MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

Fumarate induces vesicular release of mtDNA to drive innate immunity.

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

Checkpoint inhibition of origin firing prevents DNA topological stress.

A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors.

Coherent electrical control of a single high-spin nucleus in silicon.

Nuclear spins are highly coherent quantum objects. In large ensembles, their control and detection via magnetic resonance is widely exploited, for example, in chemistry, medicine, materials science and mining. Nuclear spins also featured in early proposals for solid-state quantum computers1 and demonstrations of quantum search2 and factoring3 algorithms. Scaling up such concepts requires controlling individual nuclei, which can be detected when coupled to an electron4-6. However, the need to address the nuclei via oscillating magnetic fields complicates their integration in multi-spin nanoscale devices, because the field cannot be localized or screened. Control via electric fields would resolve this problem, but previous methods7-9 relied on transducing electric signals into magnetic fields via the electron-nuclear hyperfine interaction, which severely affects nuclear coherence. Here we demonstrate the coherent quantum control of a single 123Sb (spin-7/2) nucleus using localized electric fields produced within a silicon nanoelectronic device. The method exploits an idea proposed in 196110 but not previously realized experimentally with a single nucleus. Our results are quantitatively supported by a microscopic theoretical model that reveals how the purely electrical modulation of the nuclear electric quadrupole interaction results in coherent nuclear spin transitions that are uniquely addressable owing to lattice strain. The spin dephasing time, 0.1 seconds, is orders of magnitude longer than those obtained by methods that require a coupled electron spin to achieve electrical driving. These results show that high-spin quadrupolar nuclei could be deployed as chaotic models, strain sensors and hybrid spin-mechanical quantum systems using all-electrical controls. Integrating electrically controllable nuclei with quantum dots11,12 could pave the way to scalable, nuclear- and electron-spin-based quantum computers in silicon that operate without the need for oscillating magnetic fields.

Large sensory volumes enable Southern elephant seals to exploit sparse deep-sea prey.

The ability of echolocating toothed whales to detect and classify prey at long ranges enables efficient searching and stalking of sparse prey in these time-limited dives. However, nonecholocating deep-diving seals such as elephant seals appear to have much less sensory advantage over their prey. Both elephant seals and their prey rely on visual and hydrodynamic cues that may be detectable only at short ranges in the deep ocean, leading us to hypothesize that elephant seals must adopt a less efficient reactive mode of hunting that requires high prey densities. To test that hypothesis, we deployed high-resolution sonar and movement tags on 25 females to record simultaneous predator and prey behavior during foraging interactions. We demonstrate that elephant seals have a sensory advantage over their prey that allows them to potentially detect prey 5 to 10 s before striking. The corresponding prey detection ranges of 7 to 17 m enable stealthy approaches and prey-specific capture tactics. In comparison, prey react at a median range of 0.7 m, close to the neck extension range of striking elephant seals. Estimated search swathes of 150 to 900 m2 explain how elephant seals can locate up to 2,000 prey while swimming more than 100 km per day. This efficient search capability allows elephant seals to subsist on prey densities that are consonant with the deep scattering layer resources estimated by hydroacoustic surveys but which are two orders of magnitude lower than the prey densities needed by a reactive hunter.

A role for mutations in AK9 and other genes affecting ependymal cells in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous CWH43 deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, and MYH13) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in AK9, which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated AK9 mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. AK9+/- mice displayed normal brain development and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH.

A wave of specific transcript and protein accumulation accompanies pollen dehydration.

In flowering plants, male gametes are immotile and carried by dry pollen grains to the female organ. Dehydrated pollen is thought to withstand abiotic stress when grains are dispersed from the anther to the pistil, after which sperm cells are delivered via pollen tube growth for fertilization and seed set. Yet, the underlying molecular changes accompanying dehydration and the impact on pollen development are poorly understood. To gain a systems perspective, we analyzed published transcriptomes and proteomes of developing Arabidopsis thaliana pollen. Waves of transcripts are evident as microspores develop to bicellular, tricellular, and mature pollen. Between the "early"- and "late"-pollen-expressed genes, an unrecognized cluster of transcripts accumulated, including those encoding late-embryogenesis abundant (LEA), desiccation-related protein, transporters, lipid-droplet associated proteins, pectin modifiers, cysteine-rich proteins, and mRNA-binding proteins. Results suggest dehydration onset initiates after bicellular pollen is formed. Proteins accumulating in mature pollen like ribosomal proteins, initiation factors, and chaperones are likely components of mRNA-protein condensates resembling "stress" granules. Our analysis has revealed many new transcripts and proteins that accompany dehydration in developing pollen. Together with published functional studies, our results point to multiple processes, including (1) protect developing pollen from hyperosmotic stress, (2) remodel the endomembrane system and walls, (3) maintain energy metabolism, (4) stabilize presynthesized mRNA and proteins in condensates of dry pollen, and (5) equip pollen for compatibility determination at the stigma and for recovery at rehydration. These findings offer novel models and molecular candidates to further determine the mechanistic basis of dehydration and desiccation tolerance in plants.

