Work-family conflict, financial issues and their association with self-reported health complaints among ready-made garment workers in Bangladesh: a cross-sectional study.

OBJECTIVES: This study aims to quantify the degree of work-family conflict (WFC) and financial issues among ready-made garment (RMG) workers in Bangladesh and to investigate their potential associations with self-reported health outcomes. METHODS: We conducted a cross-sectional survey among 1118 RMG workers in labor colonies in Dhaka, Bangladesh, in February and March 2021. Descriptive analyses were performed to characterize WFC (i.e., family life disturbing the job or facing problems in family due to the job) and financial issues (i.e., savings, debt, financial obligations, financial support). We ran multivariable Poisson regression models to examine possible associations between WFC and financial issues and workers' health (self-reported general health and 10 specific health complaints). RESULTS: We found low levels of WFC, low levels of savings, moderate levels of debt, and high levels of financial obligations: virtually all workers agreed they had to keep their job to financially support their spouse, children or other relatives. Only about a third of workers expected they would be able to receive financial support in case of a job loss. Work-family conflict was positively associated with poor health but not consistently with specific symptoms. Financial support was negatively associated, whereas being indebted was weakly positively associated with poor health. CONCLUSIONS: Our findings suggest low levels of WFC among RMG workers but high levels of financial obligations. Work-family conflict was positively associated with poor health, but not consistently with specific symptoms. Being indebted was weakly positively associated with poor health. Future prospective studies are needed to confirm these findings.

Social stressors and social resources at work and their association with self-reported health complaints among ready-made garment workers in Bangladesh: a cross-sectional study.

BACKGROUND: Bangladesh is one of the world's largest garment exporters. Physical working conditions of garment workers are precarious and known to largely affect their health. Research on garment workers' psychosocial working conditions, however, is scarce. We aimed to quantify psychosocial working conditions of garment workers and possible associations with workers' health. METHODS: We conducted a cross-sectional survey among 1,118 ready-made garment (RMG) workers in labor colonies in Dhaka, Bangladesh, in February 2021. Descriptive analyses were performed to characterize social stressors (e.g., being bullied at work, poor leadership) and social resources at work (e.g., receiving support at work, vertical trust between management and employees, beneficial leadership) and workers' health (self-reported overall health and 10 specific health complaints). To examine links of social stressors and social resources with self-reported health outcomes we ran multivariable Poisson regression models yielding prevalence ratios (PR) and 95% confidence intervals (CI). RESULTS: We found low to moderate levels of workplace bullying and high levels of poor leadership (i.e., supervisors not caring about workers' problems). We also found high levels of social support, vertical trust and beneficial leadership (i.e., supervisors taking decisions free of bias). Garment workers frequently suffered from health complaints, first and foremost headache (68.3%), cold (55.3%), and back pain (50.7%). Health outcomes were poorer among workers who reported to be bullied at work versus not bullied (e.g., PR 1.55 [95% CI 1.32-1.92] for poor self-reported health when bullied by colleagues) and health was better among those reporting to feel supported versus unsupported (e.g., PR 0.61 [0.52-0.71] for poor self-reported health when supported by supervisor). Perceived vertical trust between workers and management was weakly associated with better health. Leadership behavior did not display a consistent pattern. CONCLUSIONS: Our findings suggest that working conditions of RMG workers are rather good (e.g., characterized by low levels of bullying and high levels of support, vertical trust and beneficial leadership). The majority of workers reported good or very good health, although health complaints were frequently mentioned, first and foremost headache, cold, and back pain. Associations between psychosocial working conditions and health indicate worse working conditions being associated with poorer health.

Natural quorum sensing inhibitors effectively downregulate gene expression of Pseudomonas aeruginosa virulence factors.

