Human trophectoderm becomes multi-layered by internalization at the polar region.

To implant in the uterus, mammalian embryos form blastocysts comprising trophectoderm (TE) surrounding an inner cell mass (ICM), confined to the polar region by the expanding blastocoel. The mode of implantation varies between species. Murine embryos maintain a single layered TE until they implant in the characteristic thick deciduum, whereas human blastocysts attach via polar TE directly to the uterine wall. Using immunofluorescence (IF) of rapidly isolated ICMs, blockade of RNA and protein synthesis in whole embryos, or 3D visualization of immunostained embryos, we provide evidence of multi-layering in human polar TE before implantation. This may be required for rapid uterine invasion to secure the developing human embryo and initiate formation of the placenta. Using sequential fluorescent labeling, we demonstrate that the majority of inner TE in human blastocysts arises from existing outer cells, with no evidence of conversion from the ICM in the context of the intact embryo.

Differences by Sexual Orientation in Patient-Centered Care Outcomes for Veterans Utilizing Primary Care Services at the Veterans Health Administration.

Purpose: This study examined the differences by sexual orientation in patient-centered care outcomes (including health care experiences and health-related screening) of veterans utilizing Veterans Health Administration (VHA) primary care. Methods: VHA's adapted version of the Consumer Assessment of Healthcare Providers and Systems was used to compare the health care experience of primary care services among sexual minority (SM) and heterosexual veterans. Health care experience measures were dichotomized to "always" versus "less" and stratified by SM status. Health-related screening measures were dichotomous. Survey data were weighted using provided sample weights. Descriptive statistics were performed on sociodemographic characteristics. Logistic regression coefficients were represented as adjusted odds ratios (aORs). A total of 66,348 veterans were included in the analytic sample, of which 2.9% (n = 1,935) identified as SM. Sexual orientation was ascertained by self-report measures by veterans. Results: SM veterans were significantly younger (56.95 years vs. 63.43 years, p < 0.001), were less likely to report that their provider showed respect for what they had to say (aOR: 0.76; 95% confidence interval [CI]: 0.61-0.95), that they were asked about difficulties taking care of their health (aOR: 0.81; 95% CI: 0.67-0.96), and their provider listened carefully to them (aOR: 0.71; 95% CI: 0.57-0.87) compared to heterosexual veterans. Conclusion: Health care experiences differed between SM and heterosexual veterans who sought VHA primary care, suggesting the need to increase provider trainings, which may improve cultural competency and promote a more welcoming and inclusive environment.

Evaluation of regional variation in racial and ethnic differences in patient experience among Veterans Health Administration primary care users.

OBJECTIVE: To evaluate racial and ethnic differences in patient experience among VA primary care users at the Veterans Integrated Service Network (VISN) level. DATA SOURCE AND STUDY SETTING: We performed a secondary analysis of the VA Survey of Healthcare Experiences of Patients-Patient Centered Medical Home for fiscal years 2016-2019. STUDY DESIGN: We compared 28 patient experience measures (six each in the domains of access and care coordination, 16 in the domain of person-centered care) between minoritized racial and ethnic groups (American Indian or Alaska Native [AIAN], Asian, Black, Hispanic, Multi-Race, Native Hawaiian or Other Pacific Islander [NHOPI]) and White Veterans. We used weighted logistic regression to test differences between minoritized and White Veterans, controlling for age and gender. DATA COLLECTION/EXTRACTION METHODS: We defined meaningful difference as both statistically significant at two-tailed p < 0.05 with a relative difference ≥10% or ≤-10%. Within VISNs, we included tests of group differences with adequate power to detect meaningful relative differences from a minimum of five comparisons (domain agnostic) per VISN, and separately for a minimum of two for access and care coordination and four for person-centered care domains. We report differences as disparities/large disparities (relative difference ≥10%/≥ 25%), advantages (experience worse or better, respectively, than White patients), or equivalence. PRINCIPAL FINDINGS: Our analytic sample included 1,038,212 Veterans (0.6% AIAN, 1.4% Asian, 16.9% Black, 7.4% Hispanic, 0.8% Multi-Race, 0.8% NHOPI, 67.7% White). Across VISNs, the greatest proportion of comparisons indicated disparities for three of seven eligible VISNs for AIAN, 6/10 for Asian, 3/4 for Multi-Race, and 2/6 for NHOPI Veterans. The plurality of comparisons indicated advantages or equivalence for 17/18 eligible VISNs for Black and 12/14 for Hispanic Veterans. AIAN, Asian, Multi-Race, and NHOPI groups had more comparisons indicating disparities by VISN in the access domain than person-centered care and care coordination. CONCLUSIONS: We found meaningful differences in patient experience measures across VISNs for minoritized compared to White groups, especially for groups with lower population representation.

