Mendelian segregation and high recombination rates facilitate genetic analyses in Cryptosporidium parvum.

Very little is known about the process of meiosis in the apicomplexan parasite Cryptosporidium despite the essentiality of sex in its life cycle. Most cell lines only support asexual growth of Cryptosporidium parvum (C. parvum), but stem cell derived intestinal epithelial cells grown under air-liquid interface (ALI) conditions support the sexual cycle. To examine chromosomal dynamics during meiosis in C. parvum, we generated two transgenic lines of parasites that were fluorescently tagged with mCherry or GFP on chromosomes 1 or 5, respectively. Infection of ALI cultures or Ifngr1-/- mice with mCherry and GFP parasites resulted in cross-fertilization and the formation of "yellow" oocysts, which contain 4 haploid sporozoites that are the product of meiosis. Recombinant oocysts from the F1 generation were purified and used to infect HCT-8 cultures, and phenotypes of the progeny were observed by microscopy. All possible phenotypes predicted by independent segregation were represented equally (~25%) in the population, indicating that C. parvum chromosomes exhibit a Mendelian inheritance pattern. The most common pattern observed from the outgrowth of single oocysts included all possible parental and recombinant phenotypes derived from a single meiotic event, suggesting a high rate of crossover. To estimate the frequency of crossover, additional loci on chromosomes 1 and 5 were tagged and used to monitor intrachromosomal crosses in Ifngr1-/- mice. Both chromosomes showed a high frequency of crossover compared to other apicomplexans with map distances (i.e., 1% recombination) of 3-12 kb. Overall, a high recombination rate may explain many unique characteristics observed in Cryptosporidium spp. such as high rates of speciation, wide variation in host range, and rapid evolution of host-specific virulence factors.

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

Help-Seeking Among Children Impacted by Commercial Sexual Exploitation: A Scoping Review.

This scoping review aims to summarize current research on help-seeking behaviors and patterns among children who have experienced commercial sexual exploitation of children (CSEC) victimization and/or are at high risk of exploitation. Because the literature on help-seeking specific to CSEC victimization is limited, the current review was expanded to summarize findings from help-seeking research for children who have experienced harms that often co-occur with CSEC, such as maltreatment and homelessness. The authors searched three large article databases (PsycInfo, Ovid MEDLINE, and Web of Science) for articles that were (a) empirical; (b) measured or used the term "help-seeking" in their framing and/or results; (c) included children between the ages of 12 and 18; (d) primarily focused on children from the United States; (e) published in English. Ultimately, 22 articles met all inclusion criteria and were included in the final review. Results suggest that cisgender white females are the most likely to seek help, followed by sexual and gender minority children. Cisgender male children were the least likely to engage in help-seeking behaviors. Universally, children were more likely to engage in informal help-seeking rather than formal help-seeking, with younger children being more likely to reach out to parents and older children more likely to reach out to friends. Importantly, ethnically diverse children were under-represented, leading to limited information about how and why these children seek help. Implications for help-seeking by children impacted by commercial sexual exploitation are discussed, providing guidance for programming and research related to CSEC prevention.

COVID-19 and Child Sex Trafficking: Qualitative Insights on the Effect of the Pandemic on Victimization and Service Provision.

OBJECTIVES: Child sex trafficking (CST) is the involvement of minors in the commercial exchange of sex for goods, services, drugs, or money. The COVID-19 pandemic negatively affected many risk factors associated with CST victimization and the availability of CST services. We examined service providers' perspectives on how the pandemic affected trajectories of CST victimization among young people in the United States. METHODS: We collected qualitative data from 80 law enforcement professionals and service providers working with young people affected by CST from 11 US cities. Semistructured interviews lasted approximately 1 hour and were digitally recorded, transcribed verbatim, and coded via a grounded theory approach. RESULTS: We found 3 overarching themes related to the pandemic's effect on CST victimization trajectories: grooming, perpetration, and service provision. Participants described how increased online activity may have increased the risk of CST, even among children without traditional risk factors. However, technology also facilitated young people's agency in seeking help and receiving services. In addition, participants reported increases in virtual service provision that facilitated access to, and availability of, CST services more generally. CONCLUSIONS: Technology use among young people increased during the pandemic, leading to increases in the risks of experiencing technology-facilitated CST. Technology use among young people who experience CST victimization-and how it may differ from young people more generally-is underexplored and may provide insights into prevention and treatment. Collectively, results highlight the need for epidemiologic research to help identify how global and national events affect trajectories of victimization among young people.

Muskelin acts as a substrate receptor of the highly regulated Drosophila CTLH E3 ligase during the maternal-to-zygotic transition.

The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch (TRAL) are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies. In particular, Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental specificity of the CTLH complex is mediated by multipronged regulation, including transcriptional control by the transcription factor OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate acts as a substrate adaptor for the Drosophila CTLH complex. Although conserved, Muskelin has structural roles in other species, suggesting a surprising functional plasticity. Finally, we find that Muskelin has few targets beyond the three known RNA binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, seemingly with the goal of regulating three important RNA binding proteins.

More than a mask: Possible relationships between lifting of COVID-19 mask requirements and depression symptoms experienced by US adults with disabilities.

BACKGROUND: Lifting of masking restrictions at key periods during the COVID-19 pandemic may have disproportionately negatively impacted the mental health of individuals with disabilities. OBJECTIVE: This study examines the prevalence of depression-related symptoms in individuals with and without disabilities preceding and following the US rollback of COVID-19 masking mandates. METHODS: Pandemic-era data on reported symptoms of depression from the federal Household Pulse Survey from dates surrounding two major announcements on masking relaxations were analyzed. Possible interactions between disability status and type, age grouping, educational attainment, race/Hispanic ethnicity, and sex variables were considered. RESULTS: Following relaxation of major masking restrictions, people with disabilities experienced elevation in depression symptom presence while people without disabilities experienced lessening in these symptoms. Differences between people with and without disabilities were significant. CONCLUSIONS: Direct causation between masking mandate relaxations and changes in symptoms of depression cannot be drawn from the available data. However, when considered with greater vulnerabilities to COVID-19 experienced by many individuals with disabilities and dismissive rhetoric surrounding masking decisions, negative feelings arising from mandate changes may have led to elevations in symptoms of depression in people with disabilities in sharp contrast to people without disabilities who may have felt relief. Findings indicate future public health decision making, even in times of crisis, should be undertaken with as much caution as possible regarding and in partnership with populations already at risk.

Mendelian segregation and high recombination rates facilitate genetic analyses in Cryptosporidium parvum.

Very little is known about the process of meiosis in the apicomplexan parasite Cryptosporidium despite the essentiality of sex in its life cycle. Most cell lines only support asexual growth of Cryptosporidium parvum (C. parvum), but stem cell derived intestinal epithelial cells grown under air-liquid interface (ALI) conditions support the sexual cycle. To examine chromosomal dynamics during meiosis in C. parvum, we generated two transgenic lines of parasites that were fluorescently tagged with mCherry or GFP on chromosomes 1 or 5, respectively. Infection of ALI cultures or Ifngr1-/- mice with mCherry and GFP parasites produced "yellow" oocysts generated by cross-fertilization. Outcrossed oocysts from the F1 generation were purified and used to infect HCT-8 cultures, and phenotypes of the progeny were observed by microscopy. All possible phenotypes predicted by independent segregation were represented equally (~25%) in the population, indicating that C. parvum chromosomes exhibit a Mendelian inheritance pattern. Unexpectedly, the most common pattern observed from the outgrowth of single oocysts included all possible parental and recombinant phenotypes derived from a single meiotic event, suggesting a high rate of crossover. To estimate the frequency of crossover, additional loci on chromosomes 1 and 5 were tagged and used to monitor intrachromosomal crosses in Ifngr1-/- mice. Both chromosomes showed a high frequency of crossover compared to other apicomplexans with map distances (i.e., 1% recombination) of 3-12 kb. Overall, a high recombination rate may explain many unique characteristics observed in Cryptosporidium spp. such as high rates of speciation, wide variation in host range, and rapid evolution of host-specific virulence factors.

Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

ACR Appropriateness Criteria® Acute Pelvic Pain in the Reproductive Age Group: 2023 Update.

This review focuses on the initial imaging in the reproductive age adult population with acute pelvic pain, including patients with positive and negative beta-human chorionic gonadotropin (ß-hCG) levels with suspected gynecological and nongynecological etiology. For all patients, a combination of transabdominal and transvaginal pelvic ultrasound with Doppler is usually appropriate as an initial imaging study. If nongynecological etiology in patients with negative ß-hCG is suspected, then CT of the abdomen and pelvis with or without contrast is also usually appropriate. In patients with positive ß-hCG and suspected nongynecological etiology, CT of the abdomen and pelvis with contrast and MRI of the abdomen and pelvis without contrast may be appropriate. In patients with negative ß-hCG and suspected gynecological etiology, CT of the abdomen and pelvis with contrast, MRI of pelvis without contrast, or MRI of pelvis with and without contrast may be appropriate. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Clinically Suspected Adnexal Mass, No Acute Symptoms: 2023 Update.

Asymptomatic adnexal masses are commonly encountered in daily radiology practice. Although the vast majority of these masses are benign, a small subset have a risk of malignancy, which require gynecologic oncology referral for best treatment outcomes. Ultrasound, using a combination of both transabdominal, transvaginal, and duplex Doppler technique can accurately characterize the majority of these lesions. MRI with and without contrast is a useful complementary modality that can help characterize indeterminate lesions and assess the risk of malignancy is those that are suspicious. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

AIMS: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. METHODS AND RESULTS: One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R = -0.30, P < 0.001) and fewer daily steps (R = -0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). CONCLUSIONS: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

Program Directors Survey on the Impact of the COVID-19 Pandemic on Cardiology Fellowship Training.

Background: The COVID-19 pandemic catalyzed unprecedented changes to medical education, including CV fellowship programs. CV fellowship PDs offer a unique perspective regarding the impact of the pandemic on CV medical education. Objectives: The 4th annual Cardiovascular Diseases (CV) Fellowship Program Directors (PDs) Survey sought to understand the impact of the COVID-19 pandemic on CV fellows and fellowship programs. Methods: The survey contained 31 items examining the clinical, educational, and academic impact of the COVID-19 pandemic on CV fellowship programs. Results: Survey response rate was 54%. Most respondents (58%) represented university-based programs. Most PDs felt that changes to clinical practice during the COVID-19 negatively impacted fellow education in cardiac catheterization (66%), outpatient cardiology (52%), nuclear imaging (51%), and echocardiography (50%). Despite improving attendance, 75% of PDs felt that virtual educational conferences adversely impacted interaction between participants. Only 22% felt they improved fellow education. Most PDs (85%) reported a negative impact of the pandemic on fellow well-being and burnout, and 57% reported a decrease in research productivity among fellows. Even though virtual recruitment allowed programs to interview more competitive candidates, most PDs felt that virtual interviews adversely impacted interactions between their fellows and candidates (71%) and their ability to convey the culture of their program (60%). Conclusions: Most CV fellowship PDs felt the COVID-19 pandemic brought changes that negatively impacted the clinical training, didactic learning, academic productivity, and well-being among cardiology fellows. The implications of these changes on the competency of cardiologists that trained during the COVID-19 pandemic deserve future study.

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.