THE ASSOCIATION OF LEAD BIOMARKERS WITH HEALTH EFFECTS IN COMMUNITY RESIDING WOMEN AND AN OCCUPATIONAL MALE COHORT

Although environmental and occupational lead exposure has decreased over the recent decades, the health outcomes associated with past lead exposure continue to be a significant clinical and public health issue. Lead is a multitargeted toxicant, that effect skeletal, cardiovascular and nervous system. Mounting evidence supports a link between lead at levels previously considered safe, to morbidity and mortality.The objective of this dissertation was to examine association of lead biomarkers with changes in bone mineral density (BMD), incident fractures and falls, cognition and mortality. We utilized data from two epidemiological studies: a) The Study of Osteoporotic Fractures (SOF) that enrolled a population of elderly women (age 65-87), and b)The Lead Occupational study that followed a cohort of male lead exposed and control workers through middle age (40-76 years,63% exposed, 37% controls).In the longitudinal SOF analysis, baseline total hip BMD was lower in women with high blood lead levels. The annualized rate of decline in hip BMD was greater among women with the high blood lead level, who also experienced a two-fold increased risk of fracture and falls.In the longitudinal SOF mortality analysis, women with higher blood lead levels at baseline had increased risk of all cause, and cardiovascular mortality compared to women with lower blood lead levels. No association with cancer mortality was found. These relationships were independent of age and shared risk factors between blood lead levels and BMD, fractures, falls and mortality. In the Lead Occupational study, compared to controls, lead exposed workers had lower total cognitive scores cross sectionally. In longitudinal analysis, cognitive scores of lead exposed workers declined more in compared to controls. Age and important risk factors of lead exposure and cognitive change did not explain this association.Overall, our findings provide epidemiological evidence of an association between lead exposure, morbidity, and mortality in community residing elderly women as well as a male occupational cohort. A more stringent control of lead exposure and better understanding of the mechanism of its effects may help reduce the public health burden of disease

Age but not BMI Predicts Accelerated Progression of KOA: Data from the Osteoarthritis Initiative

Background/Objectives: Knee osteoarthritis (KOA) accounts for about 35% of the arthritis burden among adults. Most adults with KOA have slowly-progressing, common knee osteoarthritis (CKOA); however, some individuals experience accelerated KOA (AKOA), rapid progression to end-stage disease within 48 months. This study analyzed individuals without radiographic evidence of KOA at baseline to determine which (baseline) characteristics were associated with progression to CKOA and/or AKOA status 48 months later.Methods: Data (n = 1,561) from the Osteoarthritis Initiative (OAI) were utilized. Multinomial logistic regression was employed to determine the magnitude of association between baseline risk factors and 48-month KOA status (AKOA and CKOA, compared to no KOA).Results: Older age (p = 0.032), greater baseline BMI (p < 0.001), female gender (p = 0.009), and greater baseline PASE score (p =0.036) were significantly associated with CKOA (11.9% of participants) and/or AKOA (3.5% of participants) at 48 months. Age, BMI, andPASE were all more strongly associated with greater risk of AKOA compared to risk of CKOA (Age: OR = 1.59 vs. 0.97; BMI: OR = 1.62vs. 1.28; PASE: OR = 1.21 vs. 1.08). Of these, only BMI was significantly associated with greater risk of both AKOA and CKOA.Conclusion: Certain factors impact the risk of AKOA and CKOA differently. Age did not increase the risk of CKOA, but among thosewith CKOA or AKOA, the proportion with AKOA increased with age. Thus, older age at onset is associated with more rapid KOA progression