Circulating MicroRNAs as Predictors of Beta Cell Function in Youth-Onset Type 2 Diabetes: The TODAY study.

AIMS: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome (HbA1c ≥ 8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with decline in beta cell function. METHODS: Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. RESULTS: Using a backward selection approach, four baseline miRNA log2 fold changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p < 0.05). Increased levels of miRNA-155 (OR:1.2, 95%CI:1.1-1.4) and miRNA-130b (OR:1.3, 95%CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.6, 95%CI: 0.4-0.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R = 0.22, p < 0.01 and R = 0.19, p < 0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60- months (R = 0.26, p < 0.01, R = 0.26, p < 0.01, R = 0.18, p < 0.01, respectively). CONCLUSIONS: The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Assessing equity in the uptake of remote foot temperature monitoring in a large integrated US healthcare system.

OBJECTIVE: We assessed equity in the uptake of remote foot temperature monitoring (RTM) for amputation prevention throughout a large, integrated US healthcare system between 2019 and 2021, including comparisons across facilities and between patients enrolled and eligible patients not enrolled in RTM focusing on the Reach and Adoption dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. MATERIAL AND METHODS: To assess whether there was equitable use of RTM across facilities, we examined distributions of patient demographic, geographic, and facility characteristics across facility RTM use categories (e.g., no RTM use, and low, moderate, and high RTM use) among all eligible patients (n = 46,294). Second, to understand whether, among facilities using RTM, there was equitable enrollment of patients in RTM, we compared characteristics of patients enrolled in RTM (n = 1066) relative to a group of eligible patients not enrolled in RTM (n = 27,166) using logistic regression and including all covariates. RESULTS: RTM use increased substantially from an average of 11 patients per month to over 40 patients per month between 2019 and 2021. High-use RTM facilities had higher complexity and a lower ratio of patients per podiatrist but did not have consistent evidence of better footcare process measures. Among facilities offering RTM, enrollment varied by age, was inversely associated with Black race (vs. white), low income, living far from specialty care, and being in the highest quartiles of telehealth use prior to enrollment. Enrollment was positively associated with having osteomyelitis, Charcot foot, a partial foot amputation, BMI≥30 kg/m2, and high outpatient utilization. CONCLUSIONS: RTM growth was concentrated in a small number of higher-resourced facilities, with evidence of lower enrollment among those who were Black and lived farther from specialty care. Future studies are needed to identify and address barriers to uptake of new interventions like RTM to prevent exacerbating existing ulceration and amputation disparities.

Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

This study evaluated criteria for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE). Kable et al. (2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17y) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.

Predicting fetal alcohol spectrum disorders in preschool-aged children from early life factors.

BACKGROUND: Early life factors, including parental sociodemographic characteristics, pregnancy exposures, and physical and neurodevelopmental features measured in infancy are associated with fetal alcohol spectrum disorders (FASD). The objective of this study was to evaluate the performance of a classifier model for diagnosing FASD in preschool-aged children from pregnancy and infancy-related characteristics. METHODS: We analyzed a prospective pregnancy cohort in Western Ukraine enrolled between 2008 and 2014. Maternal and paternal sociodemographic factors, maternal prenatal alcohol use and smoking behaviors, reproductive characteristics, birth outcomes, infant alcohol-related dysmorphic and physical features, and infant neurodevelopmental outcomes were used to predict FASD. Data were split into separate training (80%: n = 245) and test (20%: n = 58; 11 FASD, 47 no FASD) datasets. Training data were balanced using data augmentation through a synthetic minority oversampling technique. Four classifier models (random forest, extreme gradient boosting [XGBoost], logistic regression [full model] and backward stepwise logistic regression) were evaluated for accuracy, sensitivity, and specificity in the hold-out sample. RESULTS: Of 306 children evaluated for FASD, 61 had a diagnosis. Random forest models had the highest sensitivity (0.54), with accuracy of 0.86 (95% CI: 0.74, 0.94) in hold-out data. Boosted gradient models performed similarly, however, sensitivity was less than 50%. The full logistic regression model performed poorly (sensitivity = 0.18 and accuracy = 0.65), while stepwise logistic regression performed similarly to the boosted gradient model but with lower specificity. In a hold-out sample, the best performing algorithm correctly classified six of 11 children with FASD, and 44 of 47 children without FASD. CONCLUSIONS: As early identification and treatment optimize outcomes of children with FASD, classifier models from early life characteristics show promise in predicting FASD. Models may be improved through the inclusion of physiologic markers of prenatal alcohol exposure and should be tested in different samples.

