Polybrominated diphenyl ethers (PBDEs) are a class of flame retardant chemicals known to biomagnify in aquatic foodwebs. However, significant biotransformation of some congeners via reductive ...dehalogenation has been observed during
in vivo and
in vitro laboratory exposures, particularly in fish models. Little information is available on the enzyme systems responsible for catalyzing this metabolic pathway in fish. This study was undertaken to characterize the biotransformation of one primary BDE congener, 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99), using
in vitro techniques. Hepatic sub-cellular fractions were first prepared from individual adult common carp (
Cyprinus carpio) to examine metabolism in both microsomal and cytosolic sub-cellular fractions. Debromination rates (i.e. BDE-99 biotransformation to BDE-47) were generally higher in the microsomal fraction than in the cytosolic fraction, and some intra-species variability was observed. Further experiments were conducted to determine the biotransformation kinetics and the influence of specific co-factors, inhibitors and competitive substrates on metabolism using pooled carp liver microsomes. The apparent
K
m and
V
max values were 19.4
μM and 1120
pmoles
h
−1
mg
protein
−1, respectively. Iodoacetate (IaC) and the two thyroid hormones, reverse triodothyronine (rT3) and thyroxine (T4), significantly inhibited the debromination of BDE-99 in microsomal sub-cellular fractions with IC
50 values of 2.2
μM, 0.83
μM, and >1.0
μM, respectively. These results support our hypothesis that deiodinase enzymes may be catalyzing the metabolism of PBDEs in fish liver tissues. Further studies are needed to evaluate metabolic activity in other species and tissues that contain these enzymes.
Disturbed sleep during early childhood predicts social-emotional problems. However, it is not known how various early childhood sleep phenotypes are associated with the development of childhood ...psychopathology, nor whether these relationships vary as a function of parental psychopathology. We identified sleep phenotypes among preschool youth; examined whether these phenotypes were associated with child and parent factors; and determined if early sleep phenotypes predicted later childhood psychopathology.
Using data from the Pittsburgh Bipolar Offspring study, parents with bipolar disorder (BD), non-BD psychopathology, and healthy controls reported about themselves and their offspring (n = 218) when their children were ages 2-5. Offspring and parents were interviewed directly approximately every 2 years from ages 6-18. Latent class analysis (LCA) identified latent sleep classes; we compared these classes on offspring demographics, parental sleep variables, and parental diagnoses. Kaplan-Meier survival models estimated hazard of developing any new-onset Axis-I disorders, as well as BD specifically, for each class.
The optimal LCA solution featured four sleep classes, which we characterized as (1) good sleep, (2) wake after sleep onset problems, (3) bedtime problems (e.g., trouble falling asleep, resists going to bed), and (4) poor sleep generally. Good sleepers tended to have significantly less parental psychopathology than the other three classes. Risk of developing new-onset Axis-I disorders was highest among the poor sleep class and lowest among the good sleep class.
Preschool sleep phenotypes are an important predictor of the development of psychopathology. Future work is needed to understand the biopsychosocial processes underlying these trajectories.
The management of liver injuries in hemodynamically stable patients is variable and includes primary treatment strategies of observation (OBS), angiography (interventional radiology IR) with ...angioembolization (AE), or operative intervention (OR). We aimed to evaluate the management of patients with liver injuries with active extravasation on computed tomography (CT) imaging, hypothesizing that AE will have more complications without improving outcomes compared with OBS.
This is a prospective, multicenter, observational study. Patients who underwent CT within 2 hours after arrival with extravasation (e.g., blush) on imaging were included. Exclusion criteria included cirrhosis, nontraumatic hemorrhage, transfers from outside facilities, and pregnancy. No hemodynamic exclusion criteria were used. The primary outcome was liver-specific complications. Secondary outcomes include length of stay and mortality. Angioembolization patients were compared with patients treated without AE. Propensity score matching was used to match based on penetrating mechanism, liver injury severity, arrival vital signs, and early transfusion.
Twenty-three centers enrolled 192 patients. Forty percent of patients (n = 77) were initially OBS. Eleven OBS patients (14%) failed nonoperative management and went to IR or OR. Sixty-one patients (32%) were managed with IR, and 42 (69%) of these had AE as an initial intervention. Fifty-four patients (28%) went to OR+/- IR. After propensity score matching (n = 34 per group), there was no difference in baseline characteristics between AE and OBS. The AE group experienced more complications with a higher rate of IR-placed drains for abscess or biloma (22% vs. 0%, p = 0.01) and an increased overall length of stay ( p = 0.01). No difference was noted in transfusions or mortality.
Observation is highly effective with few requiring additional interventions. Angioembolization was associated with higher rate of secondary drain placement for abscesses or biloma. Given this, a trial of OBS and avoidance of empiric AE may be warranted in hemodynamically stable, liver-injured patient with extravasation on CT.
Therapeutic/Care Management; Level II.
This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of ...major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.
