In search of a 'good number': knowledge controversy and population estimates in the endgame of hepatitis C elimination.

We explore the contentious life of a metric used to assess a country's progress in relation to global disease elimination targets. Our topic is hepatitis C elimination, and our context is Australia. A fundamental metric in the calculation of progress toward hepatitis C elimination targets, as set by the WHO, is the population prevalence of people living with hepatitis C. In Australia, this modelled estimate has generated some controversy, largely through its repeated downsizing as an effect of calculus. The 2015 baseline population estimate in Australia, from which measures of current elimination progress are assessed, has reduced, over time, by around 30%. Informed by a social study of science approach, we used qualitative interviews with 32 experts to explore the knowledge controversy. The controversy is narrated through the core concerns of 'scale' and 'care', with narratives aligning differently to imaginaries of 'science' and 'community'. We trace how constitutions of 'estimate' and 'number' circulate in relation to 'population' and 'people', and as affective values. We show how enactments of estimates and numbers materialise hepatitis elimination in different ways, with policy implications. The event of the knowledge controversy opens up the social and political life of enumerations-for science and community-inviting deliberation on how to make 'good numbers' in the race to eliminate hepatitis C.

Quantifying the variability in the assessment of reproductive hormone levels.

OBJECTIVE: To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. DESIGN: Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. SETTING: Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust. PATIENTS: Overall, 266 individuals, including healthy men and women (n = 142) and those with reproductive disorders and states (n = 124 [11 with functional hypothalamic amenorrhoea, 6 with polycystic ovary syndrome, 62 women and 32 men with hypoactive sexual desire disorder, and 13 postmenopausal women]), were included in the analysis. INTERVENTIONS: Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones because of pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. MAIN OUTCOME MEASURES: The ability of a single measure of reproductive hormone level to quantify the variability in reproductive hormone levels because of pulsatile secretion, diurnal variation, and nutrient intake. RESULTS: The initial morning value of reproductive hormone levels was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: luteinizing hormone level 18.4%, follicle-stimulating hormone level 9.7%, testosterone level 9.2%, and estradiol level 2.1%). Luteinizing hormone level was the most variable (CV 28%), followed by sex-steroid hormone levels (testosterone level 12% and estradiol level 13%), whereas follicle-stimulating hormone level was the least variable reproductive hormone (CV 8%). In healthy men, testosterone levels fell between 9:00 am and 5:00 pm by 14.9% (95% confidence interval 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2 = 0.53, P<.0001). Testosterone levels were reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), after an oral glucose load (6.0%), or an intravenous glucose load (7.4%). CONCLUSION: Quantification of the variability of a single measure of reproductive hormone levels informs the reliability of reproductive hormone assessment.

Risk factors for delayed termination of pregnancy following increased nuchal translucency.

OBJECTIVES: Termination of pregnancy after increased nuchal translucency (NT) is a common occurrence. This study aimed to identify characteristics of a cohort with a NT ≥3.0 mm who underwent a pregnancy termination ≥15 weeks compared with those who terminated <15 weeks. METHODS: All NT ≥3.0 mm identified within our department over an 11-year period (2010-2021) (n = 689) were retrospectively examined and characteristics of the cohort of increased NTs ending in termination were further categorized. RESULTS: There were 221 (32.1%) individuals with an increased NT (≥3 mm) who underwent a termination of pregnancy within our study period (2010-2021). Pregnancy termination occurred at a gestational age <15 weeks in 162 (73.3%) and ≥15 weeks in 59 individuals. Pregnant individuals without positive NIPT for aneuploidy were at a higher risk for a ≥15-week termination (p = 0.004). In 29% (17/59) of late terminations, there were additional imaging findings after the NT scan (ultrasound, echocardiogram, magnetic resonance imaging) that ultimately triggered the decision to pursue termination. CONCLUSIONS: As the options for workup of an increased NT expand, potential delays in decision-making surrounding termination increase. This study identifies multiple reasons for delayed termination and proposes several approaches to care aimed at maximizing diagnostic information by imaging and diagnostic testing in an expedited manner.

Postnatal genetic testing on cord blood for prenatally identified high-probability cases.

