Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists.

BACKGROUND: Mas-related G protein-coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSIONS: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

The Relationship between Vaping Cannabis and Frequency of Cannabis Use and Cannabis-Related Problems among Urban High School Students.

Background: Vaping, including vaping cannabis, is increasing among adolescents. In this longitudinal study, we examined the relationship between vaping cannabis and frequency of cannabis use and related problems over 6 months among adolescents. Material and Methods: Data were from 233 participants (46.8% male, 93.1% African American, mean age = 16.4 years) reporting cannabis use. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) assessed frequency of past 30-day cannabis use and cannabis-related problems at baseline, 3- and 6-months post-baseline. We used latent growth curve modeling to compare vaping to non-vaping adolescents on trends in cannabis use frequency and ASSIST cannabis scores. Results: Adolescents who vaped cannabis (11.7%) had higher past 30-day frequency (mean = 17.89 days, SD = 10.49) of cannabis use at baseline compared to adolescents who had not vaped (mean = 12.1 days, SD = 10.93), but reported a significantly sharper decline in frequency of cannabis use (b = -0.34, p = 0.017). A significantly steeper decrease existed in the mean cannabis ASSIST scores for the vaping group than for the non-vaping group (b = -0.34, p = 0.014). Mean ASSIST scores on the cannabis subscale between the two groups were significantly different at 6-month follow-up (Vape mean = 6.00, SD = 8.12 vs. Non-vape mean = 9.6, SD = 9.39; p < 0.021). Conclusions: In a sample of cannabis-using adolescents, adolescents with experience vaping cannabis, compared to adolescents without vaping experience, on average reported sharper decreases in frequency of cannabis use and cannabis-related problems such as health or social problems.

Screening behaviours, demographics, and stage at diagnosis in the publicly funded Ontario Breast Screening Program.

PURPOSE: The Ontario Breast Screening Program (OBSP) offers free screening mammograms every 2 years, to women aged 50-74. Study objectives were to determine demographic characteristics associated with the adherence to OBSP and if women screened in the OBSP have a lower stage at diagnosis than non-screened eligible women. METHODS: We used the Ontario cancer registry (OCR) to identify 48,927 women, aged 51-74 years, diagnosed with breast cancer between 2010 and 2017. These women were assigned as having undergone adherent screening (N = 26,108), non-adherent screening (N = 6546) or not-screened (N = 16,273) in the OBSP. We used multinomial logistic regression to investigate the demographic characteristics associated with screening behaviour, as well as the association between screening status and stage at diagnosis. RESULTS: Among women with breast cancer, those living in rural areas (versus the largest urban areas) had a lower odds of not being screened (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.68, 0.78). Women in low-income (versus high-income) communities were more likely not to be screened (OR 1.42, 95% CI 1.33, 1.51). When stratified, the association between income and screening status only held in urban areas. Non-screened women were more likely to be diagnosed with stage II (OR 1.91, 95% CI 1.82, 2.01), III (OR 2.96, 95% CI 2.76, 3.17), or IV (OR 8.96, 95% CI 7.94, 10.12) disease compared to stage I and were less likely to be diagnosed with ductal carcinoma in situ (DCIS) (OR 0.91, 95% CI 0.84-0.98). CONCLUSIONS: This study suggests that targeting OBSP recruitment efforts to lower income urban communities could increase screening rates. OBSP adherent women were more likely to be diagnosed with earlier stage disease, supporting the value of this initiative and those like it.

Validation of the International Breast Cancer Intervention Study (IBIS) model in the High Risk Ontario Breast Screening Program: A retrospective cohort study.

