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OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Reference-free genome phasing is vital for understanding allele inheritance and the impact of single-molecule DNA variation on phenotypes. To achieve thorough phasing across homozygous or repetitive regions of the genome, long-read sequencing technologies are often used to perform phased de novo assembly. As a step toward reducing the cost and complexity of this type of analysis, we describe new methods for accurately phasing Oxford Nanopore Technologies (ONT) sequence data with the Shasta genome assembler and a modular tool for extending phasing to the chromosome scale called GFAse. We test using new variants of ONT PromethION sequencing, including those using proximity ligation, and show that newer, higher accuracy ONT reads substantially improve assembly quality.

Abstract Background Missing outcome data can pose a serious threat to the validity of randomised clinical trial results. We aimed to study the extent of missing outcome data in randomised clinical trials of psychological interventions. Methods We performed a retrospective study of randomised clinical trial reports of psychological interventions published in World Psychiatry, JAMA Psychiatry, Lancet Psychiatry, American Journal of Psychiatry, British Journal of Psychiatry, or Psychotherapy and Psychosomatics from 2017 to 2022. We assessed the proportion of missing outcome data, whether missing data patterns differed between types of outcomes, participants, intervention lengths, and psychological intervention types, how missing outcome data were handled in the statistical analyses, and whether trialists discussed missing outcome data in the discussion section of the manuscript. Results We identified 182 randomised clinical trials (233 primary outcomes), of which 206 outcomes (88.4%) were assessed at high risk of bias due to missing data. The overall mean percentage of missing outcome data was 18.3% (95% confidence interval (CI): 16.7–20%) for all outcomes. The percentages of missing data were 18.9% (95% CI: 17.1–20.6%; 180 outcomes) for symptom severity scales and 1.8% (95% CI: 2.3–3.3%; 6 outcomes) for ‘hard’ binary outcomes. Trials including participants with borderline personality disorder had the highest percentage of missing outcome data (33.1%; 95% CI: 22.3–43.9%) compared with other psychiatric disorders. Fisher’s exact test showed that intervention lengths and psychological intervention types were associated with the proportion of missing outcome data (p

Abstract Background Interventions targeting healthcare professionals’ confidence in managing ethical issues in dementia care are limited despite documented positive effects of educational programs on staff knowledge and self-efficacy. However, inconsistencies in the literature regarding the impact of educational programs underscore the need for targeted interventions. The CARE intervention, specifically designed to enhance confidence in ethical decision-making, aims to address this gap. This study evaluates the effectiveness of the CARE intervention in enhancing the ethical self-efficacy of healthcare professionals caring for people with dementia, particularly those with initially low levels of self-efficacy. Methods Using a non-experimental pre-post evaluation design, the CARE intervention was administered to healthcare professionals (n = 86), measuring ethical self-efficacy pre-and post-intervention. We hypothesized significant differences in ethical self-efficacy mean scores pre- and post-intervention for all participants, particularly those with low pre-measurement scores, whom we expected to benefit most from the intervention. Statistical analysis included paired t-tests and Wilcoxon tests for the low pre-measurement subgroup analysis. Results While no significant change was observed in the entire sample, participants with low initial self-efficacy showed a statistically significant improvement post-intervention. Conclusions The CARE intervention holds promise in improving ethical self-efficacy among healthcare professionals with initial low confidence levels. Targeted interventions are essential in addressing confidence gaps in managing ethical challenges in dementia care, with implications for professional well-being and quality of care. Further research should explore long-term effects and expand sample size to enhance generalizability and sustainability of findings.

Abstract Urogenital reconstructive malformation surgery is sometimes hampered by lack of tissue for the repair. We have previously shown that autologous micrografting allows for single-staged scaffold cellularization after surgical implantation. Here, a collagen-based scaffold reinforced with biodegradable mesh and a stent was implanted as a bladder conduit in ten full-grown female minipigs. We aimed to assess short-term regenerative outcomes, safety, and feasibility of implanting tubular urinary micrografted scaffolds versus acellular controls. Five scaffolds were embedded with autologous urothelial micrografts harvested perioperatively. After six weeks, all animals were assessed by cystoscopy, CT-urography, and microanatomical assessment of the urinary conduits. The procedure proved technically feasible within the confines of a regular surgical theater, with duration-times comparable to corresponding conventional procedures. No animals experienced postoperative complications, and all implanted conduits were patent at follow-up. Improved tissue regeneration was observed in the micrografted conduits compared with the acellular controls, including increased luminal epithelialization, increased cell proliferation, decreased cell apoptosis, and increased conduit vascularization. We concluded that single-staged on-site construction and implantation of tissue engineered urinary conduits proved feasible and safe, with improved regenerative potentials in micrografted conduits. This study presents a new approach to urinary conduits, and merits further investigations for advancement towards clinical translation.

