Levels of PFAS concentrations in the placenta and pregnancy complications.

BACKGROUND: Recent research has raised concerns about the potential health effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure, particularly during critical periods of development such as pregnancy. In this study, we sought to investigate the presence and potential impacts of PFAS in the placenta. METHODS: We measured 13 PFAS compounds in placental tissue samples among 50 women who gave birth at a tertiary medical center in southern Israel. The sample comprised of 10 women with pregnancy-related complications (preterm birth, preeclampsia, gestational diabetes or small-for-gestational age) and 40 women without complications individually matched to cases by age. RESULTS: For five (5) out of 13 PFAS compounds (Perfluorooctane Sulfonate (PFOS), perfluorooctanoic acid (PFOA), Perfluorohexanesulphonic acid (PFHxS), Perfluorononanoic acid (PFNA), Perfluorodecanoic acid (PFDA)) median concentrations were lower or comparable to placental measurements in different international populations. Geometric mean was estimated at 0.09 ng/g (90%CI:0.07;0.10) for PFOA, 0.05 ng/g for PFNA (90%CI:0.04;0.07), 0.03 ng/g for PFDA (90%CI:0.01;0.03), 0.06 ng/g for PFHxS (90%CI:0.05;0.07), 0.23 ng/g for PFOS linear measurement (90%CI:0.20;0.26) and 0.25 ng/g (90%CI:0.22;0.30) for PFOS summed concentrations that included non-linear isomers. Composite outcome of pregnancy-related complications was associated with elevated PFOA placental concentrations at an odds ratio (OR)= 1.82 (90%CI:1.06;3.13) for an increase of one quintile of PFOA value and adjusted to maternal gravidity in a conditional logistic regression. CONCLUSION: This pilot study indicates a widespread exposure to multiple PFAS compounds in placental tissue of pregnant women in Israel. These findings warrant further validation through comprehensive national human biomonitoring initiatives.

Linking between ambient pollution and metals concentration in blood. Nationwide study based on the national blood banking system.

This study was aimed to describe the chemical traces of air pollution in blood of residents and evaluate the association between ambient pollution and its dose absorbed internally by a human body. The national Magen David Adom Blood Services blood donation collection platform and the National Public Health Laboratory's testing services were utilized to conduct a human biomonitoring study among blood donors in Israel. The donors' residential addresses and donations sites' locations were geocoded and merged with the levels of pollutants recorded by the nearby monitoring stations. Pollutants included nitrogen dioxide (NO2), sulfate dioxide (SO2), ozone (O3), carbon monoxide (CO) and particulate matter of size <10 and 2.5 µm in diameter (PM10 & PM2.5). Metal concentrations were statistically analyzed by ratio t-test and a lognormal regression, and adjusted to age, gender and smoking (defined based on Cadmium values). The findings indicate an independent positive association between pollutants and metals' concentrations in blood. Specifically, an increase in interquartile range (IQR) of NO2 was associated with 9.5 % increase in As in blood. The increase in one IQR of PM10 and SO2 was associated with an increase in Pb, of 16.6 % and 12.4 %, respectively. SO2 was also adversely associated with Cd concentrations, by increasing its levels by 5.7 %. The donors' proximity to quarries was related to the Pb blood levels higher 1.47 times compared to donors without quarries close to their residence (p-value = 0.013). To conclude, ambient pollution levels are associated with internal metals' concentrations, reaffirming the link between the two in the pathological pathway from air pollution to morbidity.

National blood bank services as a platform for national human biomonitoring - A proof-of-concept study.