International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials.

PURPOSE: Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: Twenty-five international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Increasing spread rates of tropical non-native macrophytes in the Mediterranean Sea.

Warming as well as species introductions have increased over the past centuries, however a link between cause and effect of these two phenomena is still unclear. Here we use distribution records (1813-2023) to reconstruct the invasion histories of marine non-native macrophytes, macroalgae and seagrasses, in the Mediterranean Sea. We defined expansion as the maximum linear rate of spread (km year-1) and the accumulation of occupied grid cells (50 km2) over time and analyzed the relation between expansion rates and the species' thermal conditions at its native distribution range. Our database revealed a marked increase in the introductions and spread rates of non-native macrophytes in the Mediterranean Sea since the 1960s, notably intensifying after the 1990s. During the beginning of this century species velocity of invasion has increased to 26 ± 9 km2 year-1, with an acceleration in the velocity of invasion of tropical/subtropical species, exceeding those of temperate and cosmopolitan macrophytes. The highest spread rates since then were observed in macrophytes coming from native regions with minimum SSTs two to three degrees warmer than in the Mediterranean Sea. In addition, most non-native macrophytes in the Mediterranean (>80%) do not exceed the maximum temperature of their range of origin, whereas approximately half of the species are exposed to lower minimum SST in the Mediterranean than in their native range. This indicates that tropical/subtropical macrophytes might be able to expand as they are not limited by the colder Mediterranean SST due to the plasticity of their lower thermal limit. These results suggest that future warming will increase the thermal habitat available for thermophilic species in the Mediterranean Sea and continue to favor their expansion.

The use of machine learning in paediatric nutrition.

PURPOSE OF REVIEW: In recent years, there has been a burgeoning interest in using machine learning methods. This has been accompanied by an expansion in the availability and ease of use of machine learning tools and an increase in the number of large, complex datasets which are suited to machine learning approaches. This review summarizes recent work in the field and sets expectations for its impact in the future. RECENT FINDINGS: Much work has focused on establishing good practices and ethical frameworks to guide the use of machine learning in research. Machine learning has an established role in identifying features in 'omics' research and is emerging as a tool to generate predictive models to identify people at risk of disease and patients at risk of complications. They have been used to identify risks for malnutrition and obesity. Machine learning techniques have also been used to develop smartphone apps to track behaviour and provide healthcare advice. SUMMARY: Machine learning techniques are reaching maturity and their impact on observational data analysis and behaviour change will come to fruition in the next 5 years. A set of standards and best practices are emerging and should be implemented by researchers and publishers.

Socioeconomic disparities in the postnatal growth of preterm infants: a systematic review.

OBJECTIVE: To determine the effect of parental socioeconomic status (SES) on the postnatal growth of preterm infants. METHODS: A systematic review (PROSPERO registration CRD42020225714) of original articles from Medline, Embase, CINAHL Plus and Web of Science published 1946-2023 was undertaken. Studies were included if they reported anthropometric growth outcomes for preterm infants according to parental SES. Data extraction and assessments of bias and health equity impact were conducted using custom-designed forms. RESULTS: A narrative synthesis of twelve included studies was performed. Most infants were moderate to late preterm. The settings, growth outcomes, timings of growth measurement, and SES measures were heterogenous. Six studies demonstrated an adverse effect of low parental SES on the extrauterine growth of preterm infants, five studies showed no effect, and one study showed a potentially beneficial effect. All studies had a high risk of bias, especially confounding and selection bias. The health equity impact of included studies was largely negative. CONCLUSION: Limited and low-quality evidence suggests that socioeconomic minoritisation may adversely impact the growth of preterm infants, thereby widening existing socioeconomic health inequities. Observational studies informed by theorisation of the mechanistic pathways linking socioeconomic minoritisation to adverse postnatal growth are required to identify targets for intervention. IMPACT: Limited evidence suggests low parental socioeconomic status (SES) adversely affects the postnatal growth of preterm infants across different settings. Early growth of preterm infants predicts neurodevelopmental outcomes and the risk of cardiovascular and metabolic disease in adulthood. Systematic screening of over 15,000 articles identified only twelve studies which reported postnatal growth outcomes for preterm infants according to parental SES. The health equity impact of the included studies was systematically assessed, and found to be negative overall. This study highlights limitations in existing evidence on the association between parental SES and postnatal growth, and delineates avenues for future research.

