A dynamic, spatially periodic, micro-pattern of HES5 underlies neurogenesis in the mouse spinal cord.

Ultradian oscillations of HES Transcription Factors (TFs) at the single-cell level enable cell state transitions. However, the tissue-level organisation of HES5 dynamics in neurogenesis is unknown. Here, we analyse the expression of HES5 ex vivo in the developing mouse ventral spinal cord and identify microclusters of 4-6 cells with positively correlated HES5 level and ultradian dynamics. These microclusters are spatially periodic along the dorsoventral axis and temporally dynamic, alternating between high and low expression with a supra-ultradian persistence time. We show that Notch signalling is required for temporal dynamics but not the spatial periodicity of HES5. Few Neurogenin 2 cells are observed per cluster, irrespective of high or low state, suggesting that the microcluster organisation of HES5 enables the stable selection of differentiating cells. Computational modelling predicts that different cell coupling strengths underlie the HES5 spatial patterns and rate of differentiation, which is consistent with comparison between the motoneuron and interneuron progenitor domains. Our work shows a previously unrecognised spatiotemporal organisation of neurogenesis, emergent at the tissue level from the synthesis of single-cell dynamics.

Cardiovascular and Mortality Risks in Migrant South Asians with Type 2 Diabetes: Are We Winning the Battle?

PURPOSE OF REVIEW: We seek to describe the relationship between diabetes mellitus and cardiovascular risk in migrant South Asians compared to native white Europeans, and to determine the temporal change in this relationship over recent years. RECENT FINDINGS: Recent evidence suggests that the excess mortality risk associated with diabetes is lower in the migrant South Asian population compared with white Europeans. By contrast, South Asians continue to demonstrate elevated cardiovascular morbidity compared to white Europeans, although to a lesser extent than was observed in previous decades. The excess mortality previously observed in South Asian migrants has attenuated with a lower mortality risk compared to white Europeans observed in several recent studies. We speculate that these findings may relate in part to earlier diabetes diagnosis and more prolonged exposure to cardiovascular risk factor management in the South Asian population. Further study is required to confirm these hypotheses.

Characteristics of tuberculosis cases that started outbreaks in the United States, 2002-2011.

A review of 26 tuberculosis outbreaks in the United States (2002-2011) showed that initial source case-patients had long infectious periods (median 10 months) and were characterized by substance abuse, incarceration, and homelessness. Improved timeliness of diagnosis and thorough contact investigations for such cases may reduce the risk for outbreaks.

Neonatal herpes simplex presenting as a zosteriform eruption.

Herpes simplex virus (HSV) infection in newborn infants is a potentially devastating disease leading to death and disability. Skin, eye and mouth (SEM) infections account for approximately half of the cases in the USA. The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection, prompt interventions and life-saving management; however, less than half of neonates with proven disease present with characteristic vesicular lesions. Furthermore, if SEM infections are not treated promptly, there is significant risk of progression to central nervous system and disseminated disease. We present a case of HSV-2 infection in a neonate with an atypical zosteriform eruption on day 3 of life. This case demonstrates that neonatal HSV can unusually present in a zosteriform rash. By elucidating this unique presentation, we highlight atypical HSV skin presentation and emphasise on the importance of earlier diagnosis and antiviral treatment to prevent the associated morbidity and mortality.

Chronic postsurgical pain in children and young adults with cancer and choice of regional anesthesia for amputation and limb-sparing surgery.