BACKGROUND: Human biomonitoring (HBM) is crucial for identifying potential risks to human health from exposure to environmental hazards. However, it is an expensive and labor-intensive endeavor. To save on samples' collection process we suggested using a national blood banking system as a platform for a national HBM program. For the case study, we used a comparison of blood donors from heavily industrialized Haifa Bay region, northern Israel, with donors from the rest of the country. METHODS: The study population comprised a random sample of blood donors donating blood all over Israel. Samples of whole blood were tested for arsenic (As), cadmium (Cd), chromium (Cr) and lead (Pb). Donors' donations sites and residential locations were geocoded. Smoking status was verified based on Cd levels, after calibrating their concentrations vs Cotinine in a sub-sample of 45 subjects. Metal concentrations were compared between regions using a lognormal regression, while controlling for age, gender, and predicted probability of smoking. RESULTS: During Mar 2020-Feb 2022, we collected 6230 and tested 911 samples. Concentrations of most of the metals were modified by age, gender, and smoking. Cr and Pb appeared to be 1.08-1.10 times higher among Haifa Bay residents than in the rest of the country (although with borderline significance of 0.069 for Cr). Cr and Pb were 1.13-1.15 times higher for those who donated blood in the Haifa Bay region, but not necessarily resided in the area. Donors from Haifa Bay had lower levels of As and Cd as compared to other donors in Israel. CONCLUSIONS: Using a national blood banking system for HBM proved to be feasible and efficient. Blood donors from Haifa Bay area were characterized by elevated levels of Cr and Pb and lower levels of As and Cd. An extensive investigation of industries in the area is warranted.

Cesarean section in the second stage of labor is associated with early-term and late preterm birth in subsequent pregnancies.

OBJECTIVES: The objectives of this study were to determine in a population-based cohort study the association between cesarean section (CS) during the second stage of labor and the risk for preterm birth and/or cervical insufficiency in the subsequent pregnancy; to identify maternal and neonatal risk factors for long-term complications following CS due to prolonged second stage of labor. METHODS: We conducted a retrospective population-based cohort study including women who had at least one consecutive delivery following a CS at our institution from 1991 to 2018, provided that the first delivery was at term. We divided the study cohort into two groups: (1) women who delivered by CS due to failure to progress during the first stage of labor (n = 1068); and (2) those who delivered by CS due to arrest of descent at the second stage of labor (n = 603). RESULTS: Of the 120,147 women who met the inclusion criteria, 78,407 had a subsequent delivery during the study period. Women of group 1 were significantly older than those of group 2 (p = .018), and had a higher rate of assisted reproductive technology [61 (5.7%) vs. 18 (3.1%), p < .022,]. Additionally, their hospitalization period was significantly longer (p < .001). The rate of preterm birth in the subsequent delivery was higher among women who had a CS due to arrest of descent than those who had a CS due to arrest in dilatation [43 (7.3%) vs 49 (4.6%), p < .026]. This was confirmed after adjusting for confounding factors In a multivariable regression analysis (OR 1.78, 95% CI 1.14-2.76, p value = .011) A Cox regression analysis implying gestational age at delivery at the time factor identifies CS due to arrest of descent as a risk factor for subsequent preterm birth (Hazard ratio 1.19 95% CI 1.07-1.31). CONCLUSION: CS due to arrest of descent is an independent risk factor for subsequent preterm birth. The exact mechanisms contributing to this association are yet to be determined. SYNOPSIS: Cesarean section during the second stage of labor is an independent risk factor for late preterm birth in the subsequent pregnancy when compared to cesarean section in the first stage of labor.

Qualifying coronavirus disease 2019 convalescent plasma donors in Israel.

BACKGROUND AND OBJECTIVES: Passive immunization using investigational COVID-19 convalescent plasma (CCP) is a promising therapeutic strategy and could improve outcome if transfused early and contain high levels of anti-SARS-CoV-2 antibodies. We report the management of a national CCP collection and distribution program in Israel. MATERIALS AND METHODS: From 1 April 2020 to 15 January 2021, 4020 volunteer donors donated 5221 CCP units and 837 (20.8%) donors donated more than once. Anti-nucleocapsid IgG antibodies were determined using chemiluminescent immunoassay method (Abbott). A statistical model based on repeated IgG tests in sequential donations was created to predict the time of antibody decline below sample/cut-off (S/CO) level of 4.0. RESULTS: Ninety-six percent of CCP donors suffered a mild disease or were asymptomatic. Older donors had higher antibody levels. Higher antibody levels (S/CO ≥4) were detected in 35.2% of the donors. Low positive (S/CO ≥1.4-3.99) were found in 37%, and 27.8% had undetectable antibodies (S/CO ≤1.4). The model predicted decrease antibody thresholds of 0.55%/day since the first CCP donation, providing guidance for the effective timing of future collections from donors with high antibody levels. CONCLUSIONS: An efficient CCP collection and distribution program was achieved, based on performing initial and repeated plasma collections, preferably from donors with higher antibody levels, and only antibody-rich units were supplied for therapeutic use. The inventory met the quantity and quality standards of the authorities, enabled to respond to the growing demand of the medical system and provide a product that may contribute to improve prognosis in patients with COVID-19.