At present, anti-virulence drugs are being considered as potential therapeutic alternatives and/or adjuvants to currently failing antibiotics. These drugs do not kill bacteria but inhibit virulence factors essential for establishing infection and pathogenesis through targeting non-essential metabolic pathways reducing the selective pressure to develop resistance. We investigated the effect of naturally isolated plant compounds on the repression of the quorum sensing (QS) system which is linked to virulence/pathogenicity in Pseudomonas aeruginosa. Our results show that trans-cinnamaldehyde (CA) and salicylic acid (SA) significantly inhibit expression of QS regulatory and virulence genes in P. aeruginosa PAO1 at sub-inhibitory levels without any bactericidal effect. CA effectively downregulated both the las and rhl QS systems with lasI and lasR levels inhibited by 13- and 7-fold respectively compared to 3- and 2-fold reductions with SA treatment, during the stationary growth phase. The QS inhibitors (QSI) also reduced the production of extracellular virulence factors with CA reducing protease, elastase and pyocyanin by 65%, 22% and 32%, respectively. The QSIs significantly reduced biofilm formation and concomitantly with repressed rhamnolipid gene expression, only trace amount of extracellular rhamnolipids were detected. The QSIs did not completely inhibit virulence factor expression and production but their administration significantly lowered the virulence phenotypes at both the transcriptional and extracellular levels. This study shows the significant inhibitory effect of natural plant-derived compounds on the repression of QS systems in P. aeruginosa.

Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO.

OBJECTIVE: Our objective was to examine the association between adherence to tyrosine kinase inhibitors (TKIs) and molecular monitoring and the risk of disease progression or mortality among patients with chronic phase chronic myeloid leukemia (CML). DESIGN: We assembled a retrospective cohort of patients with CML (chronic phase, no prior cancer history, and confirmed to be Philadelphia chromosome positive) using data from electronic health records and chart reviews. Medication possession ratio (MPR) was used to measure drug adherence. SETTING: A large, community-based, integrated health plan in Southern California. PARTICIPANTS: The cohort consisted of 245 adult patients (≥18 years old) with Philadelphia positive chronic phase CML diagnosed from 2001 to 2012 and followed through 2013. MAIN OUTCOME MEASURES: In survival analyses, we examined the association of TKI adherence (MPR) and polymerase chain reaction (PCR) monitoring test frequency with the composite clinical outcome, progression to accelerated phase disease-blast crisis or mortality (progression-free survival). The cohort was followed for a maximum of 13 years (median 4.6 years). RESULTS: Over 90% of the cohort initiated TKI therapy within 3 months of diagnosis, and the mean MPR was 88% (SD 18%). Virtually all patients (96%) started on imatinib. The rates of progression to accelerated phase-blast crisis and mortality were lower in patients with greater TKI adherence (20.4/1000 person-years) versus lower adherence (27.0/1000 person-years). Patients who underwent PCR monitoring had a significantly reduced risk of progression or mortality, which was seen in patients with high and low TKI adherence status from both the groups (hazard ratio [HR] 0.07 [95% CI 0.03-0.19 if MPR >90%] and HR 0.70 [95% CI 0.02-0.21 if MPR<90%]). CONCLUSION: Our results suggest that close clinical monitoring, which includes PCR monitoring in patients with high and low TKI drug adherence, is associated with a lower risk of progression or mortality.

Association of Glycated Hemoglobin With a Risk of Pancreatic Cancer in High-Risk Individuals Based on Genetic and Family History.