BACKGROUND: Patients undergoing limb amputation (LA) or limb-sparing (LS) for lower extremity oncologic diagnoses are at similar risk for chronic postsurgical pain of neuropathic nature (CPSP/NP). Regional anesthesia (RA) techniques are pre-emptive measures to prevent the occurrence of the CPS/NP. However, recommendations for epidural (EP) versus peripheral nerve blocks (PNBs) lack in pediatric literature. AIMS: This study investigates the incidence and duration of CPSP/NP and describes NP-directed regimens. METHODS AND RESULTS: Data on demographics, use of EP or PNB, duration of CPSP/NP, and NP-directed medication were retrospectively collected for LA and LS between 2009 and 2019. Mixed effects logistic regression was used to compare the odds of CPSP/NP between EP and PNB. Cox PH model with adjustment for clustering due to multiple surgeries on patients was used to quantify rate of pain relief between surgery groups (LA vs. LS) and RA groups (EP vs. PNB). The incidence of CPSP/NP was 36 (23.8%) after 165 surgeries (150 patients). The odds of CPSP/NP after PNB were 2.5 times those of CPSP/NP after EP (p = .11). The rate of pain relief at any instant after the EP was 1.2 times that after PNB (p = .3). The rate of pain relief for LS with EP was 1.9 times that of pain relief for LA with EP, a statistically significant difference (p = .03). Gabapentin was used (94.5%), with addition of amitriptyline (24.2%) and both amitriptyline and methadone (12.7%). CONCLUSION: The LS with the EP group had a significantly higher rate of relief of CPSP/NP than LA with EP. Odds of CPSP/NP after PNB were 2.5 times those of CPSP after EP.

A novel and robust method for counting components within bio-molecular complexes using fluorescence microscopy and statistical modelling.

Cellular biology occurs through myriad interactions between diverse molecular components, many of which assemble in to specific complexes. Various techniques can provide a qualitative survey of which components are found in a given complex. However, quantitative analysis of the absolute number of molecules within a complex (known as stoichiometry) remains challenging. Here we provide a novel method that combines fluorescence microscopy and statistical modelling to derive accurate molecular counts. We have devised a system in which batches of a given biomolecule are differentially labelled with spectrally distinct fluorescent dyes (label A or B), and mixed such that B-labelled molecules are vastly outnumbered by those with label A. Complexes, containing this component, are then simply scored as either being positive or negative for label B. The frequency of positive complexes is directly related to the stoichiometry of interaction and molecular counts can be inferred by statistical modelling. We demonstrate this method using complexes of Adenovirus particles and monoclonal antibodies, achieving counts that are in excellent agreement with previous estimates. Beyond virology, this approach is readily transferable to other experimental systems and, therefore, provides a powerful tool for quantitative molecular biology.

High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study.

STUDY OBJECTIVES: To determine the prevalence of obstructive sleep apnea (OSA) in a cohort of women with class III obesity, and a comparator lean group, in the second and third trimesters of pregnancy. Secondary objectives were to compare characteristics of women with obesity with and without OSA and to assess factors that were predictive of OSA. METHODS: We performed a prospective cohort study involving 33 women with class III obesity (mean body mass index 43.5 ± 3.9 kg/m2) and 39 lean women (body mass index 22.0 ± 1.7 kg/m2) with singleton pregnancies. Participants completed 2 level 3 sleep studies between 12-22 weeks and 32-38 weeks gestation. OSA was defined as a respiratory event index ≥ 5 events/h (≥ 3% desaturation criteria). Levels of interleukin-6, glucose, and C-peptide were quantified in maternal blood. Logistic regression analysis was performed to determine predictors of OSA. RESULTS: OSA was identified in 12 (37.5%) and 14 (50.0%) women with obesity and in 1 (2.6%) and 3 (9.1%) lean women in the second and third trimesters, respectively. Women with obesity with OSA were older than those with no OSA but otherwise had similar characteristics. In unadjusted analysis of women with obesity, increased age, body mass index, homeostatic model assessment of insulin resistance, and history of nonsmoking were associated with increased odds of OSA. In multivariable analysis, only increased age remained significantly associated with OSA. CONCLUSIONS: OSA is highly prevalent in pregnant women with class III obesity. Further research is required to establish effective management strategies for the growing number of women in this high-risk group. CITATION: Johns EC, Hill EA, Williams S, et al. High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study. J Clin Sleep Med. 2022;18(2):423-432.

Gene expression profiling of placentae from women with obesity and obstructive sleep apnoea.