Exposure to metals and morbidity at eight years follow-up in women of childbearing age.

This exploratory study was aimed to investigate the link between toxic metal content in women's urine and their morbidity 2 years before and 6 years after the test. Concentrations of 25 metals in urine were analyzed for 111 pregnant women collected prior to delivery. All women were of Arab-Bedouin origin. Information on primary care and hospital visits during the study period was obtained. In a Poisson regression model, a health outcome was regressed over metal exposure and other factors. A Weighted Quantile Sum Regression (WQS) approach was used to indicate metals dominating in their possible impact on women's morbidity. Obesity was the most frequently diagnosed condition in this population (27.9%). Diagnoses in a neurological category accounted for 36.0%, asthma or respiratory-25.2%, psychiatric-12.6%, cardiovascular-14.4% and cancer or benign growth-for 13.5%. Based on WQS analysis, cancer and benign growth were mostly attributed to the increased levels of cadmium, cardiovascular outcomes were linked with lead, and obesity was found associated with elevated levels of nickel. Hematological, neurological and respiratory outcomes were attributed to multiple non-essential metals. The health and exposure profile of women in the study warrants a periodic biomonitoring in attempt to identify and reduce exposure to potentially dangerous elements.

Bisphosphonate treatment and the risk of atypical femoral fracture among patients participating in a Fracture Liaison Service of a tertiary medical center.

Bisphosphonates are common treatment for osteoporosis. Among patients admitted with hip fracture, atypical femoral fractures (AFF) were more prevalent in those who were treated with Bisphosphonates for five or more years. Five years of Bisphosphonates treatment may signify an increased risk for AFF, though the absolute risk remains very low. PURPOSE: Atypical femoral fractures (AFF) are a rare complication of bisphosphonate (BP) treatment. We evaluated the correlation between BP exposure and AFF risk among hip fracture patients. METHODS: This retrospective nested case-control study included patients over age 50 years, operated for osteoporotic hip fracture between July 2014 and November 2018, who attended our Fracture Liaison Service. We classified fracture radiographs and compared demographic, clinical, biochemical, and drug purchase data between patients with AFF and those with typical osteoporotic hip fracture (controls). To correct for the younger age of patients with AFF, we matched each case (AFF) with three controls according to age ([Formula: see text] 1 year) and sex and performed a conditional logistic regression model. RESULTS: Of 989 patients, 31 (3%) had AFF. Patients with AFF were younger than those with inter-trochanteric fractures (mean ± SD: 72.3 ± 10.3 vs. 80.2 ± 9.6 years, p < 0.001). Following matching, the mean Charlson's Comorbidity Index (CCI) was lower in the AFF than in the control group (2.9 ± 3.7 vs. 4.7 ± 4.2; p = 0.030) and a higher proportion of them were treated with BP for 5 years or more (58.1 vs. 16.0%; p < 0.001). Among patients admitted with hip fracture who were treated with BP for 5 years or more, the odds ratio of this fracture being atypical was significantly higher compared with no BP treatment (21.7; 95% CI-4.1-113.9). CONCLUSIONS: Patients with AFF compared to typical hip fractures showed better baseline medical conditions irrespective of their younger age. Five years of BP treatment may be associated with an increased risk for AFF, though the absolute risk remains very low.

Indications and Findings of Upper Endoscopies in Males and Females, Are They the Same or Different?