INTRODUCTION: Screening for pancreatic cancer (PC) is suggested for high-risk individuals. Additional risk factors may enhance early detection in this population. METHODS: Retrospective cohort study among patients with germline variants and/or familial pancreatic cancer in an integrated healthcare system between 2003 and 2019. We calculated the incidence rate (IR) by risk category and performed a nested case-control study to evaluate the relationship between HbA1C and PC within 3 years before diagnosis (cases) or match date (controls). Cases were matched 1:4 by age, sex, and timing of HbA1c. Logistic regression was performed to assess an independent association with PC. RESULTS: We identified 5,931 high-risk individuals: 1,175(19.8%) familial PC, 45(0.8%) high-risk germline variants ( STK11, CDKN2A ), 4,097(69.1%) had other germline variants ( ATM, BRCA 1, BRCA 2, CASR, CDKN2A, CFTR, EPCAM, MLH1, MSH2, MSH6, PALB2, PRSS1, STK11, and TP53 ), and 614(10.4%) had both germline variants and family history. Sixty-eight patients (1.1%) developed PC; 50% were metastatic at diagnosis. High-risk variant was associated with greatest risk of PC, IR = 85.1(95% confidence interval: 36.7-197.6)/10,000 person-years; other germline variants and first-degree relative had IR = 33 (18.4, 59.3), whereas IR among ≥2 first-degree relative alone was 10.7 (6.1, 18.8). HbA1c was significantly higher among cases vs controls (median = 7.0% vs 6.4%, P = 0.02). In multivariable analysis, every 1% increase in HbA1c was associated with 36% increase in odds of PC (odds ratio 1.36, 95% confidence interval: 1.08-1.72). Pancreatitis was independently associated with a risk of PC (odds ratio 3.93, 95% confidence limit 1.19, 12.91). DISCUSSION: Risk of PC varies among high-risk individuals. HbA1c and history of pancreatitis may be useful additional markers for early detection in this patient population.

Identifying the current status and future needs of clinical, educational, and laboratory genetics services in Pakistan: a web-based panel discussion.

While the prevalence of genetic disorders has been well documented in the Muslim-majority, low-socioeconomic country of Pakistan, the provision of medical genetic services remains limited and cost-prohibitive to the masses in the country. With the objective of identifying gaps in the provision of medical genetics services as perceived by the healthcare providers and the general public, the Pakistani Society of Medical Genetics and Genomics (PSMG) organized a needs assessment webinar on December 6, 2020, titled, "A Vibrant Discussion on the Current Status and Future Needs of Medical Genetic Services in Pakistan." The objectives of the webinar were (1) to explore the current availability of medical genetics services, (2) to identify areas in clinical genetics delivery models needed to improve the state of medical genetics in the country, and (3) to garner the interest in such provisions from the expert and lay audience. The webinar consisted of a moderator-led, structured interview of an expert panel including the following topics: (1) postgraduate clinical genetics and genetic counseling training programs, (2) medical genetics clinics and formal genetic counseling services), (3) clinical genetic testing and (4) patient support and advocacy groups. The webinar was followed by a short, web-based survey completed by 35 of the 60 attendees. The results of this survey indicated overwhelming support for establishing formal genetic counseling educational opportunities (91.6%) and increasing the availability of genetic testing (100%). This report further summarizes the opinions and recommendations of the panelists and the audience survey results.

Workplace stressors and their association with hair cortisol concentrations among ready-made garment workers in Bangladesh: A cross-sectional study.

OBJECTIVES: Psychosocial working conditions of ready-made garment (RMG) workers have been associated with poorer self-reported health outcomes. However, no such research has been done with respect to physiological markers that are considered to reflect stress. We consequently aimed to investigate associations of psychosocial working conditions with such a marker, that is, hair cortisol, among RMG workers in Bangladesh. METHODS: We conducted semi-structured face-to-face interviews in labor colonies in the Mirpur area, Dhaka, Bangladesh, in February and March 2021 with individuals identifying as garment workers. The interview inquired after various workplace stressors and resources (i.e., workplace support, workplace bullying, vertical trust, beneficial leadership, work-family conflict, and financial issues including savings, debts, financial obligations, and financial support). In addition, hair samples of 2 cm length were collected from participants. Hair cortisol concentrations (HCC) were determined based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear regression models were run to detect possible associations of workplace stressors and resources with HCC. RESULTS: In total, data of 576 participants were included in the analysis (71.9% female, mean age = 25.9 years). Mean HCC was 4.4 pg/mg (standard deviation = 2.1 pg/mg). The sole variable significantly associated with increased HCC was "having to keep your job to support your children or spouse financially" (ß = 0.28 [95% confidence interval 0.02-0.55]). CONCLUSIONS: The sole workplace stressor significantly associated with increased HCC was the necessity to keep one's job to support children or spouse financially. This observation can, however, barely be disentangled from the fact that one has children/a spouse.