INTRODUCTION: Obstructive sleep apnoea (OSA), a condition characterised by intermittent hypoxia and reoxygenation during sleep, is associated with an increased risk of adverse pregnancy outcomes including gestational diabetes and hypertensive disorders of pregnancy. The biological mechanisms of these associations are poorly understood. The impact of OSA on placental function has not been well characterised. METHODS: We performed 3' mRNA sequencing on placenta from women with obesity and OSA (n = 11) and women with obesity and no OSA (n = 9). RESULTS: After correcting for multiple testing, there were no statistically significant differences in gene expression between OSA and no OSA groups (adjusted p < 0.05). In unadjusted analyses, 101 genes were differentially expressed in OSA compared to no OSA placentae (p < 0.01). In Reactome pathway and GO term analysis, this included downregulation of genes involved in O-linked glycosylation (B3GNT5 and B3GNT8) and Wnt signalling (TRABD2B and FRZB) pathways. In gene set enrichment analysis, genes within 24 pathways had a non-random distribution in OSA compared to no OSA placentae (adjusted p < 0.05). This included an increase in genes relating to the reversible hydration of carbon dioxide in OSA placentae, a potential novel mechanism contributing to the development of adverse pregnancy outcomes in women with OSA. DISCUSSION: There is overall similarity in the placental transcriptome of women with obesity who do and do not have OSA during pregnancy. Alterations in the reversible hydration of carbon dioxide are a potential mechanism contributing to the development of adverse pregnancy outcomes in maternal OSA, however this finding requires validation in larger cohorts.

First and second pregnancy outcomes in women with class III obesity: An observational cohort study.

INTRODUCTION: Class III obesity (BMI ≥ 40 kg/m2) during pregnancy predisposes mother and offspring to a range of adverse pregnancy complications and outcomes. Risk profiles vary between pregnancies and are affected by interpregnancy weight gain. We evaluated the risk of adverse outcomes in women with BMI ≥ 40 kg/m2 in first and second pregnancies, and the impact of interpregnancy weight change on this risk. MATERIALS AND METHODS: Data were extracted for all women with BMI ≥ 40 kg/m2 at first antenatal visit, who completed antenatal and delivery care for first and second pregnancies in NHS Lothian between 1/1/2009-31/12/2018. Multiple pregnancies and recipients of bariatric surgery were excluded. RESULTS: 442 pregnancies among 221 women were included. In first pregnancy, median (interquartile range) weight was 117 kg (108.5-126.7), age 28 years (24-31) and BMI 42 kg/m2 (41.0-44.5), 14.4% had gestational diabetes (GDM), 11.3% had pregnancy-induced hypertension and 44.6% had a post-partum haemorrhage (PPH). 20.8% of babies were large for gestational age (LGA, ≥97% centile at birth). In second pregnancy, women were heavier with a median weight of 119.9 kg (109.0-130.0, p = 0.00) with 19.9% gaining over 10 kg. Women were more likely to develop GDM (21.6%, p = 0.02). Babies were heavier with 40% of babies LGA (p < 0.0001). Interpregnancy weight change had no significant impact on GDM, pregnancy induced hypertension, PPH, perinatal mortality or LGA. CONCLUSIONS: In a population of women with BMI ≥ 40 kg/m2, pregnancy complications are common and risk is higher in second pregnancy. The interpregnancy period is a critical time to engage women in health improvement and weight loss strategies to maximise outcomes for mother and offspring.

Force networks, torque balance and Airy stress in the planar vertex model of a confluent epithelium.