Sex and gender can affect the prevalence and prognosis of diseases. Our aim was to assess similarities and differences for males and females who underwent an upper endoscopy, with regards to indications and results. We reviewed all upper endoscopy reports from 2012 to 2016. Data regarding demographics, indications, and procedure findings were collected. The upper endoscopy findings were compared regarding the most common indications: gastroesophageal reflux, abdominal pain, gastrointestinal bleeding, and anemia. We investigated 12,213 gastroscopies among males (age, 56.7 ± 17.4) and 15,817 among females (age, 56.0 ± 17.3, p = 0.002). Males who underwent an upper endoscopy for gastroesophageal reflux had higher rates of esophagitis (7.7% vs. 3.4%, p < 0.001) and Barret's esophagus (4.4% vs. 1.5%, p < 0.001). Females who underwent an upper endoscopy for abdominal pain had a higher rate of hiatal hernia, whereas males had higher rates of esophagitis, helicobacter pylori infection, gastritis, gastric ulcer, duodenitis, and duodenal ulcer (p < 0.001). Gastrointestinal bleeding as an indication for upper endoscopy showed that helicobacter, duodenitis, and duodenal ulcers are more common among males compared to females (p < 0.001). Males with anemia who underwent an upper endoscopy had higher rates of esophagitis (p = 0.021) gastritis (p = 0.002), duodenitis (p < 0.001), and duodenal ulcer (p < 0.001). We found significant differences regarding the pathological gastroscopy findings between males and females in relation to the different indications.

Maternal metal concentration during gestation and pediatric morbidity in children: an exploratory analysis.

BACKGROUND: The majority of studies linking exposure to metals with certain health outcomes focus on known toxic metals. Alternatively, this study assesses the extent to which exposure to a wider range of metals during gestation is associated with childhood morbidity. METHODS: We analyzed the concentrations of 25 metals found in urine samples of 111 pregnant women of Arab-Bedouin origin collected prior to birth. In addition, we collected medical records on their offspring for six years following birth, including every interaction with HMOs, local hospitals, and pharmacies. RESULTS: The main types of morbidities diagnosed and treated during this period were preterm births, malformations, asthma-like morbidity, cardiovascular and behavioral problems, and obesity. Multivariable analysis showed that offspring born before term were more likely to have been exposed to elevated maternal concentrations of zinc, thallium, aluminum, manganese, and uranium, all with adjusted relative risk above 1.40 for an increase by each quintile. Likewise, children with asthma had been exposed to higher levels of magnesium, strontium, and barium at gestation, while behavioral outcomes were associated with elevated biometals, i.e., sodium, magnesium, calcium, selenium, and zinc, as well as higher levels of lithium, cobalt, nickel, strontium, cadmium, vanadium, arsenic, and molybdenum. A heatmap of adjusted relative risk estimates indicates the considerable implications that exposure to metals may have for preterm birth and developmental outcomes. CONCLUSIONS: The current study shows that perinatal exposure to metals is adversely associated with pediatric morbidity. Further such analyses on additional samples are warranted.

Atrial Fibrillation and Mortality in the Oldest Old after Surgery for Hip Fractures.

INTRODUCTION: One-year mortality following hip fractures increases steeply with age, from 2% in the 60- to 69-year-old population up to 28% in the oldest old (older than 90 years). Of the various factors that contribute to hip fractures, atrial fibrillation (AF) is an independent risk factor at any age. OBJECTIVE: The objective of this study was to assess the association of AF with mortality among the oldest old with hip fractures. METHOD: This is a retrospective cohort study of 701 persons above age 90 years who underwent orthopedic repair for a hip fracture during 2000-2018. Of them, 218 (31%) had AF at hospital admission. The primary outcome was survival following surgery. We compared patient characteristics and 30-day, 180-day, 1-year, and 3-year survival between patients with and without AF. RESULTS: The adjusted odds ratio for 30-day postoperative mortality for those with AF versus without AF group was 1.03 (95% confidence interval [CI] 0.63-1.66). Survival estimates were higher among those without AF than with AF at 180 days postoperative: 0.85 (95% CI 0.82-0.89) versus 0.68 (95% CI 0.61-0.74), p < 0.001; at 1 year postoperative: 0.68 (95% CI 0.63-0.72) versus 0.48 (95% CI 0.42-0.55), p < 0.001; and at 3 years postoperative: 0.47 (95% CI 0.42-0.52) versus 0.28 (95% CI 0.27-0.34), p < 0.001. CONCLUSIONS: Among individuals aged >90 years, operated for hip fractures, mortality was similar for those with and without AF at 30 days postoperative. However, the survival curves diverged sharply after 180 days. Our findings suggest that AF is not an immediate surgical risk factor, but rather confers increased long-term risk in this population.