OBJECTIVE: To evaluate the utility of postnatal genetic testing on umbilical cord blood (CB) for prenatally identified high-probability fetuses. METHOD: CB for genetic testing was offered to individuals who met one of the following criteria: (i) fetal anomaly, (ii) positive non-invasive prenatal screening by cfDNA or biochemical analysis, or (iii) family history. Individuals with diagnostic testing, but not microarray, were also included when recommended by society guidelines. CB was collected at Brigham and Women's and Emerson Hospitals between 2016 and 2021. RESULTS: 448 individuals consented for cord blood testing (370 (82.6%) for fetal anomalies, 51 (11.4%) for high-probability cfDNA, and 27 (6.0%) for family history) and a total of 393 (87.7%) samples were analyzed. Genetic testing yielded a diagnosis in 92 (23.4%) neonates by karyotype (n = 37), chromosomal microarray (CMA) (n = 32), and other molecular analysis (n = 23). Testing averaged 10.3 days (range 1-118 days). 68 (73.9%) diagnoses potentially impacted neonatal management. MCC could not be definitively excluded in only 1.4% (6/418) of samples. CONCLUSION: Prenatal identification of high-probability fetuses and genetic testing on CB facilitates timely genetic diagnoses and neonatal management. Testing provides reassurance and reduces a postnatal diagnostic odyssey for high-probability neonates.

Undoing elimination: Modelling Australia's way out of the COVID-19 pandemic.

In the middle of 2020, with its borders tightly closed to the rest of the world, Australia almost achieved the local elimination of COVID-19 and subsequently maintained 'COVID-zero' in most parts of the country for the following year. Australia has since faced the relatively unique challenge of deliberately 'undoing' these achievements by progressively easing restrictions and reopening. Exploring the role of mathematical modelling in navigating a course through the pandemic through qualitative interviews with modellers and others working closely with modelling, we argue that each of these two significant phases of Australia's COVID-19 experience can be understood as distinct forms of 'model society'. This refers at once to the society enacted through the governance of risk, and to the visions of societal outcomes - whether to be sought or to be avoided - that are offered up by models. Each of the two model societies came about through a reflexive engagement with risk facilitated by models, and the iterative relationship between the representations of society enacted within models and the possibilities that these representations generate in the material world beyond them.

Single gene non-invasive prenatal screening for autosomal dominant conditions in a high-risk cohort.

PURPOSE: To determine the utility of single gene non-invasive prenatal screening (NIPS-SGD) in a high-risk reproductive genetics clinic. METHODS: A clinical pilot for NIPS-SGD was conducted from March 2020 to November 2021. A NIPS-SGD panel assessing pathogenic variants in 30 genes was offered to pregnant individuals for the following indications: (1) advanced sperm age ≥40 years, (2) nuchal translucency (NT) ≥ 3.5 mm, (3) fetal anomaly, or (4) family history of a condition covered by the panel. Diagnostic testing was offered concurrently. RESULTS: NIPS-SGD was ordered for 253 individuals: 88 (34.8%) for fetal anomalies, 96 (37.9%) for advanced sperm age, 37 (14.6%) for increased NT, and 5 (2.0%) for family history. Among 228 (90.1%) completed tests, 8 (3.5%) were positive. Diagnostic testing for 78 individuals revealed no false positive or negative results. Of 41 (25.9%) individuals who received a molecular diagnosis, 34 (82.9%) were outside the scope of NIPS-SGD. Positive NIPS-SGD altered medical management in five cases. CONCLUSIONS: NIPS-SGD in a high-risk population can lead to earlier prenatal diagnosis, enhanced surveillance, and targeted genetic analysis, but should not replace clinically indicated diagnostic testing. Potential incidental findings include parental diagnoses and misattributed parentage.

The impact of COVID-19 on youth mental health: A mixed methods survey.

The COVID-19 pandemic has presented profound disruptions to young people at a critical period of psychosocial development. The current study aimed to explore the perceived negative and positive impacts of the COVID-19 pandemic on young people's mental health and wellbeing across a spectrum of clinical needs. A cross-sectional online survey including both quantitative and qualitative responses captured positive and negative impacts of COVID-19 across 593 young people with and without mental health care needs. Findings revealed high levels of clinical depression (48%), anxiety (51%), and loneliness in both samples. Approximately 75% of young people in primary mental health care services, and over 80% in the general population, reported a negative impact on work, non-work activities and mental health and wellbeing. Open-ended responses reflected positive impacts in the domains of greater capacity for self-care and reflection due to the decreased pressures of daily life. Negative impacts reflected worsening mental health, disruptions to key developmental milestones regarding relationships with self and others, and limited capacity for self-care. Together, these data highlight the critical need for early intervention support for the psychosocial impacts experienced by young people due to the pandemic, particularly among those with existing mental health care needs.