Risk of bleeding after percutaneous endoscopic gastrostomy (PEG).

BACKGROUND: Patients who undergo percutaneous endoscopic gastrostomy (PEG) placement are often on anticoagulation and/or antiplatelet therapy with a potential thromboembolic risk if these medications are discontinued. Data on the safety of peri-procedural use of these drugs is limited. AIMS: To assess the risk and to identify any predictive factors for post-PEG bleeding, and to determine if clopidogrel increases the risk of bleeding following PEG. METHODS: A retrospective chart audit was conducted from January 1, 2002 to June 30, 2011. RESULTS: A total of 1,541 patients underwent PEG placement during this period. Gastrointestinal bleeding after PEG placement occurred in 51 cases (3.3%) and bleeding directly attributed to PEG was noted in six patients (0.4%). Multivariate logistic regression analysis of variables (age, gender, length of hospitalization, indication for PEG, antiplatelet or anticoagulant medications) showed that heparin infusion (P = 0.018) and length of hospitalization (P = 0.029) were statistically significant predictors of bleeding. The mean period for cessation and resumption of clopidogrel with PEG placement were 2.2 and 1.3 days, respectively. CONCLUSION: Although PEG is classified as a high-risk endoscopic procedure, bleeding with PEG placement was rare, even with use of anticoagulation and antiplatelet medications. In selected patients on heparin infusion undergoing PEG, delaying the procedure, alternative use of low-molecular-weight heparin or close monitoring and frequent assessments should be considered. Clopidogrel did not contribute to an increase in bleeding risk, despite being held for a much shorter peri-procedural period as recommended by expert consensus.

Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing.

Pseudomonas aeruginosa uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in P. aeruginosa is complex, intricate and is dominated by two main N-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in P. aeruginosa. Paradoxically, LasR mutants are frequently isolated from chronic P. aeruginosa infections, typically among cystic fibrosis (CF) patients. This suggests P. aeruginosa can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of P. aeruginosa from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the rhlR locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease lasA and rhamnolipid rhlA, rhlB, rhlC. Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e., mexT, mucA, algR, rpoN, exsS, ampR). Whole genome comparisons show that P. aeruginosa strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI's) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of rhlR has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of lasR. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of rhlR and mutation of rhlI. This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of P. aeruginosa in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.

Hedgehog transcriptional effector GLI mediates mTOR-Induced PD-L1 expression in gastric cancer organoids.

Tumors evade immune surveillance by expressing Programmed Death-Ligand 1 (PD-L1), subsequently inhibiting CD8+ cytotoxic T lymphocyte function. Response of gastric cancer to immunotherapy is relatively low. Our laboratory has reported that Helicobacter pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Hedgehog (Hh) signaling pathway. The PI3K/AKT/mTOR pathway is activated in gastric cancer and may have immunomodulatory potential. We hypothesize that Hh signaling mediates mTOR-induced PD-L1 expression. Patient-derived organoids (PDOs) were generated from gastric biopsies and resected tumor tissues. Autologous organoid/immune cell co-cultures were used to study the immunosuppressive function of MDSCs. NanoString Digital Spatial Profiling (DSP) of immune-related protein markers using FFPE slide-mounted tissues from gastric cancer patients was performed. DSP analysis showed infiltration of immunosuppressive MDSCs expressing Arg1, CD66b, VISTA and IDO1 within cancer tissues. Orthotopic transplantation of patient derived organoids (PDOs) resulted in the engraftment of organoids and the development of histology similar to that observed in the patient's tumor tissue. PDO/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of PMN-MDSCs within these co-cultures sensitized the organoids to anti-PD-1/PD-L1-induced cancer cell death. Rapamycin decreased phosphorylated S6K, Gli2 and PD-L1 expression in PDO/immune cell co-cultures. Transcriptional regulation of PD-L1 by GLI1 and GLI2 was blocked by rapamycin. In conclusion, the PDO/immune cell co-cultures may be used to study immunosuppressive MDSC function within the gastric tumor microenvironment. The mTOR signaling pathway mediates GLI-induced PD-L1 expression in gastric cancer.

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.

BACKGROUND: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. RESULTS: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation. CONCLUSIONS: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.

Impact of the societal response to COVID-19 on access to healthcare for non-COVID-19 health issues in slum communities of Bangladesh, Kenya, Nigeria and Pakistan: results of pre-COVID and COVID-19 lockdown stakeholder engagements.

INTRODUCTION: With COVID-19, there is urgency for policymakers to understand and respond to the health needs of slum communities. Lockdowns for pandemic control have health, social and economic consequences. We consider access to healthcare before and during COVID-19 with those working and living in slum communities. METHODS: In seven slums in Bangladesh, Kenya, Nigeria and Pakistan, we explored stakeholder perspectives and experiences of healthcare access for non-COVID-19 conditions in two periods: pre-COVID-19 and during COVID-19 lockdowns. RESULTS: Between March 2018 and May 2020, we engaged with 860 community leaders, residents, health workers and local authority representatives. Perceived common illnesses in all sites included respiratory, gastric, waterborne and mosquitoborne illnesses and hypertension. Pre-COVID, stakeholders described various preventive, diagnostic and treatment services, including well-used antenatal and immunisation programmes and some screening for hypertension, tuberculosis, HIV and vectorborne disease. In all sites, pharmacists and patent medicine vendors were key providers of treatment and advice for minor illnesses. Mental health services and those addressing gender-based violence were perceived to be limited or unavailable. With COVID-19, a reduction in access to healthcare services was reported in all sites, including preventive services. Cost of healthcare increased while household income reduced. Residents had difficulty reaching healthcare facilities. Fear of being diagnosed with COVID-19 discouraged healthcare seeking. Alleviators included provision of healthcare by phone, pharmacists/drug vendors extending credit and residents receiving philanthropic or government support; these were inconsistent and inadequate. CONCLUSION: Slum residents' ability to seek healthcare for non-COVID-19 conditions has been reduced during lockdowns. To encourage healthcare seeking, clear communication is needed about what is available and whether infection control is in place. Policymakers need to ensure that costs do not escalate and unfairly disadvantage slum communities. Remote consulting to reduce face-to-face contact and provision of mental health and gender-based violence services should be considered.

Metoclopramide does not influence the frequency of propofol-induced spontaneous movements.

STUDY OBJECTIVE: To evaluate the effects of metoclopramide on the frequency and severity of propofol-induced movements. DESIGN: Randomized, double blind, placebo-controlled trial. SETTING: Veterans Administration Medical Center. PATIENTS: One hundred thirty-seven consenting adults scheduled to receive general anesthesia with propofol induction. INTERVENTIONS: Patients were randomized to receive either metoclopramide 10 mg intravenously (IV) or placebo (saline) 3 min before induction of general anesthesia. All patients received midazolam 1 to 2 mg IV, fentanyl 50 to 150 microg IV, and lidocaine 50 to 80 mg IV before induction of anesthesia. MEASUREMENTS: Occurrence of spontaneous movements and severity during the observation period were recorded after propofol induction by observing movement in the hands/arms and feet/legs, as well as presence of a hiccup. The dosage of anesthetic medications administered was also recorded for each patient. MAIN RESULTS: No differences were noted in the frequency and severity of spontaneous movement in the patients who had received metoclopramide and placebo. However, compared with the patients who did not move, patients who experienced movements received a significantly higher dose of propofol (P = 0.025) and a lower dose of fentanyl (P = 0.049). CONCLUSIONS: Metoclopramide does not affect the frequency of propofol-induced movements, but propofol and fentanyl doses influence the frequency of movements during propofol induction.

LRP-1 Pathway Targeted Inhibition of Vascular Abnormalities in the Retina of Diabetic Mice.

PURPOSE: The cell surface LDL (low-density lipoprotein) receptor-related protein-1 (LRP-1) is important for lipid transport and several cell signaling processes. Human apolipoprotein E (apoE) is a ligand of LRP-1. We previously reported that a short peptide (apoEdp) mimicking the LRP-1 binding region of apoE prevents hyperglycemia-induced retinal endothelial cell dysfunction in vitro. The in-vivo outcome of apoE-based peptidomimetic inhibition of LRP-1 in the treatment of diabetic retinopathy is unknown. METHODS: Six months after streptozotocin induction of diabetes, male C57Bl/6 mice were intravitreally inoculated with apoEdp in a controlled release formulation. On the 15th day post-apoEdp treatment, mouse retinas were harvested to examine (1) blood-retinal-barrier (BRB) permeability by Evans blue dye, inflammatory leukostasis by concanavalin staining of leukocytes and LRP-1 pathway-related protein expression by Western blot analysis and gelatin zymography. RESULTS: Intravitreal apoEdp treatment of diabetic mice significantly reduced Evans blue extravasation and the number of adherent leukocytes in the diabetic mouse retinas. ApoEdp treatment inhibited the expression of extracellular matrix (ECM) degrading proteases heparanase and MMP-2, and restores the BRB tight junction proteins occludin and ZO-1. ApoEdp treatment also inhibited Wnt/ß-catenin-related expression of pro-inflammatory molecules ICAM-1, HIF-1α, and VEGF through negative regulation by LRP-1. CONCLUSION: Intravitreal apoEdp treatment of diabetic mice resulted a significant decrease in retinal vascular abnormalities through downregulation of LRP-1-related ECM protein degradation and Wnt/ß-catenin-related pro-angiogenic molecules.

Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors.

BACKGROUND: Controversy persists about whether certain antidepressants reduce tamoxifen's effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer. METHODS: We examined 16 887 breast cancer survivors (TNM stages 0-II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables. RESULTS: Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non-statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen-only users. For the other antidepressants, we again found no such associations. CONCLUSIONS: Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine.

Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases.

We report nine novel DNA alterations in the RET proto-oncogene in 12 unrelated cases identified by DNA sequencing of exons 10 and 11 of the gene. The novel variants K666E, IVS9-11G-->A, D631V in cis with H665Q, D631E (with C634Y), E623K (in trans with C618S), 616delGAG (in trans with C609Y), Y606C, C630R, and R635-T636insELCR;T636P were detected in patients with various clinical presentations ranging from thyroid goiter, medullary thyroid carcinoma, and pheochromocytoma to classic multiple endocrine neoplasia type 2A. When novel DNA alterations are found, extended family studies can be helpful in determining the clinical significance of such findings. Segregation within families suggests that K666E and T636insELCR;T636P are likely to be disease-causing mutations. However, the mechanism by which they affect the normal activity of the RET receptor is unclear. Absence of segregation with disease was observed for E623K and 616delGAG. For the remainder of the DNA alterations, family studies were not possible, and the clinical significance of these novel variants needs further assessment. Additional case reports, animal models, and/or functional studies are needed to determine the clinical significance of these newly identified variants.

Botulinum neurotoxin: unique folding of enzyme domain of the most-poisonous poison.