Genomic resources for the Yellowfin tuna Thunnus albacares.

BACKGROUND: The Yellowfin tuna (Thunnus albacares) is a large tuna exploited by major fisheries in tropical and subtropical waters of all oceans except the Mediterranean Sea. Genomic studies of population structure, adaptive variation or of the genetic basis of phenotypic traits are needed to inform fisheries management but are currently limited by the lack of a reference genome for this species. Here we report a draft genome assembly and a linkage map for use in genomic studies of T. albacares. METHODS AND RESULTS: Illumina and PacBio SMRT sequencing were used in combination to generate a hybrid assembly that comprises 743,073,847 base pairs contained in 2,661 scaffolds. The assembly has a N50 of 351,587 and complete and partial BUSCO scores of 86.47% and 3.63%, respectively. Double-digest restriction associated DNA (ddRAD) was used to genotype the 2 parents and 164 of their F1 offspring resulting from a controlled breeding cross, retaining 19,469 biallelic single nucleotide polymorphism (SNP) loci. The SNP loci were used to construct a linkage map that features 24 linkage groups that represent the 24 chromosomes of yellowfin tuna. The male and female maps span 1,243.8 cM and 1,222.9 cM, respectively. The map was used to anchor the assembly in 24 super-scaffolds that contain 79% of the yellowfin tuna genome. Gene prediction identified 46,992 putative genes 20,203 of which could be annotated via gene ontology. CONCLUSIONS: The draft reference will be valuable to interpret studies of genome wide variation in T. albacares and other Scombroid species.

TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway.

Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underlies facial shape variation, yet how those networks in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest, even during the late migratory phase, results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both TFAP2 family members dysregulates numerous midface GRN components involved in midface morphogenesis, patterning and differentiation. Notably, Alx1, Alx3 and Alx4 (ALX) transcript levels are reduced, whereas ChIP-seq analyses suggest TFAP2 family members directly and positively regulate ALX gene expression. Tfap2a, Tfap2b and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish implies conservation of this regulatory axis across vertebrates. Consistent with this notion, tfap2a zebrafish mutants present with abnormal alx3 expression patterns, Tfap2a binds ALX loci and tfap2a-alx3 genetic interactions are observed. Together, these data demonstrate TFAP2 paralogs regulate vertebrate midfacial development in part by activating expression of ALX transcription factor genes.

Genetic predictors of neurocognitive outcomes in survivors of pediatric brain tumors.

BACKGROUND: Neurocognitive deficits are common in pediatric brain tumor survivors. The use of single nucleotide polymorphism (SNP) analysis in DNA repair genes may identify children treated with radiation therapy for brain tumors at increased risk for treatment toxicity and adverse neurocognitive outcomes. MATERIALS: The Human 660W-Quad v1.0 DNA BeadChip analysis (Illumina) was used to evaluate 1048 SNPs from 59 DNA repair genes in 46 subjects. IQ testing was measured by the Wechsler Intelligence Scale for Children. Linear regression was used to identify the 10 SNPs with the strongest association with IQ scores while adjusting for radiation type. RESULTS: The low vs high IQ patient cohorts were well matched for time from first treatment to most recent IQ, first treatment age, sex, and treatments received. 5 SNPs on 3 different genes (CYP29, XRCC1, and BRCA1) and on 3 different chromosomes (10, 19, and 17) had the strongest association with most recent IQ score that was not modified by radiation type. Furthermore, 5 SNPs on 4 different genes (WRN, NR3C1, ERCC4, RAD51L1) on 4 different chromosomes (8, 5, 16, 14) had the strongest association with change in IQ independent of radiation type, first IQ, and years between IQ measures. CONCLUSIONS: SNPs offer the potential to predict adverse neurocognitive outcomes in pediatric brain tumor survivors. Our results require validation in a larger patient cohort. Improving the ability to identify children at risk of treatment related neurocognitive deficits could allow for better treatment stratification and early cognitive interventions.

FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.

BACKGROUND: Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. METHODS: We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. RESULTS: FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. CONCLUSIONS: Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.

Genetic Predictors of Neurocognitive Outcomes in Survivors of Pediatric Brain Tumors.

Purpose: Neurocognitive deficits are common in pediatric brain tumor survivors. The use of single nucleotide polymorphism (SNP) analysis in DNA repair genes may identify children treated with radiation therapy for brain tumors at increased risk for treatment toxicity and adverse neurocognitive outcomes. Methods: The Human 660W-Quad v1.0 DNA BeadChip analysis (Illumina) was used to evaluate 1048 SNPs from 59 DNA repair genes in 46 subjects. IQ testing was measured by the Wechsler Intelligence Scale for Children. Linear regression was used to identify the 10 SNPs with the strongest association with IQ scores while adjusting for radiation type. Results: The low vs high IQ patient cohorts were well matched for time from first treatment to most recent IQ, first treatment age, gender, and treatments received. 5 SNPs on 3 different genes (CYP29, XRCC1, and BRCA1) and on 3 different chromosomes (10, 19, and 17) had the strongest association with most recent IQ score that was not modified by radiation type. Furthermore, 5 SNPs on 4 different genes (WRN, NR3C1, ERCC4, RAD51L1) on 4 different chromosomes (8, 5, 16, 14) had the strongest association with change in IQ independent of radiation type, first IQ, and years between IQ measures. Conclusions: SNP polymorphisms offer potential to predict adverse neurocognitive outcomes in pediatric brain tumor survivors. Our results require validation in a larger patient cohort. Improving the ability to identify children at risk of treatment related neurocognitive deficits could allow for better treatment stratification and early cognitive interventions.

Molecular disparities in colorectal cancers of White Americans, Alabama African Americans, and Oklahoma American Indians.

In the US, the majority of cancer samples analyzed are from white people, leading to biases in racial and ethnic treatment outcomes. Colorectal cancer (CRC) incidence and mortality rates are high in Alabama African Americans (AAs) and Oklahoma American Indians (AIs). We hypothesized that differences between racial groups may partially explain these disparities. Thus, we compared transcriptomic profiles of CRCs of Alabama AAs, Oklahoma AIs, and white people from both states. Compared to CRCs of white people, CRCs of AAs showed (a) higher expression of cytokines and vesicle trafficking toward modulated antitumor-immune activity, and (b) lower expression of the ID1/BMP/SMAD axis, IL22RA1, APOBEC3, and Mucins; and AIs had (c) higher expression of PTGS2/COX2 (an NSAID target/pro-oncogenic inflammation) and splicing regulators, and (d) lower tumor suppressor activities (e.g., TOB2, PCGF2, BAP1). Therefore, targeting strategies designed for white CRC patients may be less effective for AAs/AIs. These findings illustrate needs to develop optimized interventions to overcome racial CRC disparities.

The Effects of Nitric Oxide on Choroidal Gene Expression.

Purpose: Nitric oxide (NO) is recognized as an important biological mediator that controls several physiological functions, and evidence is now emerging that this molecule may play a significant role in the postnatal control of ocular growth and myopia development. We therefore sought to understand the role that nitric oxide plays in visually-guided ocular growth in order to gain insight into the underlying mechanisms of this process. Methods: Choroids were incubated in organ culture in the presence of the NO donor, PAPA-NONOate (1.5 mM). Following RNA extraction, bulk RNA-seq was used to quantify and compare choroidal gene expression in the presence and absence of PAPA-NONOate. We used bioinformatics to identify enriched canonical pathways, predicted diseases and functions, and regulatory effects of NO in the choroid. Results: Upon treatment of normal chick choroids with the NO donor, PAPA-NONOate, we identified a total of 837 differentially expressed genes (259 upregulated genes, 578 down-regulated genes) compared with untreated controls. Among these, the top five upregulated genes were LSMEM1, STEAP4, HSPB9, and CCL19, and the top five down-regulated genes were CDCA3, SMC2, a novel gene (ENSALGALG00000050836), an uncharacterized gene (LOC107054158), and SPAG5. Bioinformatics predicted that NO treatment will activate pathways involved in cell and organismal death, necrosis, and cardiovascular system development, and inhibit pathways involved in cell proliferation, cell movement, and gene expression. Conclusions: The findings reported herein may provide insight into possible effects of NO in the choroid during visually regulated eye growth, and help to identify targeted therapies for the treatment of myopia and other ocular diseases.

TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway.

Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underly facial shape variation, yet how those in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest even during the late migratory phase results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both Tfap2 members dysregulated numerous midface GRN components involved in midface fusion, patterning, and differentiation. Notably, Alx1/3/4 (Alx) transcript levels are reduced, while ChIP-seq analyses suggest TFAP2 directly and positively regulates Alx gene expression. TFAP2 and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish further implies conservation of this regulatory axis across vertebrates. Consistent with this notion, tfap2a mutant zebrafish present abnormal alx3 expression patterns, and the two genes display a genetic interaction in this species. Together, these data demonstrate a critical role for TFAP2 in regulating vertebrate midfacial development in part through ALX transcription factor gene expression.

Single Cell Transcriptomics Identifies Distinct Choroid Cell Populations Involved in Visually Guided Eye Growth.

Postnatal ocular growth is regulated by a vision-dependent mechanism, termed emmetropization, which acts to minimize refractive error through coordinated growth of the ocular tissues. Many studies suggest that the ocular choroid participates in the emmetropization process via the production of scleral growth regulators that control ocular elongation and refractive development. To elucidate the role of the choroid in emmetropization, we used single-cell RNA sequencing (scRNA-seq) to characterize the cell populations in the chick choroid and compare gene expression changes in these cell populations during conditions in which the eye is undergoing emmetropization. UMAP clustering analysis identified 24 distinct cell clusters in all chick choroids. 7 clusters were identified as fibroblast subpopulations; 5 clusters represented different populations of endothelial cells; 4 clusters were CD45+ macrophages, T cells and B cells; 3 clusters were Schwann cell subpopulations; and 2 clusters were identified as melanocytes. Additionally, single populations of RBCs, plasma cells and neuronal cells were identified. Significant changes in gene expression between control and treated choroids were identified in 17 cell clusters, representing 95% of total choroidal cells. The majority of significant gene expression changes were relatively small (< 2 fold). The highest changes in gene expression were identified in a rare cell population (0.11% - 0.49% of total choroidal cells). This cell population expressed high levels of neuron-specific genes as well as several opsin genes suggestive of a rare neuronal cell population that is potentially light sensitive. Our results, for the first time, provide a comprehensive profile of the major choroidal cell types and their gene expression changes during the process of emmetropization as well as insights into the canonical pathways and upstream regulators that coordinate postnatal ocular growth.

The painful truth of waiting for hip and knee arthroplasty in Northern Ireland.

Aims: The aim of this study was to report health-related quality of life (HRQoL) and joint-specific function in patients waiting for total hip or knee arthroplasty surgery (THA or TKA) in Northern Ireland, compared to published literature and a matched normal population. Secondary aims were to report emergency department (ED) and out-of-hours general practitioner (OOH GP) visits, new prescriptions of strong opioids, and new prescriptions of antidepressants while waiting. Methods: This was a cohort study of 991 patients on the waiting list for arthroplasty in a single Northern Ireland NHS trust: 497 on the waiting list for ≤ three months; and 494 waiting ≥ three years. Postal surveys included the EuroQol five-dimension five-level questionnaire (EQ-5D-5L), visual analogue scores (EQ-VAS), and Oxford Hip and Knee scores to assess HRQoL and joint-specific function. Electronic records determined prescriptions since addition to the waiting list and patient attendances at OOH GP/EDs. Results: Overall, 712/991 (71.8%) responded at ≤ three months for THA (n = 164) and TKA (n = 199), and ≥ three years for THA (n = 88) and TKA (n = 261). The median EQ-5D-5L score in those waiting ≤ three months was 0.155 (interquartile range (IQR) -0.118 to 0.375) and 0.189 (IQR -0.130 to 0.377) for ≥ three years. Matched controls had a median EQ-5D-5L 0.837 (IQR 0.728 to 1.000). Compared to matched controls, EQ-5D-5L scores were significantly lower in both waiting cohorts (p < 0.001) with significant differences found in every domain. Negative scores, indicating a state "worse than death", were present in 40% at ≤ three months and 38% at ≥ three years. Patients waiting ≥ three years had significantly more opioid (28.4% vs 15.2%; p < 0.001) and antidepressant prescriptions (15.2% vs 9.9%; p = 0.034) and significantly more joint-related attendances at unscheduled care (11.7% vs 0% with ≥ one ED attendance (p < 0.001) and (25.5% vs 2.5% ≥ one OOH GP attendance (p < 0.001)). Conclusion: Patients on waiting lists in Northern Ireland are severely disabled with the worst HRQoL and functional scores studied. The lack of deterioration in EQ-5D-5L and joint-specific scores between patients waiting ≤ three months and ≥ three years likely reflects floor effects of these scores. Prolonged waits were associated with increased dependence on strong opiates, depression, and attendances at unscheduled care.

