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Purpose: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context., Methods: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders., Results: Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity., Conclusion: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics., Competing Interests: Competing interests: SW is an employee of Genomics England Limited. MMM is an employee of GeneDx, LLC. The remaining authors have no potential conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq). There was no evidence of a frameshift, nor of reduced expression consistent with nonsense-mediated decay, for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame insertions or deletions, 3.6% resulted in full exon skipping (in frame), and 0.6% resulted in full intron inclusion (in frame). Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. The predicted impact on splicing using (1) SpliceAI, (2) MaxEntScan, and (3) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63%, and 61% of CSSVs, respectively. In summary, approximately one in four rare CSSVs did not show evidence for LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data., Competing Interests: Declaration of interests S.W. is an employee of Genomics England Limited., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.

Aim: In the surgical treatment of placenta accreta spectrum disorders, cystoscopy for prophylactic stent placement is performed to protect the ureters from potential injury. Despite its frequent use, the use of cystoscopy in assessing the severity of these disorders has not been explored. Our objective was to find out if the abnormal findings documented during cystoscopy are associated with disease severity., Methods: In this retrospective, observational cohort study (n = 56), the bladder wall was evaluated at the time of ureteral stent placement via cystoscopy in prenatally diagnosed placenta accreta spectrum cases. Three abnormal findings were commonly present in these cases: bulging of the posterior bladder wall, neovascularization and arterial pulsatility in the area of neovascularization. These findings were stratified according to severity in histologically confirmed specimens. Continuous variables were compared via two-tailed t-tests and Wilcoxon rank sum tests. Categorical data were evaluated using logistic regression analysis., Results: Neovascularization affected 84%, bulging 71% and pulsatility 54% of the cases. Bulging and neovascularization increased with disease severity. Pulsatility occurred exclusively in percretas. Bulging was associated with a 12-fold (OR = 11.6, 95% CI 2.94-46.33, P = 0.0005) increased likelihood of percreta and neovascularization with a 17-fold (OR = 17.06, 95% CI 2.98-97.79, P = 0.0014) increase. Neovascularization and/or the presence of bulging of the bladder have high positive predictive value for placenta increta and percreta (91.5% and 95.0%, respectively). Cystoscopy can be used to assess the severity of placenta accreta spectrum cases preoperatively, especially when placentation is over the previous uterine scar and is in proximity to the bladder wall., (© 2018 Japan Society of Obstetrics and Gynecology.)

Introduction: Histologic chorioamnionitis (HC) is a common finding in the placenta from patients with preterm premature rupture of membranes (PPROM). The purpose of this study is to determine if HC differs based on the Group B streptococcus (GBS) status in patients managed expectantly with PPROM <34 weeks gestation., Methods: A retrospective study was performed of patients admitted with PPROM between 23 0/7 and 33 6/7 weeks from 2003 to 2014 at one institution. Patients were excluded if in labor, evidence of clinical chorioamnionitis, nonreassuring fetal status, multifetal gestation, HIV positive, or if GBS specimens or placental histology were not available. Placental pathology results were compared using Fisher's exact test., Results: One hundred eighty-one patients met inclusion criteria and 55 (30.3%) were GBS positive. The prevalence of HC did not differ between the GBS positive and GBS negative groups (69 versus 64.2%, respectively; p = .62). Clinical chorioamnionitis, endomyometritis, wound infection, maternal and neonatal sepsis did not differ between the two groups., Conclusions: Vaginal-rectal colonization with GBS on admission does not appear to affect the rate of HC nor neonatal outcome in patients managed conservatively with PPROM <34 weeks gestation.

Telomere length (TL) trajectories in somatic tissues during human growth and development are poorly understood. We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, r = 0.76, P < 0.0001; children, r = 0.87, P < 0.0001). LTL was shorter than MTL in fetuses (10.63 vs. 11.01 kb; P = 0.0004) and children (8.46 vs. 9.40 kb; <0.0001). The LTL-MTL gap was smaller in fetuses than children. TL in children was inversely correlated with body mass index (BMI) (LTL: -0.047 ± 0.016 kb/BMI, P < 0.005; MTL: -0.037 ± 0.017 kb/BMI, P = 0.03). We conclude that variations in TL across adults and differences in TL between somatic tissues are largely established in early life. Because TL plays a significant role in aging-related diseases, insight into the factors that fashion TL in somatic tissues during early development should contribute to an understanding of the relationship of TL with these disease and longevity in humans.-Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Telomere length dynamics in early life: the blood-and-muscle model., (© FASEB.)