Botulinum neurotoxin (BoNT), the most toxic substance known to mankind, is the first example of the fully active molten globule state. To understand its folding mechanism, we performed urea denaturation experiments and theoretical modeling using BoNT serotype A (BoNT/A). We found that the extent of BoNT/A denaturation from the native state (N) shows a nonmonotonic dependence on urea concentration indicating a unique multistep denaturation process, N → I1 [Formula: see text] I2 [Formula: see text] U, with two intermediate states I1 and I2. BoNT/A loses almost all its secondary structure in 3.75 M urea (I1), yet it displays a native-like secondary structure in 5 M urea (I2). This agrees with the results of theoretical modeling, which helped to determine the molecular basis of unique behavior of BoNT/A in solution. Except for I2, all the states revert back to full enzymatic activity for SNAP-25 including the unfolded state U stable in 7 M urea. Our results stress the importance of structural flexibility in the toxin's mechanism of survival and action, an unmatched evolutionary trait from billion-year-old bacteria, which also correlates with the long-lasting enzymatic activity of BoNT inside neuronal cells. BoNT/A provides a rich model to explore protein folding in relation to functional activity.

Identifying primary and recurrent cancers using a SAS-based natural language processing algorithm.

OBJECTIVE: Significant limitations exist in the timely and complete identification of primary and recurrent cancers for clinical and epidemiologic research. A SAS-based coding, extraction, and nomenclature tool (SCENT) was developed to address this problem. MATERIALS AND METHODS: SCENT employs hierarchical classification rules to identify and extract information from electronic pathology reports. Reports are analyzed and coded using a dictionary of clinical concepts and associated SNOMED codes. To assess the accuracy of SCENT, validation was conducted using manual review of pathology reports from a random sample of 400 breast and 400 prostate cancer patients diagnosed at Kaiser Permanente Southern California. Trained abstractors classified the malignancy status of each report. RESULTS: Classifications of SCENT were highly concordant with those of abstractors, achieving κ of 0.96 and 0.95 in the breast and prostate cancer groups, respectively. SCENT identified 51 of 54 new primary and 60 of 61 recurrent cancer cases across both groups, with only three false positives in 792 true benign cases. Measures of sensitivity, specificity, positive predictive value, and negative predictive value exceeded 94% in both cancer groups. DISCUSSION: Favorable validation results suggest that SCENT can be used to identify, extract, and code information from pathology report text. Consequently, SCENT has wide applicability in research and clinical care. Further assessment will be needed to validate performance with other clinical text sources, particularly those with greater linguistic variability. CONCLUSION: SCENT is proof of concept for SAS-based natural language processing applications that can be easily shared between institutions and used to support clinical and epidemiologic research.

Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer.

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0-IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ≥80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28-0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30-0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36-0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.

Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades.

BACKGROUND: We investigated the impact of breast cancer molecular subtypes and treatment on survival in a cohort of medically insured women followed for more than 20 years. METHODS: We examined 934 female members of an integrated health care delivery system newly diagnosed with invasive breast cancer between 1988 and 1995 and followed them through 2008. Tumors were classified into four molecular subtypes on the basis of their expression profile: luminal A; luminal B; basal-like; and HER2-enriched. We followed women from the surgery date to death, health plan disenrollment, or study's end. HR and 95% confidence intervals (CI) were fit using Cox proportional hazards models adjusting for cancer treatments and tumor characteristics. RESULTS: A total of 223 (23.9%) women died because of breast cancer during the 21-year study period. Compared with women with luminal A tumors, women with HER2-enriched (HR 2.56, 95% CI 1.53-4.29) and luminal B tumors (HR 1.96, 95% CI: 1.08-3.54) had roughly a two-fold increased adjusted risk of breast cancer mortality. In addition, the survival curves suggest that risk of late mortality persists in women with luminal A tumors. CONCLUSION: Among women with health care coverage, molecular subtypes were important predictors of breast cancer mortality. Women with HER2-enriched tumors and luminal B subtypes had the poorest survival despite adjusting for important covariates. IMPACT: In a cohort followed for more than 20 years, women with HER2-enriched tumors had worse survival, but interestingly, the survival curve for women with luminal A tumors continued to steadily decline after 10 years of follow-up.