Prenatal Exposure to Cannabis and Risk of Major Structural Birth Defects: A Systematic Review and Meta-analysis.

OBJECTIVE: To review and perform a meta-analysis of observational studies that examined associations between prenatal cannabis exposure and major structural birth defects. DATA SOURCES: Information sources included Google Scholar, BIOSIS, PubMed/MEDLINE, EMBASE CINAHL, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: Study titles and abstracts were reviewed with Abstrackr software. We included observational studies that examined the risk of major structural birth defects in people who used cannabis during pregnancy compared with those who had not used cannabis. We excluded case reports, ecologic studies, conference abstracts, manuscript preprints, studies designed to examine effects of cannabis used concurrently with other drugs, and studies that included synthetic cannabinoids. This process yielded 23 studies that analyzed data from birth years 1968-2021. TABULATION, INTEGRATION, AND RESULTS: We clustered and meta-analyzed measures of association for birth defects by anatomic group. Eleven articles reported an association between cannabis use and the risk of a nonspecific outcome (eg, congenital anomaly). We estimated a pooled odds ratio of 1.33 (95% CI 1.14-1.56) and a pooled adjusted odds ratio (aOR) of 1.22 (95% CI 1.00-1.50). Anatomic groups examined were cardiac (nine studies), oral cleft (three studies), digestive (four studies), genitourinary (three studies), musculoskeletal (seven studies), and nervous system (five studies). Across most outcomes, we reported positive pooled unadjusted associations that were usually attenuated after the inclusion of only adjusted estimates. Two specific anomalies, with limited data, had pooled effect estimates that did not attenuate to the null after adjustment: Ebstein anomaly (two studies, aOR 2.19, 95% CI 1.25-3.82) and gastroschisis (five studies, aOR 2.50, 95% CI 1.09-5.740). CONCLUSION: Studies examining associations between prenatal exposure to cannabis and major structural birth defects were heterogeneous. Most published effect estimates were unadjusted and scored low on our risk-of-bias assessment. Overall, we found inconsistent evidence to suggest that prenatal cannabis exposure is associated with birth defects. However, findings related to specific anomalies should be considered in further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022319041.

Vision outcomes in children with fetal alcohol spectrum disorders.

BACKGROUND: Previous studies demonstrated that children with Fetal Alcohol Spectrum Disorders (FASD) are more likely to have vision impairments. However, existing human clinical and epidemiological investigations are few and include limited sample sizes. This study aimed to explore the association between ophthalmologic abnormalities and FASD in a sample of 5-7 year old children in the general population. METHODS: This was a cross-sectional study nested in a larger study intended to estimate the prevalence of FASD in San Diego, California, conducted between 2012 and 2014. Prenatal exposure to alcohol, dysmorphology examinations, and a neurobehavioral testing battery were collected for each child and an FASD diagnosis was assigned. Parents of participating children were asked to release their child's vision screening or diagnostic records. RESULTS: Vision records were obtained for 424 participants in the larger prevalence study. Of these, 53 children were classified as having FASD. A statistically significant association was found between FASD and a diagnosis of strabismus; 5/42 (11.9%) of children who were classified as having FASD had strabismus compared to 6/290 (2.1%) of children who were not classified as having FASD (p = .01). All five cases of strabismus in the FASD group occurred in 19 children classified as having partial fetal alcohol syndrome (pFAS). No association was found between FASD and vision impairment (p = .23), refractive errors (p = .66), glasses/contact lens prescription (p = .30), or having one or more ophthalmological abnormalities (p = .97). CONCLUSIONS: An association between strabismus and FASD, specifically partial FAS, suggests that the effect of alcohol exposure on risk of strabismus must be severe enough to result in facial features consistent with FASD. This emphasizes the importance of vision screening in children with FASD.