Association of Perfluoroalkyl Substance with Lung Function in the US Population

Background/Aim: Perfluoroalkyl substances (PFASs) are chemical compounds used in consumer products and are linked with increases in cholesterol, thyroid disease, and pregnancy-induced hypertension. However, their association with lung function is not completely understood.Methods: Cross-sectional 2011-2012 US population data from the National Health and Nutrition Examination Survey (NHANES) were analyzed (n = 1450, aged 12 to 79 years, 50.5% females). Serum concentrations of 4 PFASs, perfluoronon-anoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS), were assessed using mass spectrometry and categorized into quartiles. Lung function was measured by spirome-try as forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the ratio of FEV1/FVC (%). Survey weighted sex stratified adjusted linear regression analysis was used to predict lung function with PFASs quartiles.Results: In males, compared to females, all 4 PFASs serum concentrations and lung function indices were higher, except FEV1/FVC (%) which was lower than females. No association of any PFAS with decrease in lung function was seen in multivariable-adjusted models in both males and females.Conclusion: In this exploratory analysis, PFAS exposure was not associated with lung function. PFAS contamina-tion has been ongoing for many years across the US and Ohio, and cleanup efforts are now underway. The association between PFAS exposure and lung function needs further exploration in longitudinal studies

Regulation of stanniocalcin-1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia.

Stanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown. Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP (8 Br-cAMP) to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia

Association of Perfluoroalkyl Substances, Bone Mineral Density, and Osteoporosis in the U.S. Population in NHANES 2009-2010

Background Perfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), are detectable in the serum of 95% of the U.S. population. Objective Considering the role of PFASs as endocrine disruptors, we examined their relationships with bone health. Methods The association between serum PFAS concentration and bone mineral density at total femur (TFBMD), femoral neck (FNBMD), lumbar spine (LSBMD), and physician-diagnosed osteoporosis was assessed in 1,914 participants using data from the National Health and Nutritional Examination Survey 2009–2010. Results The mean age of the participants was 43 years. Men had higher serum PFAS concentrations than women (p < 0.001) except for PFNA. In both sexes, serum PFOS concentrations were inversely associated with FNBMD (p < 0.05). In women, significant negative associations were observed for natural log (ln)–transformed PFOS exposure with TFBMD and FNBMD, and for ln-transformed PFOA exposure with TFBMD (p < 0.05). In postmenopausal women, serum PFOS was negatively associated with TFBMD and FNBMD, and PFNA was negatively associated with TFBMD, FNBMD, and LSBMD (all p < 0.05). With one log unit increase in serum PFOA, PFHxS, and PFNA, osteoporosis prevalence in women increased as follows: [adjusted odds ratios (aORs)] 1.84 (95% CI: 1.17, 2.905), 1.64 (95% CI: 1.14, 2.38), and 1.45 (95% CI: 1.02, 2.05), respectively. In women, the prevalence of osteoporosis was significantly higher in the highest versus the lowest quartiles of PFOA, PFHxS, and PFNA, with aORs of 2.59 (95% CI: 1.01, 6.67), 13.20 (95% CI: 2.72, 64.15), and 3.23 (95% CI: 1.44, 7.21), respectively, based on 77 cases in the study sample. Conclusion In a representative sample of the U.S. adult population, serum PFAS concentrations were associated with lower bone mineral density, which varied according to the specific PFAS and bone site assessed. Most associations were limited to women. Osteoporosis in women was also associated with PFAS exposure, based on a small number of cases

ANTIBIOTIC SUSCEPTIBILITY PATTERN OF ESCHRICHIA COLI ISOLATES FROM CLINICAL SPECIMENS AT PIMS, ISLAMABAD

Background: E. coli is the most common producer of extended spectrum beta lactamase enzyme (ESBL) which confers broad spectrum resistance to antibiotics like penicillin, cephalosporin and monobactum. Methods and Materials: The present study was carried out at Pakistan Institute of Medical Sciences, Islamabad. The marked resistance was viewed against amoxicilline-clavulanic acid, ceftriaxone and ceftazidime. The most effective drugs established were sulbactum-cefoparazone, amikacin, pepircillin-tazobactum. A total of 220 samples of wide range were selected, i.e., blood, urine, pus, sputum, etc. and were analyzed using various techniques of Gram staining and biochemical identification. Results: After performing antibiotic sensitivity tests, 83% samples came out to be ESBL positive and 17% were ESBL negative. Conclusion: It was concluded that to ensure adequate treatment of infections arising especially from urinary pathogens and controlling spread of bacterial resistant strains, the continuous monitoring by bacterial susceptibility testing is essential

Is Cerebroplacental Ratio A Marker of Impaired Fetal Growth Velocity and Adverse Pregnancy Outcome?