PURPOSE: Women with a remaining lifetime risk of breast cancer of ≥25%, estimated using the International Breast Cancer Intervention Study (IBIS) model, were eligible for the High Risk Ontario Breast Screening Program. This study examined the performance of IBIS 10-year risk estimates in the program. METHODS: This retrospective study included 7487 women aged 30 to 69 years referred to the High Risk Ontario Breast Screening Program between July 1, 2011, and December 31, 2016, with follow-up until December 31, 2018. Model calibration and discrimination were assessed. Analyses were conducted overall and stratified by age (< or ≥50 years). Different 10-year risk thresholds were compared with the current eligibility criteria. RESULTS: Overall, IBIS overestimated the risk of breast cancer with an expected vs observed case ratio of 1.17 (95% CI = 1.04-1.35). Overestimation was highest in women aged 50 to 69 years (expected vs observed case ratio = 1.29, 95% CI = 1.03-1.69) and for those in the top quartile of risk. Overall discrimination was fair with a concordance statistic of 0.66 (95% CI = 0.63-0.70). Furthermore, when using different 10-year risk eligibility thresholds, most cases would have been missed in the 30 to 49 age group using the 8% 10-year risk threshold, whereas relatively few women aged 50 to 69 would have been ineligible at any of the thresholds examined. CONCLUSION: We found that IBIS overestimated the risk of breast cancer in this screening cohort but had adequate discrimination. Age-specific risk thresholds should be considered to optimize the program eligibility criteria.

Maternal acetaminophen use and cognitive development at 4 years: the Ontario Birth Study.

BACKGROUND: Studies have suggested a link between prenatal maternal acetaminophen use and adverse developmental outcomes in children. However, there exists a knowledge gap regarding overall cognitive development and use of acetaminophen, especially concerning the timing of use in pregnancy. This study aimed to characterize the relationship between maternal acetaminophen use and cognitive development at 4 years. METHODS: This analysis included data collected throughout pregnancy and delivery from women in the Ontario Birth Study prospective cohort from 2013 to 2019 and from the NIH Toolbox Early Childhood Cognition battery administered to 4-year-old children between 2018 and 2021 (n = 436). The exposure was maternal acetaminophen use and the primary outcome was a cognition composite score. The relationship between exposure and outcome was determined using Poisson regression with a robust error variance. RESULTS: We did not observe any association between maternal acetaminophen intake any time before or during pregnancy and low cognition composite score of offspring. The IRR of suboptimal overall cognition was 1.38 (0.78-2.45), 1.22 (0.67-2.22), 0.80 (0.44-1.47), and 1.56 (0.74-3.29) for maternal use of acetaminophen before, in early, late, or overall pregnancy, respectively. CONCLUSION: Current data do not provide evidence to support a relationship of maternal acetaminophen use during pregnancy with adverse cognitive effects at 4 years. IMPACT: Acetaminophen use during pregnancy may influence the risk of child neurocognitive disorders, but there is conflicting evidence of its relationship to sub-clinical measures of cognitive development such as executive function. The study design allowed us to examine the role of timing of acetaminophen use in its relationship with cognitive development, based on a validated and standardized tablet-administered instrument for children, instead of a teacher or parent report. We did not observe a clear relationship between maternal acetaminophen use at different timepoints during pregnancy and child cognitive development.

Association between estimated cardiorespiratory fitness and breast cancer: a prospective cohort study.

OBJECTIVE: To examine the association between cardiorespiratory fitness (CRF) and the risk of breast cancer in postmenopausal women. METHODS: This study used data from 17 840 cancer-free postmenopausal women with a CRF assessment from the UK Biobank. High estimated CRF (eCRF) was categorised as being >80th percentile within 10-year age bands. Fine and Gray regression was used to examine the association between eCRF and breast cancer risk, accounting for both non-breast cancer diagnoses and all-cause mortality as competing risks. Age was used as the time scale. Several different models were produced, including those adjusting for known breast cancer risk factors, and stratified by measures of body fat (body mass index and per cent body fat). RESULTS: Over a median follow-up of 11.0 years there were 529 cases of invasive breast cancer, 1623 cases of non-breast cancer disease and 241 deaths. With adjustment for breast cancer risk factors, high eCRF was associated with a 24% (subdistribution HR (SDHR) 0.76, 95% CI 0.60 to 0.97) lower risk of breast cancer. When stratified by measures of body fat, we found evidence of effect measure modification. Mainly, having high eCRF was only associated with a lower risk of breast cancer among those classified as having overweight/obesity (SDHR 0.33, 95% CI 0.11 to 1.01) or percentage body fat above the 1st quintile (SDHR 0.65, 95% CI 0.45 to 0.94). CONCLUSION: Having higher CRF may be a protective factor against breast cancer in postmenopausal women but only for women with elevated body fat.

Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds.

Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.

Polygenic risk scores and risk-stratified breast cancer screening: Familiarity and perspectives of health care professionals.

PURPOSE: Health care professionals are expected to take on an active role in the implementation of risk-based cancer prevention strategies. This study aimed to explore health care professionals' (1) self-reported familiarity with the concept of polygenic risk score (PRS), (2) perceived level of knowledge regarding risk-stratified breast cancer (BC) screening, and (3) preferences for continuing professional development. METHODS: A cross-sectional survey was conducted using a bilingual-English/French-online questionnaire disseminated by health care professional associations across Canada between November 2020 and May 2021. RESULTS: A total of 593 professionals completed more than 2 items and 453 responded to all questions. A total of 432 (94%) participants were female, 103 (22%) were physicians, and 323 (70%) were nurses. Participants reported to be unfamiliar with (20%), very unfamiliar (32%) with, or did not know (41%) the concept of PRS. Most participants reported not having enough knowledge about risk-stratified BC screening (61%) and that they would require more training (77%). Online courses and webinar conferences were the preferred continuing professional development modalities. CONCLUSION: The study indicates that health care professionals are currently not familiar with the concept of PRS or a risk-stratified approach for BC screening. Online information and training seem to be an essential knowledge transfer modality.

Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52-0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54-0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12-0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10-1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator.

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.

Consensus Statement by the American Association of Clinical Endocrinology (AACE) and the American Head and Neck Society Endocrine Surgery Section (AHNS) on Pediatric Benign and Malignant Thyroid Surgery.

OBJECTIVES: To provide a clinical disease state review of recent relevant literature and to generate expert consensus statements regarding the breadth of pediatric thyroid cancer diagnosis and care, with an emphasis on thyroid surgery. To generate expert statements to educate pediatric practitioners on the state-of-the-art practices and the value of surgical experience in the management of this unusual and challenging disease in children. METHODS: A literature search was conducted and statements were constructed and subjected to a modified Delphi process to measure the consensus of the expert author panel. The wording of statements, voting tabulation, and statistical analysis were overseen by a Delphi expert (J.J.S.). RESULTS: Twenty-five consensus statements were created and subjected to a modified Delphi analysis to measure the strength of consensus of the expert author panel. All statements reached a level of consensus, and the majority of statements reached the highest level of consensus. CONCLUSION: Pediatric thyroid cancer has many unique nuances, such as bulky cervical adenopathy on presentation, an increased incidence of diffuse sclerosing variant, and a longer potential lifespan to endure potential complications from treatment. Complications can be a burden to parents and patients alike. We suggest that optimal outcomes and decreased morbidity will come from the use of advanced imaging, diagnostic testing, and neural monitoring of patients treated at high-volume centers by high-volume surgeons.

Advances in the Development of Therapeutics for Cytomegalovirus Infections.

The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others. The development of monoclonal antibodies, sirtuins, and cyclopropovir may provide new treatment options.

Association of breast cancer with MRI background parenchymal enhancement: the IMAGINE case-control study.

BACKGROUND: Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. METHODS: The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years' experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. RESULTS: The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05-2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92-2.27; p = 0.1). CONCLUSIONS: BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

Association between maternal acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort.