Nutritional interventions to prevent retinopathy of prematurity.

Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%. IMPACT: Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP. Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials.

Nutritional management after necrotizing enterocolitis and focal intestinal perforation in preterm infants.

Nutritional management of preterm infants recovering from necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) is challenging, especially in infants managed surgically. The logistics of how, when, and what to feed are unclear and current nutritional practices are primarily based on physiological principles and consensus opinion in individual units, rather than high-quality evidence. The aim of this narrative review is to summarize the literature on nutritional management after NEC or FIP in preterm infants: when to restart enteral nutrition, type of enteral nutrition to use, and how to advance nutrition. We also discuss treatment of micronutrient deficiencies, cholestasis, replacement of stoma losses, and optimal time of stoma closure. In conclusion, there are in sufficient high-quality studies available to provide evidence-based recommendations on the best nutritional practice after NEC or FIP in preterm infants. A local or national consensus based early nutrition guideline agreed upon by a multidisciplinary team including pediatric surgeons, pediatricians/neonatologists, nurses, and nutritionists is recommended. Further studies are urgently needed. IMPACT: There is no good quality evidence or nutritional standard across neonatal units treating infants after medical or surgical NEC or FIP. With this review we hope to start providing some consistency across patients and between providers treating patients with NEC and FIP. Mother's own milk is recommended when restarting enteral nutrition after NEC or FIP. In the absence of high-quality evidence, a consensus based early nutrition guideline agreed upon by a multidisciplinary team is recommended. Nutritional research projects are urgently needed in NEC and FIP patients.

Editorial Perspective: The paradox of precision health in early development - building large samples to yield individual-level measures.

Precision health refers to the use of individualised biomarkers or predictive models to provide more tailored information about an individual's likely prognosis. For child psychiatry and psychology, we argue that this approach requires a focus on neurocognitive measures collected in early life and at large scale. However, the large sample sizes necessary to uncover individual-level predictors are currently rare in studies of neurodevelopmental conditions in early childhood. We recommend two strategies going forward: first, including neurocognitive measures in new national cohort studies, and second, synergising measures and data across currently funded longitudinal studies.

The roles of sensory hyperreactivity and hyporeactivity in understanding infant fearfulness and emerging autistic traits.

BACKGROUND: Existing evidence indicates that atypical sensory reactivity is a core characteristic of autism, and has been linked to both anxiety (and its putative infant precursor of fearfulness) and repetitive behaviours. However, most work has used cross-sectional designs and not considered the differential roles of hyperreactivity and hyporeactivity to sensory inputs, and is thus limited in specificity. METHODS: 161 infants with and without an elevated likelihood of developing autism and attention-deficit hyperactivity disorder (ADHD) were followed from 10 to 36 months of age. Parents rated an infant precursor of later anxiety (fearfulness) using the Infant Behaviour Questionnaire at 10 and 14 months, and the Early Childhood Behavioural Questionnaire at 24 months, and sensory hyperreactivity and hyporeactivity at 10, 14 and 24 months using the Infant Toddler Sensory Profile. Domains of autistic traits (restrictive and repetitive behaviours; RRB, and social communication interaction, SCI) were assessed using the parent-rated Social Responsiveness Scale at 36 months. Cross-lagged models tested (a) paths between fearfulness and hyperreactivity at 10-24 months, and from fearfulness and hyperreactivity to later autism traits, (b) the specificity of hyperreactivity effects by including hyporeactivity as a correlated predictor. RESULTS: Hyperreactivity at 14 months was positively associated with fearfulness at 24 months, and hyperreactivity at 24 months was positively associated with SCI and RRB at 36 months. When hyporeactivity was included in the model, paths between hyperreactivity and fearfulness remained, but paths between hyperreactivity and autistic traits became nonsignificant. CONCLUSIONS: Our findings indicate that alterations in early sensory reactivity may increase the likelihood of showing fearfulness in infancy, and relate to later social interactions and repetitive behaviours, particularly in individuals with a family history of autism or ADHD.

Automated morphological phenotyping using learned shape descriptors and functional maps: A novel approach to geometric morphometrics.

The methods of geometric morphometrics are commonly used to quantify morphology in a broad range of biological sciences. The application of these methods to large datasets is constrained by manual landmark placement limiting the number of landmarks and introducing observer bias. To move the field forward, we need to automate morphological phenotyping in ways that capture comprehensive representations of morphological variation with minimal observer bias. Here, we present Morphological Variation Quantifier (morphVQ), a shape analysis pipeline for quantifying, analyzing, and exploring shape variation in the functional domain. morphVQ uses descriptor learning to estimate the functional correspondence between whole triangular meshes in lieu of landmark configurations. With functional maps between pairs of specimens in a dataset we can analyze and explore shape variation. morphVQ uses Consistent ZoomOut refinement to improve these functional maps and produce a new representation of shape variation, area-based and conformal (angular) latent shape space differences (LSSDs). We compare this new representation of shape variation to shape variables obtained via manual digitization and auto3DGM, an existing approach to automated morphological phenotyping. We find that LSSDs compare favorably to modern 3DGM and auto3DGM while being more computationally efficient. By characterizing whole surfaces, our method incorporates more morphological detail in shape analysis. We can classify known biological groupings, such as Genus affiliation with comparable accuracy. The shape spaces produced by our method are similar to those produced by modern 3DGM and to auto3DGM, and distinctiveness functions derived from LSSDs show us how shape variation differs between groups. morphVQ can capture shape in an automated fashion while avoiding the limitations of manually digitized landmarks, and thus represents a novel and computationally efficient addition to the geometric morphometrics toolkit.

Characterizing and Predicting nvPM Size Distributions for Aviation Emission Inventories and Environmental Impact.

Concerns about civil aviation's air quality and environmental impacts have led to recent regulations on nonvolatile particulate matter (nvPM) mass and number emissions. Although these regulations do not mandate measuring particle size distribution (PSD), understanding PSDs is vital for assessing the environmental impacts of aviation nvPM. This study introduces a comprehensive data set detailing PSD characteristics of 42 engines across 19 turbofan types, ranging from unregulated small business jets to regulated large commercial aircraft. Emission tests were independently performed by using the European and Swiss reference nvPM sampling and measurement systems with parallel PSD measurements. The geometric mean diameter (GMD) at the engine exit strongly correlated with the nvPM number-to-mass ratio (N/M) and thrust, varying from 7 to 52 nm. The engine-exit geometric standard deviation ranged from 1.7 to 2.5 (mean of 2.05). The study proposes empirical correlations to predict GMD from N/M data of emissions-certified engines. These predictions are expected to be effective for conventional rich-burn engines and might be extended to novel combustor technologies if additional data become available. The findings support the refinement of emission models and help in assessing the aviation non-CO2 climate and air quality impacts.

Cardiogenic shock in pregnancy.

Cardiac disease complicates 1%-4% of pregnancies globally, with a predominance in low and middle-income countries (LMICs). Increasing maternal age, rates of obesity, cardiovascular comorbidities, pre-eclampsia and gestational diabetes all contribute to acquired cardiovascular disease in pregnancy. Additionally, improved survival in congenital heart disease (CHD) has led to increasing numbers of women with CHD undergoing pregnancy. Implementation of individualised care plans formulated through pre-conception counselling and based on national and international guidance have contributed to improved clinical outcomes. However, there remains a significant proportion of women of reproductive age with no apparent comorbidities or risk factors that develop heart disease during pregnancy, with no indication for pre-conception counselling. The most extreme manifestation of cardiac disease is cardiogenic shock (CS), where the primary cardiac pathology results in inadequate cardiac output and hypoperfusion, and is associated with significant mortality and morbidity. Key to management is early recognition, intervention to treat any potentially reversible underlying pathology and supportive measures, up to and including mechanical circulatory support (MCS). In this narrative review we discuss recent developments in the classification of CS, and how these may be adapted to improve outcomes of pregnant women with, or at risk of developing, this potentially lethal condition.

Differences in Factors Associated With Preterm and Term Stillbirth: A Secondary Cohort Analysis of the DESiGN Trial.

OBJECTIVE: To identify whether maternal and pregnancy characteristics associated with stillbirth differ between preterm and term stillbirth. DESIGN: Secondary cohort analysis of the DESiGN RCT. SETTING: Thirteen UK maternity units. POPULATION: Singleton pregnant women and their babies. METHODS: Multiple logistic regression was used to assess whether the 12 factors explored were associated with stillbirth. Interaction tests assessed for a difference in these associations between the preterm and term periods. MAIN OUTCOME MEASURE: Stillbirth stratified by preterm (<37+0 weeks') and term (37+0-42+6 weeks') births. RESULTS: A total of 195 344 pregnancies were included. Six hundred and sixty-seven were stillborn (3.4 per 1000 births), of which 431 (65%) were preterm. Significant interactions were observed for maternal age, ethnicity, IMD, BMI, parity, smoking, PAPP-A, gestational hypertension, pre-eclampsia and gestational diabetes but not for chronic hypertension and pre-existing diabetes. Stronger associations with term stillbirth were observed in women with obesity compared to BMI 18.5-24.9 kg/m2 (BMI 30.0-34.9 kg/m2 term adjusted OR 2.1 [95% CI 1.4-3.0] vs. preterm aOR 1.1 [0.8-1.7]; BMI ≥ 35.0 kg/m2 term aOR 2.2 [1.4-3.4] vs. preterm aOR 1.5 [1.2-1.8]; p-interaction < 0.01), nulliparity compared to parity 1 (term aOR 1.7 [1.1-2.7] vs. preterm aOR 1.2 [0.9-1.6]; p-interaction < 0.01) and Asian ethnicity compared with White (p-interaction < 0.01). A weaker or lack of association with term, compared to preterm, stillbirth was observed for older maternal age, smoking and pre-eclampsia. CONCLUSION: Differences in association exist between mothers experiencing preterm and term stillbirth. These differences could contribute to design of timely surveillance and interventions to further mitigate the risk of stillbirth.

Twenty-four-month effortful control predicts emerging autism characteristics.

Longitudinal research can assess how diverging development of multiple cognitive skills during infancy, as well as familial background, are related to the emergence of neurodevelopmental conditions. Sensorimotor and effortful control difficulties are seen in infants later diagnosed with autism; this study explored the relationships between these skills and autism characteristics in 340 infants (240 with elevated familial autism likelihood) assessed at 4-7, 8-10, 12-15, 24, and 36 months. We tested: (1) the relationship between parent-reported effortful control (Rothbart's temperament questionnaires) and sensorimotor skills (Mullen Scales of Early Learning), using random intercept cross-lagged panel modelling; (2) whether household income and maternal education predicted stable individual differences in cognition; (3) sensorimotor and effortful control skills as individual and interactive predictors of parent-reported autism characteristics (Social Responsiveness Scale) at 3 years, using multiple regression; and (4) moderation of interactions by familial likelihood. Sensorimotor skills were longitudinally associated with effortful control at the subsequent measurement point from 12-15 months. Socioeconomic status indicators did not predict stable between-infant differences in sensorimotor or effortful control skills. Effortful control skills were longitudinally related to 3-year autism characteristics from the first year of life, with evidence for an interaction with sensorimotor skills at 24 months. Effects of effortful control increased with age and were particularly important for infants with family histories of autism. Results are discussed in relation to different theoretical frameworks: Developmental Cascades and Anterior Modifiers in the Emergence of Neurodevelopmental Disorders. We suggest a role for 24-month effortful control in explaining the emergent autism phenotype. RESEARCH HIGHLIGHTS: Sensorimotor skills longitudinally predicted effortful control from 12-15 months onward but effortful control did not longitudinally predict sensorimotor skills during infancy. Measures of effortful control skills taken before the age of 1 predicted continuous variation in autism characteristics at 36 months, with associations increasing in strength with age. Effortful control (measured at 12-15 and 24 months) was a stronger predictor of 36-month autism characteristics in infants with elevated familial likelihood for autism. The relationship between 24-month sensorimotor skills and 36-month autism characteristics was stronger in infants with weaker effortful control skills.