Increased use of diagnostic testing after increased nuchal translucency: The influence of non-invasive prenatal testing and chromosomal microarray.

OBJECTIVE: The utilization of non-invasive prenatal testing (NIPT) and chromosomal microarray (CMA) has significantly altered the options for testing following the diagnosis of an increased nuchal translucency (NT). This study defines the rates of utilization of diagnostic testing in the pre-NIPT, pre-CMA, and post-CMA eras. METHODS: We retrospectively examined NT scans performed in our department from January 2010 to December 2020 and identified all NTs ≥3.0 mm for analysis. We divided our data into three distinct periods (2010-2012, 2013-2016, and 2017-2020) corresponding to our institutional practice shifts in recommending and offering use of NIPT (2013) and CMA (2016), respectively. RESULTS: 689 patients with NT ≥ 3.0 mm met inclusion criteria in our study, of which 355 (51.5%) individuals underwent diagnostic testing and 334 (48.5%) did not. There was a significant decline in rates of diagnostic testing with NIPT (2013), which has returned to pre-NIPT levels with the availability of microarray. CONCLUSIONS: Since the routine use of CMA (2016), the rates of diagnostic testing for increased NT have returned to pre-NIPT levels. This study validates data suggesting an initial decline in the rates of diagnostic testing following abnormal NT but suggests that the decline may be reversing in the post-CMA era due to a rise in rates of chorionic villus sampling.

Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial.

Background: Treatment resistance is a significant problem among young people experiencing moderate-to-severe anxiety, affecting nearly half of all patients. This study investigated the safety and efficacy of cannabidiol (CBD), a non-intoxicating component of Cannabis sativa, for anxiety disorders in young people who previously failed to respond to standard treatment.Methods: In this open-label trial, 31 young people aged 12-25 years with a DSM-5 anxiety disorder and no clinical improvement despite treatment with cognitive-behavioral therapy and/or antidepressant medication were enrolled between May 16, 2018, and June 28, 2019. All participants received add-on CBD for 12 weeks on a fixed-flexible schedule titrated up to 800 mg/d. The primary outcome was improvement in anxiety severity, measured with the Overall Anxiety Severity and Impairment Scale (OASIS), at week 12. Secondary outcomes included comorbid depressive symptoms, Clinical Global Impressions scale (CGI) score, and social and occupational functioning.Results: Mean (SD) OASIS scores decreased from 10.8 (3.8) at baseline to 6.3 (4.5) at week 12, corresponding to a -42.6% reduction (P < .0001). Depressive symptoms (P < .0001), CGI-Severity scale scores (P = .0008), and functioning (P = .04) improved significantly. Adverse events were reported in 25 (80.6%) of 31 participants and included fatigue, low mood, and hot flushes or cold chills. There were no serious and/or unexpected adverse events.Conclusions: These findings suggest that CBD can reduce anxiety severity and has an adequate safety profile in young people with treatment-resistant anxiety disorders. Randomized controlled trials are needed to confirm the efficacy and longer-term safety of this compound.Trial Registration: New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12617000825358.

Ownership, Use of, and Interest in Digital Mental Health Technologies Among Clinicians and Young People Across a Spectrum of Clinical Care Needs: Cross-sectional Survey.

BACKGROUND: There is currently an increased interest in and acceptance of technology-enabled mental health care. To adequately harness this opportunity, it is critical that the design and development of digital mental health technologies be informed by the needs and preferences of end users. Despite young people and clinicians being the predominant users of such technologies, few studies have examined their perspectives on different digital mental health technologies. OBJECTIVE: This study aims to understand the technologies that young people have access to and use in their everyday lives and what applications of these technologies they are interested in to support their mental health. The study also explores the technologies that youth mental health clinicians currently use within their practice and what applications of these technologies they are interested in to support their clients' mental health. METHODS: Youth mental health service users (aged 12-25 years) from both primary and specialist services, young people from the general population (aged 16-25 years), and youth mental health clinicians completed a web-based survey exploring technology ownership, use of, and interest levels in using different digital interventions to support their mental health or that of their clients. RESULTS: A total of 588 young people and 73 youth mental health clinicians completed the survey. Smartphone ownership or private access among young people within mental health services and the general population was universal (611/617, 99%), with high levels of access to computers and social media. Youth technology use was frequent, with 63.3% (387/611) using smartphones several times an hour. Clinicians reported using smartphones (61/76, 80%) and video chat (69/76, 91%) commonly in clinical practice and found them to be helpful. Approximately 50% (296/609) of the young people used mental health apps, which was significantly less than the clinicians (χ23=28.8, n=670; P<.001). Similarly, clinicians were significantly more interested in using technology for mental health support than young people (H3=55.90; P<.001), with 100% (73/73) of clinicians being at least slightly interested in technology to support mental health compared with 88% (520/591) of young people. Follow-up tests revealed no difference in interest between young people from the general population, primary mental health services, and specialist mental health services (all P>.23). Young people were most interested in web-based self-help, mobile self-help, and blended therapy. CONCLUSIONS: Technology access is pervasive among young people within and outside of youth mental health services; clinicians are already using technology to support clinical care, and there is widespread interest in digital mental health technologies among these groups of end users. These findings provide important insights into the perspectives of young people and clinicians regarding the value of digital mental health interventions in supporting youth mental health.