Differences in environmental factors contributing to preterm labor and PPROM - Population based study.

BACKGROUND: Previous reports indicate an association between ambient temperature (Ta) and air pollution exposure during pregnancy and preterm birth (PTB). Nevertheless, information regarding the association between environmental factors and specific precursors of spontaneous preterm birth is lacking. We aimed to determine the association between Ta and air pollution during gestation and the precursors of spontaneous preterm parturition, i.e. preterm labor (PTL) and preterm prelabor rupture of membranes (PPROM). METHODS: From 2003 to 2013 there were 84,476 deliveries of singleton gestation that comprised the study cohort. Exposure data during pregnancy included daily measurements of temperature and particulate matter <2.5 µm and <10 µm, PM2.5 and PM10, respectively. Deliveries were grouped into PPROM, PTL and non-spontaneous preterm and term deliveries. Exposure effect was tested in windows of a week and two days prior to admission for delivery and adjusted to gestational age and socio-economic status. Poisson regression models were used for analyses. RESULTS: There is an association of environmental exposure with the precursors of spontaneous preterm parturition; PPROM was more sensitive to Ta fluctuations than PTL. This effect was modified by the ethnicity, Bedouin-Arabs were susceptible to elevated Ta, especially within the last day prior to admission with PPROM (Relative Risk (RR) =1.19 [95% CI, 1.03; 1.37]). Jews, on the other hand, were susceptible to ambient pollutants, two (RR=1.025 [1.010; 1.040]) and one (RR= 1.017 [1.002; 1.033]) days prior to spontaneous PTL with intact membranes resulting in preterm birth. CONCLUSION: High temperature is an independent risk factor for PPROM among Bedouin-Arabs; ambient pollution is an independent risk factor for spontaneous PTL resulting in preterm birth. Thus, the precursors of spontaneous preterm parturition differ in their association with environmental factors.

Human biologic monitoring based on blood donations to the National Blood Services.

BACKGROUND: The ambient exposure does not always reflect the internal levels of pollution absorbed in the body. While human biomonitoring (HBM) could provide a valid estimate of exposure extent, it is usually an expensive and a heavily manpowered enterprise. Using samples collected during blood donations for HMB may provide a more efficient platform for a routine biomonitoring. METHODS: The current study is aimed to explore the feasibility of using the national blood banking system for the purposes of HBM, to compare between residents of a suspected polluted area in northern Israel (Haifa Bay) to the rest of the country. Specifically, we will assemble a geographically representative sample of blood donors residing in the study area and of the general population, to test for four industry and traffic-related metals: lead (Pb), cadmium (Cd), arsenic (As) and chromium (Cr). Samples of whole blood from donors will be tested in the Laboratory of Public Health Services managed by the Ministry of Health. The information on donors' biomarkers levels will be further linked with the air pollution and meteorological data assessed at the location of the blood collection sites (short-term exposure) and donors' permanent address (long-term exposure), as recorded by the monitoring stations spread throughout Israel and the satellite-based exposure models. The association between biomarkers and ambient environmental exposures will be assessed. The samples' collection is planned for 2 years of 2020-2021. DISCUSSION: The information collected in this study could lead to environmental regulations within Haifa Bay area aimed to prevent exposure to high levels of hazardous chemicals.

Improvement of Blood Samples Preanalytic Management Alters the Clinical Results of Glucose Values: Population Study.

