 4, and 7, with all GO doses capped at 4.5 mg. CLAG-M consisted of cladribine 5 mg/m 2/day (days 1-5), cytarabine 2 g/m 2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight &amp;lt;76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m 2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative (MRDneg) complete remission (CR) or MRDneg CR with incomplete count recovery (CRi) was not achieved. MRD was measured by multiparameter flow cytometry (MFC) and cytogenetics. One cycle of CLAG (mitoxantrone omitted) followed by 2 cycles of high-dose cytarabine was allowed as post-remission therapy. Dose escalation to GO3 was permitted if fewer than 2 dose-limiting toxicities (DLTs) were observed among 6 GO1 patients. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting &amp;gt;48 hours that resulted in &amp;gt;7-day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms. The primary efficacy outcome was 6-month event-free survival (EFS). Results: Eighteen patients (median age 66 [range: 28-77] years, median TRM score 3.92 [range: 0.14-10.3]) were treated in phase 1. One of 6 GO1 patients experienced a DLT of grade 3 left ventricular systolic dysfunction. Among 12 GO3 patients, there were 3 DLTs: 1 each of grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, and grade 3 intracranial hemorrhage. This established GO3 as the recommended phase 2 dose. A total of 60 patients (median age; 65 [range: 19-80] years) with either AML (n=48) or HG-MN (n=12) and a median TRM score of 3.4 (range: 0.02-11.8) were treated at GO3 in either phase 1 or phase 2. By ELN 2017 criteria, 20 had favorable-, 13 intermediate-, and 27 adverse-risk disease. Forty-six (77%) achieved CR and 6 (10%) achieved CRi for a CR/CRi rate of 87% (95% CI: 75-94%). Forty-five CR/CRi patients were negative for MRD by both MFC and cytogenetics for an overall MRDneg CR/CRi rate of 75% (95% CI: 62-85%). Two patients had morphologic leukemia free state (MFLS), 2 underwent hematopoietic stem cell transplant (HCT) in aplasia not meeting MLFS criteria, and 4 had resistant disease. With median follow-up of 15 months, 6-month EFS, 12-month EFS, 6-month overall survival (OS) and 12-month OS were 73% (95% CI: 61-85%), 59% (48-73%), 90% (83-98%) and 75% (65-89%), respectively. For patients achieving CR after cycle 1 (n=45), median time to neutrophil count of 1000/µL and platelet count of 100,000/µL was 32 days (range: 22-51) and 31 days (range: 21-48), respectively. Besides infections and neutropenic fever, hypertension and hemorrhage were the most common grade ≥3 adverse events. There were no deaths within 8 weeks of study start. Of note, 1 patient had reversible early liver injury not meeting sinusoidal obstructive syndrome (SOS) criteria, and 1/25 (4%) of patients who underwent allogeneic HCT after study therapy was diagnosed with nonfatal post-HCT SOS. Conclusion: CLAG-M with fractionated-dose GO resulted in an MRDneg CR/CRi rate of 75% and a 6-month EFS rate of 73% in adults with newly diagnosed AML/HG-MN. Formal comparison of outcomes with institutional patients given CLAG-M alone is ongoing. Disclosures Godwin: Pfizer: Research Funding; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Percival: Glycomimetics: Research Funding; Cardiff Oncology: Research Funding; BMS/Celgene: Research Funding; Biosight: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Nohla Therapeutics: Research Funding; Oscotec: Research Funding; Trillium: Research Funding. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Halpern: Pfizer: Research Funding; Nohla Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Imago Pharmaceuticals: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Tolero Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding; Abbvie: Consultancy; Gilead: Research Funding; Agios: Consultancy. Oehler: BMS: Consultancy; OncLive: Honoraria; Takeda: Consultancy; Pfizer: Research Funding. Orozco: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Cassaday: Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding. Walter: Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Selvita: Research Funding; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. OffLabel Disclosure: The label for cladribine does not include acute myeloid leukemia, however cladribine is frequently used to treat AML and related conditions. In this study cladribine is used in induction chemotherapy for the treated of AML and related disorders. </jats:sec

Differential expression of parental alleles of BRCA1 in human preimplantation embryos

Gene expression from both parental genomes is required for completion of embryogenesis. Differential methylation of each parental genome has been observed in mouse and human preimplantation embryos. It is possible that these differences in methylation affect the level of gene transcripts from each parental genome in early developing embryos. The aim of this study was to investigate if there is a parent-specific pattern of BRCA1 expression in human embryos and to examine if this affects embryo development when the embryo carries a BRCA1 or BRCA2 pathogenic mutation. Differential parental expression of ACTB, SNRPN, H19 and BRCA1 was semi-quantitatively analysed by minisequencing in 95 human preimplantation embryos obtained from 15 couples undergoing preimplantation genetic diagnosis. BRCA1 was shown to be differentially expressed favouring the paternal transcript in early developing embryos. Methylation-specific PCR showed a variable methylation profile of BRCA1 promoter region at different stages of embryonic development. Embryos carrying paternally inherited BRCA1 or 2 pathogenic variants were shown to develop more slowly compared with the embryos with maternally inherited BRCA1 or 2 pathogenic mutations. This study suggests that differential demethylation of the parental genomes can influence the early development of preimplantation embryos. Expression of maternal and paternal genes is required for the completion of embryogenesis

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women

AbstractAnti-Müllerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in MCM8 has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p &lt; 5×10−8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41, and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among SNPs for AMH levels and for age at menopause (rg= 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the AMH gene and three other loci that may affect circulating AMH levels in women.</jats:p

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management