Purpose: To determine if vaginal deliveries exposed to assisted reproductive technologies (ART) are associated with an increased time between delivery of the neonate and placenta and select complications., Methods: A retrospective cohort of patients enrolled in an infertility practice who had term, singleton, vaginal deliveries at two academic hospitals from 2008 to 2013 was analyzed. Controls were patients with spontaneous conceptions after infertility consultations. The exposure groups were patients with controlled ovarian hyper-stimulation (COH) with in vivo fertilization, COH with in vitro fertilization and fresh embryo transfer (COH/IVF), and frozen embryo transfer or oocyte donation recipients without COH (non-COH ET). Multiple gestations and stillbirths were excluded. Median time of third stage was compared using the Mann-Whitney U test. Secondary outcomes of retained placenta, manual placental extraction, and post-partum hemorrhage (PPH) were compared using Chi-square or Fisher's exact analyses., Results: A total of 769 patients met criteria and were analyzed. While there were no differences in time of third stage of labor, retained placenta, or PPH, manual extraction was significantly more common among non-COH ET [age-adjusted OR 5.6 (95 % CI 2.2-13.8); p < 0.001]., Conclusions: Patients who conceived after non-COH ET were at increased risk for manual placental extraction. This association was not influenced by age differences between groups. Further research must be done to determine which elements of the ART process are responsible for these differences.

Introduction: A pilomatrixoma is a benign appendage tumour related to hair cells matrix. Most of the literature review about pilomatrixoma is in the form of case reports with fewer cohort studies. The objective of this cohort is to study the variable demographic characteristics, presentation and histopathology of this condition among a larger group of patients., Materials and Methods: We conducted a retrospective study of patients who had excision of pilomatrixoma between February 1998 and August 2011 in a District General Hospital in UK., Results: The study included 67 patients with histopathologically diagnosed pilomatrixoma. The mean age was 32 years. Male to Female ratio was 35:32. The average diameter of the lesion at presentation was 13 mm (range: 2-30 mm). 66 of 67 (98.5%) patients presented with solitary lesion, while 1 patient (1.5%) had two lesions., Conclusion: Pilomatrixoma is not an uncommon benign lesion. It is more common in the maxillofacial area.

Field experiments were carried out in the two growing seasons of 1999/2000 and 2000/2001 on faba bean (Vicia faba) plants in the Experimental Farm of Agriculture Research Station at Nubaria region, Alexandria, which is considered as a newly reclaimed calcareous soil. The present investigation aimed to evaluate the effect of spraying faba bean plants with certain micronutrients, i.e. Iron, Manganese and Zinc either in single double or triple combinations on the infestation by the aphid, Aphis craccivora Koch (Aphididae, Homoptera) and the leaf miner, Liriomyza trfolü (Burgess) (Agromyzidae, Diptera). The infestation by these insects was assessed using the parameters of Infestation grades as well as the injury indices. Faba bean plants cv. Giza Blanca were sprayed twice (45 and 66 days) after planting with the above-mentioned micronutrients. However, results of this investigation showed, with no doubt, that Mn, Zn and Fe individually or in double or triple combinations have increased to varied extents the infestation rates (%) of faba bean plants compared to the untreated ones. Such varied increases were mainly due to the metabolic roles of the used foliar sprays and their interactions, which indirectly affect the physio-biological actions of plants that may render them suitable for either A. craccivora or L. trifoii reproduction. This phenomenon might be also due to the different environmental factors. In both seasons, the relationship between nutrients applications and pests Infestation followed the same trend of increase in the percentages of infested plants. This assures and confirms the constant metabolic roles of such micronutrients. The biological seed weight (ton/fed.) was positively affected by the application of the used micronutrients. It is worth mentioning that the maximum response was observed in case of the triple treatment followed by the double and single treatments in a descending order. Application of the investigated micronutrients alone or in mixtures resulted in significant increases in yield and its components. Such increases were due to the fact that ions of Zn, Fe and Mn are cofactors of several enzymes, but rarely if ever with a high degree of specificity.

To assess environmental lead contamination in the household environment of children in high-risk areas of California, three urban locations were surveyed by the California Department of Health Services. Plant, soil, and dust lead levels were measured and a questionnaire was administered. This survey estimates that 3 million homes in California (27%) may have exterior paint lead levels > or = 5000 ppm, and 1.3 million homes (12%) may have interior paint lead levels > or = 5000 ppm. The highest concentrations of lead in paint were found on exterior surfaces and, for homes built between 1920 and 1959, on trim. Age of housing was the best predictor of lead in soil and dust; homes built before 1920 were 10 times more likely to have soil lead levels > or = 500 ppm compared to post-1950 homes. Most of the variability in dust lead levels could not be explained by factors measured in this survey. Sources of lead in the home were more highly correlated with lead dust concentration levels than they were with lead dust loading levels. Households with members reporting a lead job were twice as likely to have high dust lead levels compared to households with no one reporting a lead job. The significant differences in dust lead concentration levels between communities were not reflected in differences in dust lead loading levels. Measuring dust lead loading levels does not appear to be a meaningful sampling method for risk assessment in the context of prioritizing abatement.