New directions for participatory modelling in health: Redistributing expertise in relation to localised matters of concern.

Participatory modelling seeks to foster stakeholder engagement to better attune models to their decision-making and policy contexts. Such approaches are increasingly advocated for use in the field of health. We review the instrumental and epistemological claims made in support of participatory modelling approaches. These accentuate participatory models as offering a better evidence-base for health policy decisions. By drawing attention to recent modelling experiments in a sector outside of health, that of water management, we outline a different way of thinking about participation and modelling. Here, the participatory model is configured in relation to matters of 'knowledge controversy', with modelling constituted as an 'evidence-making intervention' in relation to the making of science and expertise. Rather than presenting participatory models as an improved technical solution to addressing given policy problems within an evidence-based intervention approach, models are alternatively potentiated as sites for the redistribution of expertise among actor networks as they seek to engage politically in a matter of concern. This leads us to consider possible new directions for participatory modelling in the field of health.

Multinucleation associated DNA damage blocks proliferation in p53-compromised cells.

Nuclear atypia is one of the hallmarks of cancers. Here, we perform single-cell tracking studies to determine the immediate and long-term impact of nuclear atypia. Tracking the fate of newborn cells exhibiting nuclear atypia shows that multinucleation, unlike other forms of nuclear atypia, blocks proliferation in p53-compromised cells. Because ~50% of cancers display compromised p53, we explored how multinucleation blocks proliferation. Multinucleation increases 53BP1-decorated nuclear bodies (DNA damage repair platforms), along with a heterogeneous reduction in transcription and protein accumulation across the multi-nucleated compartments. Multinucleation Associated DNA Damage associated with 53BP1-bodies remains unresolved for days, despite an intact NHEJ machinery that repairs laser-induced DNA damage within minutes. Persistent DNA damage, a DNA replication block, and reduced phospho-Rb, reveal a novel replication stress independent cell cycle arrest caused by mitotic lesions. These findings call for segregating protective and prohibitive nuclear atypia to inform therapeutic approaches aimed at limiting tumour heterogeneity.

Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing.

PURPOSE: Copy-number variant (CNV) assessment is recommended for patients undergoing prenatal diagnostic testing. Noninvasive screening tests have not been extensively validated for CNV detection. The objective of this study was to compare the ability of genome-wide noninvasive prenatal screening (NIPS) to chromosomal microarray to detect clinically significant findings. METHODS: We prospectively enrolled 198 subjects at the time of consent for diagnostic prenatal testing. Genome-wide NIPS results were compared with diagnostic testing results to assess NIPS test performance (n = 160, 38 subjects without microarray results excluded). Cohen's kappa statistic was used to assess test agreement. RESULTS: Genome-wide NIPS did not detect clinically significant chromosomal abnormalities at the same rate as diagnostic testing, κ = 0.75 (95% confidence interval [CI], 0.62-0.87). When excluding CNVs <7 Mb and findings outside the limits of genome-wide NIPS, test agreement improved, κ = 0.88 (0.79-0.97) driven by agreement for common aneuploidies (κ = 1.0). However, among patients with an abnormal fetal survey, agreement was only fair, κ = 0.38 (0.08-0.67). CONCLUSION: While NIPS is an excellent screening test for common aneuploidies, genome-wide NIPS misses clinically significant findings detected on routine diagnostic testing. False positive and false negative cases highlight the importance of pretest counseling regarding NIPS limitations, especially in the setting of fetal anomalies.

Implementation lessons from the transition to telehealth during COVID-19: a survey of clinicians and young people from youth mental health services.