The Northeast Greenland Shelf is a region currently considered to be an annual net sink of carbon dioxide (CO2) from the atmosphere. Water from the Northeast Greenland Shelf is advected to the formation regions of North Atlantic Deep Water; therefore, any carbon stored in the region may be retained in the global oceans on the timescales of the thermohaline circulation. We present the most extensive study of carbon chemistry on the Northeast Greenland Shelf to date, made possible by opportunistic sampling due to a sudden decrease in the sea ice concentration in late-August and September 2017. These are the first full-depth measurements of total alkalinity and dissolved inorganic carbon at latitudes between 75 and 79° N, with additional data collected in the region of the Northeast Water Polynya and outside of Young Sound. We find that surface mixed-layer concentrations are variable and (for many stations) higher than the interpolated atmospheric concentration for the region during the sampling period. Below the surface mixed layer, CO2 concentrations increase linearly with decreasing apparent oxygen utilisation. The mixed layer deepens during the study period; this is associated with apparent changes in CO2 uptake. The Northeast Greenland Shelf is a hydrologically complex region with many processes influencing the carbonate system at smaller scales than our sampling density. The scatter in the dataset represents more than mere outliers, and the lack of relationship between the outliers and any measured variable indicates a strong influence of a currently undescribed (set of) variable(s) and/or process(es) at the sampled scales. These data were collected during a time of radically low sea ice concentrations for the region and may be an indication of future conditions. As they indicate the potential of the region to act as a seasonal source of CO2 to the atmosphere, this may modify our current estimate of the region as a strong annual net sink that is relatively protected from the immediate influence of atmospheric warming and climate change.

Purpose: This study investigated how correlations between rapid automatized naming (RAN) and reading depend on characteristics of the stimuli. RAN tasks using stimuli with high phonological demands were predicted to be the strongest correlates of decoding efficiency, while high semantic demands were predicted to lead to stronger correlations with comprehension. Method: At two time points, 132 Grade 2 children completed four different RAN versions, two using letter stimuli (low semantic load) and two using object stimuli (high semantic load). Both types of stimuli were used in either a repeated version, where a set of four items were repeated multiple times (low semantic load), or in a unique version, where each item appeared only once (high semantic load). Decoding efficiency and reading comprehension were assessed in Grade 5. Results: Analyses showed that confirmatory factor models with separate factors for each version provided better fit than grouping factors according to time point. Repetition (lowering semantic load) increased the longitudinal association between RAN objects and decoding efficiency. There was a tendency for conditions with higher semantic load to correlate more strongly with reading comprehension after control for decoding efficiency, but the differences were not significant. Conclusion: The results indicate that increasing semantic load weakens the relationship with decoding efficiency.

Research from around the world has shown that COVID-19 emergency remote teaching in schools has generally struggled to maintain student satisfaction and engagement: students lacked social relatedness, a sense of belonging and ownership of school activities. This study examines the idea of using a dialogic teaching approach in synchronous online video-learning environments. The aim was to deliver proof of concept that dialogic tools can increase student satisfaction with emergency remote teaching. The authors designed and implemented 58 online dialogues and compared student satisfaction with this learning environment to student satisfaction with 'normal' emergency remote teaching and with traditional physical teaching. They found that dialogic online teaching achieved high student satisfaction that was comparable to student satisfaction with physical teaching. This result is relevant not only for emergency and regular remote teaching because online dialogue can be used to supplement asynchronous written dialogue in any remote teaching and learning environment.

Abstract Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.

OBJECTIVES: In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. METHODS: This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG

Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury scoring by radiologists. Materials and Methods In this secondary analysis, brain diffusion-weighted MRI data from neonates in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which recruited participants between January 2017 and October 2019, were analyzed. Volume of acute brain injury, defined as brain with apparent diffusion coefficient (ADC) less than 800 × 10-6 mm2/sec, was automatically computed across the whole brain and within the thalami and white matter. Outcomes of death and neurodevelopmental impairment (NDI) were recorded at 24-month follow-up. Associations between the presence and volume (in milliliters) of acute brain injury with 24-month outcomes were evaluated using multiple logistic regression. The correlation between quantitative acute brain injury volume and qualitative MRI scores was assessed using the Kendall tau-b test. Results A total of 416 neonates had available MRI data (mean gestational age, 39.1 weeks ± 1.4 [SD]; 235 male) and 113 (27%) showed evidence of acute brain injury at MRI. Of the 387 participants with 24-month follow-up data, 185 (48%) died or had any NDI. Volume of acute injury greater than 1 mL (odds ratio [OR], 13.9 [95% CI: 5.93, 32.45]; P < .001) and presence of any acute injury in the brain (OR, 4.5 [95% CI: 2.6, 7.8]; P < .001) were associated with increased odds of death or any NDI. Quantitative whole-brain acute injury volume was strongly associated with radiologists qualitative scoring of diffusion-weighted images (Kendall tau-b = 0.56; P < .001). Conclusion Automated quantitative volume of brain injury is associated with death, moderate to severe NDI, and cerebral palsy in neonates with hypoxic ischemic encephalopathy and correlated well with qualitative MRI scoring of acute brain injury. Clinical trial registration no. NCT02811263 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.