During the fall of 1984, we conducted a survey of umbilical cord blood lead levels of 723 live births that occurred at 5 hospitals located in 5 cities in California. Historical ambient air lead levels were used as a qualitative surrogate of air and dust exposure. The area-specific cord blood means (all means approximately 5 micrograms/dl), medians, deciles, and distributions did not vary among locations. The California distributions included means that were lower than the 6.6 micrograms/dl reported in Needleman et al.'s Boston study in 1979. Indeed, the entire California distribution was shifted to the left of the Boston study distribution, even though 3% of the California cord lead levels exceeded 10 micrograms/dl--the level above which Needleman et al. have documented psychoneurological effects in children during the first few years of life. Fourteen percent of premature babies had cord blood lead levels above 10 micrograms/dl. The association between prematurity (i.e., less than 260 d gestation) and elevated (greater than 5 micrograms/dl) cord blood lead was observed in all hospitals and yielded a relative risk of 2.9 (95% CI: .9, 9.2) and a population attributable risk of 47%. Further research is needed to confirm this association and to explore the roles of endogenous and exogenous sources of lead exposure to the mothers who give birth to premature infants.

Air monitoring in the San Francisco Bay Area was carried out to measure outdoor community air concentrations of polycyclic aromatic hydrocarbons (PAH) and mutagenic activity (mutagenicity) in particulate organic matter (POM). Monitoring began in 1979 and is currently conducted at six stations. PAH and mutagenicity tests were performed on organic extracts prepared from high volume (hi-vol) filters composited every four months, by meterological season. PAH were determined by high pressure liquid chromatography (HPLC) with fluorescence and ultraviolet detection. Mutagenicity was measured in the Ames Salmonella bioassay using strain TA98 with and without metabolic activation. The nine-year mean concentration of benzo(a)pyrene (BaP) was 0.4 ng/m3. The mutagenicity of this amount of BaP accounted for only about 0.2% of the observed mutagenicity in POM and other measured PAH accounted for even less. Concentrations of PAH and mutagenicity were three to nine times higher during the winter than during other seasons. Year-to-year wintertime trends in several PAH were also seen. Early in the 1980s, winter concentrations of BaP and benzo (g,h,i)perylene increased. However since the mid-1980's, their concentrations have fallen. The decrease in PAH concentrations may be the result of an increasing proportion of vehicles with relatively low organic emissions. In contrast to PAH, mutagenicity did not show significantly year-to-year time trends.

Two case studies are presented which apply the lead isotope ratio method to the identification of lead sources in 12 Oakland, California children. One study examined lead sources in 10 children, ages 3 to 15 yr, living together as an extended family in dilapidated housing close to a busy freeway. Eight children had elevated blood lead levels (greater than or equal to 30 micrograms/dl) and 6 children also had elevated erythrocyte protoporphyrin levels (greater than or equal to 50 micrograms/dl). A second case study examined 2-yr-old male twins, both with elevated blood lead and erythrocyte protoporphyrin levels, living in a modest, but well maintained inner city duplex apartment. Paint and surface soil samples collected in and around both households had high lead concentrations. Paint concentrations ranged from 2.9 to 273 mg/g and surface soil concentrations from 0.48 to 7.1 mg/g. The isotopic ratios of lead in the blood of these children were close to the average lead ratios of paints from exterior walls and to the lead ratios of surface soils in adjacent areas where the children played. In both case studies, the data suggest that the lead in the soil was derived mainly from weathering of lead-based exterior paints and that the lead-contaminated soil was a proximate source of lead in the blood of the children.

A simple modification of the Salmonella liquid incubation assay previously developed for detecting mutagens in urine was used to determine mutagenic activity of airborne particulate matter. The modification consists of adding ten times more bacteria (approximately 10(9) per incubation tube) and five to ten times less metabolic enzymes compared to the plate incorporation method. The mixture volume is approximately 0.2 ml, and the mixture is incubated for 90 min before pouring it according to the standard protocol. The modified procedure (micro preincubation or microsuspension) was approximately ten times more sensitive than the standard plate incorporation test for detecting mutagens in air particulate extracts and approximately ten to 31 times more sensitive for the chemical mutagens 2-nitrofluorene, 4-nitroquinoline-N-oxide, 2-aminofluorene, and benzo(a)pyrene in bacterial strain TA98. Mutagenic activity was detected in particle extracts obtained from 1 m3 of air (17 micrograms of extract) or less. This microsuspension procedure was applied to air particulate samples collected with low-volume (15-50 liters per min) virtual-dichotomous air samplers. Mutagenic activity was associated exclusively with fine particles (aerodynamic diameters of less than 2.5 microns). Diurnal patterns of mutagenic activity (TA98 revertants per cubic meter air) were investigated by measuring filter extracts from 2-hr samples collected in three San Francisco Bay Area cities during the summer or fall of 1982. Four criteria pollutants--lead, nitrogen dioxide, ozone, and sulfur dioxide--were simultaneously sampled at one location. Mutagenicity from fine particles sampled at this location was highly correlated with lead and much less correlated with nitrogen dioxide, ozone, and sulfur dioxide. The microsuspension procedure is applicable in testing samples of limited mass.

The paper describes a heated furnace atomic absorption method for determining lead in whole blood using an automated sample introduction system. It is direct and rapid. No sample pretreatment is required and up to 30 samples per hour can be analyzed. Precision and accuracy data are presented. The system has been applied to both macro (venipuncture) and micro (capillary) samples. The method uses physiologically-bound lead standards to compensate for matrix effects. It has been used in the screening of target populations and for confirming elevated blood lead levels in the California Department of Health Services Childhood Lead Program.