Whilst telehealth may overcome some traditional barriers to care, successful implementation into service settings is scarce, particularly within youth mental health care. This study aimed to leverage the rapid implementation of telehealth due to COVID-19 to understand the perspectives of young people and clinicians on how telehealth impacts service delivery, service quality, and to develop pathways for future uses. Youth mental health service users (aged 12-25) and clinicians took part in an online survey exploring service provision, use, and quality following the adoption of telehealth. Service use data from the period were also examined. Ninety-two clinicians and 308 young people responded to the survey. Service use was reduced compared to the same period in 2019, however, attendance rates were higher. Across eight domains of service quality, the majority of young people reported that telehealth positively impacted service quality, and were significantly more likely to rate telehealth as having a positive impact on service quality than clinicians. There was high interest in continuing to use telehealth as part of care beyond the pandemic, supporting its permanent role in youth mental health care for a segment of service users. Future work should explore how best to support its long-term implementation.

Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption.

Bidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EV secretion contribute to the growth and metastasis of tumor cells. However, the mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification is associated with and sufficient to promote small extracellular vesicle (SEV) secretion in pancreatic cancer cells. This is a direct result of lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream of extra centrosomes. We propose that defects in lysosome function could promote multivesicular body fusion with the plasma membrane, thereby enhancing SEV secretion. Furthermore, we find that SEVs secreted in response to amplified centrosomes are functionally distinct and activate pancreatic stellate cells (PSCs). These activated PSCs promote the invasion of pancreatic cancer cells in heterotypic 3D cultures. We propose that SEVs secreted by cancer cells with amplified centrosomes influence the bidirectional communication between the tumor cells and the surrounding stroma to promote malignancy.

Perceived need for neuropsychological assessment according to geographic location: A survey of Australian youth mental health clinicians.

Recent studies have shown that neuropsychological assessment is a scarce resource in youth mental health settings. The need for neuropsychological assessment might differ in metropolitan and nonmetropolitan areas due to characteristics inherent to these different regions. However, no formal studies have investigated this question. The aim of this research was to investigate whether need for neuropsychological assessment in youth mental health settings varies by geographic location. A cross-sectional online survey was completed by clinicians (N = 532) treating or assessing adolescents and young adults attending Australian primary care mental health (headspace) centers. Results indicated a similar need for neuropsychological assessment across the geographic areas. However, neuropsychological assessment was significantly less available to clients in outer regional, remote and very remote areas compared to major cities. Exploratory analyses further revealed that there were significantly fewer clinicians with a postgraduate degree and more clinicians with a bachelor degree in outer regional, remote and very remote areas than in major cities. Given the negative impact of cognitive impairments in youth with a mental illness, these findings reveal a necessity to enhance the availability and access to neuropsychological assessment in rural settings. Several plausible avenues to achieving increased access include increasing the funding available for this resource; providing nonmetropolitan clinicians with sufficient neuropsychological consultation, including rural training and rotations in neuropsychologists' postgraduate training; and exploring the use of tele-health in the provision of neuropsychological assessments in nonmetropolitan settings.

The Impact of COVID-19 on Interventional Radiology Services in the UK.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has created unprecedented challenges on the healthcare system. The aim of this multi-centre study was to measure the impact of COVID-19 on IR services in the UK. MATERIAL AND METHODS: Retrospective cross-sectional study of IR practice in six UK centres during the COVID-19 pandemic was carried out. All therapeutic IR procedures were identified using the respective hospital radiology information systems and COVID-19 status found on the hospital patient record systems. The total number of therapeutic IR procedures was recorded over two time periods, 25/03/2019-21/04/2019 (control group) and 30/03/2020-26/04/2020 (COVID-19 group). The data points collected were: procedure type, aerosol-generating nature, acute or elective case, modality used, in- or out-of-hours case and whether the procedure was done at the bedside (portable). RESULTS: A 31% decrease in overall number of IR procedures was observed during COVID-19 compared to the control group (1363 cases vs 942 cases); however, the acute work decreased by only 0.5%. An increase in out-of-hours work by 10% was observed. COVID-19 was suspected or laboratory proved in 9.9% of cases (n = 93), and 15% of total cases (n = 141) were classed as aerosol-generating procedures. A 66% rise in cholecystostomy was noted during COVID-19. Image-guided ablation, IVC filters, aortic stent grafting and visceral vascular stenting had the greatest % decreases in practice during COVID-19, with 91.7%, 83.3%, 80.8% and 80.2% decreases, respectively. CONCLUSION: During the global pandemic, IR has continued to provide emergency and elective treatment highlighting the adaptability of IR in supporting other specialties.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.