BACKGROUND: Prolonged time elapsing between the blood drawing and separation of the cell mass may result in decreased sample glucose levels due to continuous glycolysis. This can lead to underdiagnoses of hyperglycemic states and overdiagnosis of hypoglycemia. We aimed to evaluate the clinical impact of shortened transit time and earlier centrifugation of laboratory specimens on reported glucose results and diagnosis of clinically significant hypoglycemia (<50 mg/dL) or elevated glucose levels (>100 mg/dL). METHODS: We assessed all fasting-serum glucose tests from the adult population (190 767 subjects) without known diabetes residing in Southern Israel. Before and after intervention periods were compared: 268 359 blood tests were performed during 2009-2010, and 317 336 during 2012-2013. RESULTS: While glucose levels were 94.17 mg/dL ± 14.12 in 2012-2013 versus 83.53 mg/dL ± 14.50 in 2009-2010 (12.75% ± 0.88 increase, P < .001), the difference in glycated hemoglobin levels was statistically significant but clinically negligible: 5.84% ± 0.56 in 2012-2013 versus 5.88% ± 0.56 in 2009-2010 (0.53% ± 0.78 decrease, P < .01). There was an increased likelihood of a glucose result to be above 100 mg/dL following intervention: 9.80% versus 25.90%, P < .001. For clinics distanced over 40 km from the laboratory, age-adjusted odds ratio value was 1.26 (95% CI 1.13, 1.41). The proportion of samples with hypoglycemia values decreased from 0.33% to 0.03% (P < .001). CONCLUSIONS: We demonstrated an important change in glucose values over a two-year period following an improvement of the preanalytic processes. The intervention was related to an increase in the frequency of hyperglycemia results and a decrease in the number of hypoglycemia results. Future administrative projects should consider clinical consequences with involvement of all relevant stakeholders.

Autophagy differentially regulates macrophage lipid handling depending on the lipid substrate (oleic acid vs. acetylated-LDL) and inflammatory activation state.

The regulation of lipid droplet (LD) dynamics by autophagy in naïve macrophages is complex: Inhibiting autophagosome initiation steps attenuates oleic acid (OA) induced LD (OA-LD) biogenesis, whereas interfering with later-autophagosome maturation/lysosomal steps accelerates OA-LD biogenesis rate, but not OA-LD degradation. Here we hypothesized that regulation of macrophage lipid handling by autophagy may be lipid-substrate and activation-state-specific. Using automated quantitative live-cell imaging, initial LD biogenesis rate was ~30% slower when the lipid source was acetylated low density lipoprotein (acLDL) compared to OA. Yet, both were similarly affected by triacsin-C, an inhibitor of acyl-CoA synthase, which inhibited, and etomoxir, an inhibitor of acylcarnitine palmitoyl transferase (fatty acid oxidation), which augmented, LD biogenesis rates. An autophagy inducing peptide, Tat-Beclin1, enhanced the degradation, and inhibited (by 37%) the biogenesis of acLDL induced LD (acLDL-LD). Yet, Tat-Beclin1 increased OA-LD biogenesis rate by 70%. When macrophages were pre-activated with LPS + INFG they exhibited increased autophagosome number and area, and reduced BECN1 and ATG14 protein levels, which associated with a markedly attenuated autophagic flux. Concomitantly, OA-LD and acLDL-LD biogenesis rates increased 3 and 7.4-fold, respectively, but could not be further modulated by Tat-Beclin1, as observed in non-activated/naïve macrophages. We propose that macrophage autophagy, and/or components of its machinery, differentially regulate LD/foam-cell biogenesis depending on the lipid-source, and that inflammatory activation uncouples autophagy from LD biogenesis.

SCAPER localizes to primary cilia and its mutation affects cilia length, causing Bardet-Biedl syndrome.

Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We report humans with Bardet-Biedl syndrome who display intellectual disability, retinitis pigmentosa, obesity, short stature and brachydactyly, stemming from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings, based on linkage analysis and exome sequencing studies of two remotely related large consanguineous families, are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Using immuno-fluorescence and live cell imaging in NIH/3T3 fibroblasts and SH-SY5Y neuroblastoma cell lines over-expressing SCAPER, we demonstrate that both wild type and mutant SCAPER are expressed in primary cilia and co-localize with tubulin, forming bundles of microtubules. While wild type SCAPER was rarely localized along the ciliary axoneme and basal body, the aberrant protein remained sequestered to the cilia, mostly at the ciliary tip. Notably, longer cilia were demonstrated both in human affected fibroblasts compared to controls, as well as in NIH/3T3 cells transfected with mutant versus wildtype SCAPER. As SCAPER expression is known to peak at late G1 and S phase, overlapping the timing of ciliary resorption, our data suggest a possible role of SCAPER in ciliary dynamics and disassembly, also affecting microtubule-related mitotic progression. Thus, we outline a human ciliopathy syndrome and demonstrate that it is caused by a mutation in SCAPER, affecting primary cilia.