BACKGROUND: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term. OBJECTIVE: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between low cerebroplacental ratio at term, reduced fetal growth velocity and adverse pregnancy outcome. DESIGN: retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20-24 weeks' gestation, and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within two weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20-24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio, low abdominal circumference growth velocity (in the lowest decile), and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small for gestational age neonates. RESULTS: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted OR 2.10; 95%CI 1.71-2.57, p<0.001) and small for gestational age (adjusted OR 3.60; 95%CI 3.04-4.25, p<0.001). After the exclusion of pregnancies resulting in small for gestational age neonates, low cerebroplacental ratio multiples of median remained significantly associated with both low abdominal circumference growth velocity (adjusted OR 1.76; 95%CI 1.34-2.30, p<0.001) and birthweight centile (adjusted OR 0.99; 95%CI 0.998-0.995, p<0.001). The need for operative delivery for fetal compromise was significantly associated with low cerebroplacental ratio (adjusted OR 1.40; 95%CI 1.10-1.78, p=0.006), even after adjusting for both the umbilical artery pulsatility index multiples of median and middle cerebral artery pulsatility index multiples of median. The results were similar even after the exclusion of pregnancies resulting in small for gestational age neonates (adjusted OR 1.39; 95%CI 1.06-1.84, p=0.018). Low cerebroplacental ratio multiples of median remained significantly associated with the risk of operative delivery for presumed fetal compromise (p<0.001), even after adjusting for the known antenatal and intrapartum risk factors. These associations persisted even after exclusion of small for gestational age births. In appropriate for gestational age sized fetuses, abdominal circumference growth velocity was significantly lower in those with low cerebroplacental ratio multiples of median than in those with normal cerebroplacental ratio multiples of median (p<0.001). CONCLUSION: Cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry

Association of blood lead concentrations with mortality in older women: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Blood lead concentrations have been associated with increased risk of cardiovascular, cancer, and all-cause mortality in adults in general population and occupational cohorts. We aimed to determine the association between blood lead, all cause and cause specific mortality in elderly, community residing women.</p> <p>Methods</p> <p>Prospective cohort study of 533 women aged 65–87 years enrolled in the Study of Osteoporotic Fractures at 2 US research centers (Baltimore, MD; Monongahela Valley, PA) from 1986–1988. Blood lead concentrations were determined by atomic absorption spectrometry. Using blood lead concentration categorized as < 8 μg/dL (0.384 μmol/L), and ≥ 8 μg/dL (0.384 μmol/L), we determined the relative risk of mortality from all cause, and cause-specific mortality, through Cox proportional hazards regression analysis.</p> <p>Results</p> <p>Mean blood lead concentration was 5.3 ± 2.3 μg/dL (range 1–21) [0.25 ± 0.11 μmol/L (range 0.05–1.008)]. After 12.0 ± 3 years of > 95% complete follow-up, 123 (23%) women who died had slightly higher mean (± SD) blood lead 5.56 (± 3) μg/dL [0.27(± 0.14) μmol/L] than survivors: 5.17(± 2.0) [0.25(± 0.1) μmol/L] (<it>p </it>= 0.09). Women with blood lead concentrations ≥ 8 μg/dL (0.384 μmol/L), had 59% increased risk of multivariate adjusted all cause mortality (Hazard Ratio [HR], 1.59; 95% confidence interval [CI], 1.02–2.49) (p = 0.041) especially coronary heart disease (CHD) mortality (HR = 3.08 [CI], (1.23–7.70)(p = 0.016), compared to women with blood lead concentrations < 8 μg/dL(< 0.384 μmol/L). There was no association of blood lead with stroke, cancer, or non cardiovascular deaths.</p> <p>Conclusion</p> <p>Women with blood lead concentrations of ≥ 8 μg/dL (0.384 μmol/L), experienced increased mortality, in particular from CHD as compared to those with lower blood lead concentrations.</p

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients