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This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.This Consensus Statement, which is endorsed by the Pituitary Society, offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas.

Abstract This systematic literature review sought to reconcile the evidence of efficacy for interventions and approaches to enhancing self-regulation and/or executive function in preschool settings. Following PRISMA methodology, a comprehensive search of 20 years of intervention research identified 85 studies that met inclusion criteria. Interventions were categorised by intervention approach and coded for their characteristics (e.g. sample size, dose, duration, interventionist, intervention activities), outcomes (e.g. significance, size of effects) and study quality (i.e. risk of bias). Reconciliation of intervention results indicated (1) within intervention approaches, some approaches had more consistent and robust evidence of efficacy (e.g. mindfulness, mediated play, physical activity) and (2) across intervention approaches, characteristics that had greater (or exclusive) presence amongst the higher efficacy interventions (e.g. cognitive challenge, movement, as well as interventionist, fidelity and dose considerations). Implications for future intervention (re)design, and for theorising about mechanisms of self-regulation and executive function change, are discussed.

Abstract Context Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. Objective This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. Conclusion Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Anemia is a major public health problem for thirty-two million pregnant women worldwide. Anemia during pregnancy is a leading cause of child low birth weight, preterm birth, and perinatal/neonatal mortality. Pregnant women are at higher risk of anemia due to micronutrient deficiencies, hemoglobinopathies, infections, socio-demographic and behavioral factors. This study aimed to: 1) assess temporal and geospatial trends of anemia in Cambodia and 2) identify factors associated with anemia among pregnant women aged 15–49 years old in Cambodia. We analyzed data from the Cambodia Demographic and Health Survey (CDHS) for 2005, 2010, and 2014. Data were pooled across the three survey years for all pregnant women aged 15–49 years. Survey weights were applied to account for the complex survey design of the CDHS. Descriptive statistics were estimated for key sociodemographic characteristics of the study population. We used logistic regressions to assess factors associated with anemia among pregnant women aged 15–49 years old. Anemia in pregnant women aged 15–49 in Cambodia decreased from 56% in 2005 to 53% in 2014. With the highest in Preah Vihear and Stung Treng provinces (74.3%), in Kratie province (73%), and in Prey Veng (65.4%) in 2005, 2010, and 2014 respectively. Compared to pregnant women from the wealthiest households, women from poorest households were more likely to have anemia (AOR = 2.8; 95% CI: 1.6–4.9). Pregnant women from coastal regions were almost twice as likely of having anemia (AOR = 1.9; 95% CI: 1.2–3.0). Pregnant women were more likely anemic if they were in their 2 nd trimester (AOR = 2.6; 95% CI: 1.9–3.6) or 3 rd trimester (AOR = 1.6 95% CI: 1.1–2.3). Anemia remains highly prevalent among pregnant women in Cambodia. Public health interventions and policies to alleviate anemia should be prioritized and shaped to address these factors.

This article examines a cervical screening incident from the 1960s and draws lessons for screening policy. Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a ‘special series’ of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident. In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the ‘special series.’ A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the ‘special series,’ who ‘in retrospect and by 1987 standards’ might have benefited from earlier conisation or hysterectomy. Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate. •Cervical cytology screening began, from the late 1940s, without adequate prior evaluation. Ethical principles including informed consent were ignored. Many women suffered harm including loss of fertility and operative death.•Auckland University gynecologist Herbert Green cautioned against harmful overdiagnosis and overtreatment and advocated conisation with careful follow up, in preference to hysterectomy, thereby enabling many young women to preserve their fertility.•During 1965 to 1970 Green practiced, and published about, active monitoring in a ‘special series’ of 33 women with carcinoma in situ initially managed by limited biopsy. By 1974 he advised against this practice, reporting the treatment of 10 women whose lesions had progressed (2 clinical and 8 histological).•A 1987 Judicial Inquiry into practice at National Women’s Hospital Auckland, triggered by a magazine article, led to widely quoted claims that Green had unethically withheld treatment from as many as 100 women, and that up to thirty deaths resulted.•The review of case notes conducted for the Inquiry found only 4 patients where no reason could be found for delayed treatment. Two women managed by limited biopsy were reported to have developed cancer, and none were recorded as having died. The severity of claims made against Green do not stand up to scientific scrutiny.

Background: Comprehensive multi-system clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and review by an expert committee. Objective: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. Methods: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. Results: The number of items was reduced from 66 to 56. The sub-scores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's ρ 0.66, 95% CI 0.59-0.72), BVAS1 of version 2 (ρ 0.94, 95% CI 0.92-0.96), BVAS2 of version 2 in patients with persistent disease (ρ 0.60, 95% CI 0.21-0.83), C-reactive protein levels (ρ 0.43, 95% CI 0.31-0.54), physician's global assessment (ρ 0.91, 95% CI 0.89-0.93), and vasculitis activity index (ρ 0.88, 95%CI 0.86-0.91). The intra-class correlation coefficients for reproducibility and repeatability were 0.96 (95%CI 0.95-0.97) and 0.96 (95%CI 0.92-0.97) respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15-19) units (P<0.001, paired t test). Conclusion: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and CRP. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Background COVID-19 resulted in enormous disruption to life around the world. To quell disease spread, governments implemented lockdowns that likely created hardships for households. To improve knowledge of consequences, we examine how the pandemic period was associated with household hardships and assess factors associated with these hardships. Methods We conducted a cross-sectional study using quasi-Poisson regression to examine factors associated with household hardships. Data were collected between August and September of 2021 from a random sample of 880 households living within a Health and Demographic Surveillance System (HDSS) located in the Harari Region and the District of Kersa, both in Eastern Ethiopia. Results Having a head of household with no education, residing in a rural area, larger household size, lower income and/or wealth, and community responses to COVID-19, including lockdowns and travel restrictions, were independently associated with experiencing household hardships. Conclusions Our results identify characteristics of groups at-risk for household hardships during the pandemic; these findings may inform efforts to mitigate the consequences of COVID-19 and future disease outbreaks.

The 4D organization of the interphase nucleus, or the 4D Nucleome (4DN), reflects a dynamical interaction between 3D genome structure and function and its relationship to phenotype. We present initial analyses of the human 4DN, capturing genome-wide structure using chromosome conformation capture and 3D imaging, and function using RNA-sequencing. We introduce a quantitative index that measures underlying topological stability of a genomic region. Our results show that structural features of genomic regions correlate with function with surprising persistence over time. Furthermore, constructing genome-wide gene-level contact maps aided in identifying gene pairs with high potential for coregulation and colocalization in a manner consistent with expression via transcription factories. We additionally use 2D phase planes to visualize patterns in 4DN data. Finally, we evaluated gene pairs within a circadian gene module using 3D imaging, and found periodicity in the movement of clock circadian regulator and period circadian clock 2 relative to each other that followed a circadian rhythm and entrained with their expression. Significance We explored the human genome as a dynamical system. Using a data-guided mathematical framework and genome-wide assays, we interrogated the dynamical relationship between genome architecture (structure) and gene expression (function) and its impact on phenotype, which defines the 4D Nucleome. Structure and function entrained with remarkable persistence in genes that underlie wound healing processes and circadian rhythms. Using genome-wide intragene and intergene contact maps, we identified gene networks with high potential for coregulation and colocalization, consistent with expression via transcription factories. In an intriguing example, we found periodic movements of circadian genes in three dimensions that entrained with expression. This work can be broadly applied to identifying genomic signatures that define critical cell states during differentiation, reprogramming, and cancer.

Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types. Mapping higher order chromatin architecture is important. Here the authors use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organisation; they use hypergraph theory for data representation and analysis, and apply this to different cell types.