Frogeye leaf spot (FLS), caused by
, is an important foliar disease affecting soybean in the United States. A meta-analytic approach including 39 fungicide trials conducted from 2012 to 2021 across ...eight states (Alabama, Arkansas, Illinois, Iowa, Kentucky, Louisiana, Mississippi, Tennessee) was used to assess the relationship between FLS severity and soybean yield. Correlation and regression analyses were performed separately to determine Fisher's transformation of correlation coefficients (Z
), intercept (β
) and slope (β
). Disease pressure (low severity, ≤34.5; high severity, >34.5%) and yield class (low, ≤3,352; high, >3,352 kg/ha) were included as categorical moderators. Pearson's Formula: see text, obtained from back-transforming the Formula: see text
estimated by an overall random-effects model, showed a significant negative linear relationship between FLS severity and yield (Formula: see text = -0.60). The Formula: see text
was affected by disease pressure (
= 0.0003) but not by yield class (
= 0.8141). A random-coefficient model estimated a slope of -19 kg/ha for each percent severity for a mean attainable yield of 3,719.9 kg/ha. Based on the overall mean (95% CI) of the intercept and slope estimated by the random-coefficients model, the estimated overall relative damage coefficient was 0.51% (0.36 to 0.69), indicating that a percent increase in FLS severity reduced yield by 0.51%. The best model included yield class as a covariate, and population-average intercepts differed significantly between low (3,455.1 kg/ha) and high (3,842.7 kg/ha) yield classes. This highlights the potential impact of FLS on soybean yield if not managed and may help in disease management decisions.
Background
Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life‐threatening complications, including septic shock (SS). An area‐based measure of social determinants of ...health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS‐associated death (SS‐death).
Methods
Children treated for de novo AML on two Children’s Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS‐death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front‐line therapy, death, relapse, or removal from study. Multivariable‐adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group.
Results
The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI‐5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI‐1; SDI‐2: HR, 0.84 95% confidence interval (CI), 0.51–1.41; SDI‐3: HR, 0.70 95% CI, 0.42–1.16; SDI‐4: HR, 0.97 95% CI, 0.61–1.53; SDI‐5: HR, 0.72 95% CI, 0.45–1.14). Nine patients (4.4%) with SS experienced SS‐death; seven of these patients (78%) were in SDI‐4 or SDI‐5.
Conclusions
In a large, nationally representative cohort of trial‐enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS.
Time to first septic shock event was not associated with the social disorganization index (SDI), an area‐based measure of social determination of health, in children with acute myeloid leukemia treated on two Children’s Oncology Group trials. Septic shock–associated mortality is rare in children with acute myeloid leukemia, and differences by SDI were not able to be detected.
Background:
Keloids are disfiguring, scar-like lesions that are challenging to treat, with low response rates to current interventions and frequent recurrence. It has been widely reported that ...keloids are characterized by myofibroblasts, specialized contractile fibroblasts that express alpha-smooth muscle actin (α-SMA). However, evidence supporting a role for myofibroblasts in keloid pathology is inconclusive, with conflicting reports in the literature. This complicates development of more effective therapies, as the benefit of interventions targeting myofibroblasts is unclear. This study was undertaken to determine whether myofibroblasts can be considered characteristic of keloids.
Methods:
Myofibroblasts in tissue sections from keloids, hypertrophic scars (HTSs), and normal skin were localized by α-SMA immunostaining. Expression of α-SMA mRNA (
ACTA2
gene) in normal skin and keloid tissue, and in fibroblasts from normal skin, keloid, and HTSs, was measured using quantitative polymerase chain reaction.
Results:
Normal skin did not exhibit α-SMA-expressing myofibroblasts, but myofibroblasts were identified in 50% of keloids and 60% of HTSs. No significant differences in
ACTA2
expression between keloid and normal skin tissue were observed. Mean
ACTA2
expression was higher in HTS (2.54-fold,
P
= 0.005) and keloid fibroblasts (1.75-fold,
P
= 0.046) versus normal fibroblasts in vitro. However, α-SMA expression in keloids in vivo was not associated with elevated
ACTA2
in keloid fibroblasts in vitro.
Conclusions:
Despite elevated
ACTA2
in cultured keloid fibroblasts, myofibroblast presence is not a consistent feature of keloids. Therefore, therapies that target myofibroblasts may not be effective for all keloids. Further research is required to define the mechanisms driving keloid formation for development of more effective therapies.
Farmed mink are one of few animals in which infection with SARS-CoV-2 has resulted in sustained transmission among a population and spillback from mink to people. In September 2020, mink on a ...Michigan farm exhibited increased morbidity and mortality rates due to confirmed SARS-CoV-2 infection. We conducted an epidemiologic investigation to identify the source of initial mink exposure, assess the degree of spread within the facility's overall mink population, and evaluate the risk of further viral spread on the farm and in surrounding wildlife habitats. Three farm employees reported symptoms consistent with COVID-19 the same day that increased mortality rates were observed among the mink herd. One of these individuals, and another asymptomatic employee, tested positive for SARS-CoV-2 by real-time reverse transcription PCR (RT-qPCR) 9 days later. All but one mink sampled on the farm were positive for SARS-CoV-2 based on nucleic acid detection from at least one oral, nasal, or rectal swab tested by RT-qPCR (99%). Sequence analysis showed high degrees of similarity between sequences from mink and the two positive farm employees. Epidemiologic and genomic data, including the presence of F486L and N501T mutations believed to arise through mink adaptation, support the hypothesis that the two employees with SARS-CoV-2 nucleic acid detection contracted COVID-19 from mink. However, the specific source of virus introduction onto the farm was not identified. Three companion animals living with mink farm employees and 31 wild animals of six species sampled in the surrounding area were negative for SARS-CoV-2 by RT-qPCR. Results from this investigation support the necessity of a One Health approach to manage the zoonotic spread of SARS-CoV-2 and underscores the critical need for multifaceted public health approaches to prevent the introduction and spread of respiratory viruses on mink farms.
Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of ...genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.
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