INTRODUCTION: Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes-preterm birth, low birthweight, and small for gestational age-are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use. METHODS: Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age. RESULTS: Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use

Parathyroid 4D CT: What the Surgeon Wants to Know.

Parathyroid four-dimensional (4D) CT is an increasingly used and powerful tool for preoperative localization of abnormal parathyroid tissue in the setting of primary hyperparathyroidism. Accurate and precise localization of a single adenoma facilitates minimally invasive parathyroidectomy, and localization of multiglandular disease aids bilateral neck exploration. However, many radiologists find the interpretation of these examinations to be an intimidating challenge. The authors review parathyroid 4D CT findings of typical and atypical parathyroid lesions and provide illustrative examples. Relevant anatomy, embryology, and operative considerations with which the radiologist should be familiar to provide clinically useful image interpretations are also discussed. The most important 4D CT information to the surgeon includes the number, size, and specific location of candidate parathyroid lesions with respect to relevant surgical landmarks; the radiologist's opinion and confidence level regarding what each candidate lesion represents; and the presence or absence of ectopic or supernumerary parathyroid tissue, concurrent thyroid pathologic conditions, and arterial anomalies associated with a nonrecurrent laryngeal nerve. The authors provide the radiologist with an accessible and practical approach to performing and interpreting parathyroid 4D CT images, detail what the surgeon really wants to know from the radiologist and why, and provide an accompanying structured report outlining the key information to be addressed. By accurately reporting and concisely addressing the key information the surgeon desires from a parathyroid 4D CT examination, the radiologist substantially impacts patient care by enabling the surgeon to develop and execute the best possible operative plan for each patient. ©RSNA, 2020.

Association between maternal cannabis use and birth outcomes: an observational study.

BACKGROUND: As cannabis consumption is increasing globally, including among pregnant women, there is a critical need to understand the effects of cannabis on fetal development and birth outcomes. We had two objectives: to determine 1) the factors associated with self-reported cannabis use in the pre/early-pregnancy period, and 2) whether cannabis use is associated with low birth weight, preterm birth, or small size for gestational age (GA) infants. METHODS: Maternal questionnaire and birth outcome data was gathered from 2229 women and 1778 singleton infants in the Ontario Birth Study, a hospital-based prospective cohort study (2013-2019). Women self-reported cannabis use within 3 months of learning their pregnancy status. Multivariable linear and logistic regression was conducted to 1) identify factors associated with cannabis use, and 2) determine the associations between cannabis use with the selected birth outcomes. RESULTS: Cannabis use increased in the cohort over time. Women who reported cannabis use (N = 216) were more likely to be younger and more likely to use alcohol, tobacco, and prescription pain medication, although most did not. These women had infants born at lower average birth weights and had 2.0 times the odds of being small for GA (95% confidence interval: 1.3, 3.3) after multivariable adjustment for socioeconomic factors and other substance use. CONCLUSION: Our results suggest that women who use cannabis around the time of conception have higher odds of having infants that are small for gestational age. Targeted clinical messaging may be most applicable to women actively trying to conceive.

Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers.

Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.).

Racial discrimination, John Henryism coping, and behavioral health conditions among predominantly poor, urban African Americans: Implications for community-level opioid problems and mental health services.

The current study examined the relationship between John Henryism Active Coping (JHAC), experiences of racial discrimination, and behavioral health outcomes in a community sample of 319 Black adults. Assessments included primary health care screenings as well as self-reported survey questions to assess JHAC, experiences of discrimination, and self-reported behavioral health. Logistic regression models, adjusted for control variables, found a significant relationship between JHAC and having an opioid problem (odds ratio [OR] = 0.95, p = 0.003) and needing mental health services (OR = 0.95, p < 0.001), such that higher levels of coping were associated with lower odds of reporting an opioid problem and needing mental health services. Notably, racial discrimination was not significantly independently associated with behavioral health. Implications for interventions and community programming are discussed.