The vertex model is a popular framework for modelling tightly packed biological cells, such as confluent epithelia. Cells are described by convex polygons tiling the plane and their equilibrium is found by minimizing a global mechanical energy, with vertex locations treated as degrees of freedom. Drawing on analogies with granular materials, we describe the force network for a localized monolayer and derive the corresponding discrete Airy stress function, expressed for each N-sided cell as N scalars defined over kites covering the cell. We show how a torque balance (commonly overlooked in implementations of the vertex model) requires each internal vertex to lie at the orthocentre of the triangle formed by neighbouring edge centroids. Torque balance also places a geometric constraint on the stress in the neighbourhood of cellular trijunctions, and requires cell edges to be orthogonal to the links of a dual network that connect neighbouring cell centres and thereby triangulate the monolayer. We show how the Airy stress function depends on cell shape when a standard energy functional is adopted, and discuss implications for computational implementations of the model.

The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism.

Maternal obesity is the most common metabolic disturbance in pregnancy affecting >1 in 5 women in some countries. Babies born to obese women are heavier with more adiposity at birth, and are vulnerable to obesity and metabolic disease across the lifespan suggesting offspring health is 'programmed' by fetal exposure to an obese intra-uterine environment. The placenta plays a major role in dictating the impact of maternal health on prenatal development. Maternal obesity impacts the function of integral placental receptors and transporters for glucocorticoids and nutrients, key drivers of fetal growth, though mechanisms remain poorly understood. This review aims to summarise current knowledge in this area, and considers the impact of obesity on the epigenetic machinery of the placenta at this vital juncture in offspring development. Further research is required to advance understanding of these areas in the hope that the trans-generational cycle of obesity can be alleviated.

Sleep disordered breathing in pregnancy: A review of the pathophysiology of adverse pregnancy outcomes.

Sleep disordered breathing (SDB) is a common obesity-related co-morbidity with strong associations to cardiometabolic disease. The risk of SDB is increased during pregnancy, particularly among obese pregnant women. Accumulating evidence suggests that an association exists between maternal SDB and the development of adverse pregnancy outcomes, particularly gestational diabetes and hypertensive disorders of pregnancy. Intermittent hypoxia, a central characteristic of SDB, has been shown in animal and clinical studies to dysregulate several biological pathways. This includes the promotion of oxidative stress, increased inflammation, activation of the hypothalamic-pituitary-adrenal axis, increased sympathetic activity and impaired glucose and insulin metabolism. This review considers how, during pregnancy, these pathophysiological processes are plausible mechanisms through which SDB may contribute to an increased risk of adverse outcomes, for the mother and perhaps also the offspring. However, a lack of robust evidence specific to the pregnant population, including limited evaluation of the placental function in affected pregnancies, limits our ability to draw definite conclusions on mechanisms contributing to adverse pregnancy outcomes and, indeed, the strength of association between SDB and certain pregnancy complications.

Mechanical characterization of disordered and anisotropic cellular monolayers.

We consider a cellular monolayer, described using a vertex-based model, for which cells form a spatially disordered array of convex polygons that tile the plane. Equilibrium cell configurations are assumed to minimize a global energy defined in terms of cell areas and perimeters; energy is dissipated via dynamic area and length changes, as well as cell neighbor exchanges. The model captures our observations of an epithelium from a Xenopus embryo showing that uniaxial stretching induces spatial ordering, with cells under net tension (compression) tending to align with (against) the direction of stretch, but with the stress remaining heterogeneous at the single-cell level. We use the vertex model to derive the linearized relation between tissue-level stress, strain, and strain rate about a deformed base state, which can be used to characterize the tissue's anisotropic mechanical properties; expressions for viscoelastic tissue moduli are given as direct sums over cells. When the base state is isotropic, the model predicts that tissue properties can be tuned to a regime with high elastic shear resistance but low resistance to area changes, or vice versa.

Gestational Diabetes Mellitus: Mechanisms, Treatment, and Complications.

Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy. The prevalence is rising and correlates with the increase in maternal obesity over recent decades. The etiology of GDM is complex, with genetic and environmental factors implicated in mechanistic and epidemiological studies. GDM begets important short- and long-term health risks for the mother, developing fetus, and offspring. This includes the high likelihood of subsequent maternal type 2 diabetes (T2DM), and possible adverse cardiometabolic phenotypes in the offspring. The most clinically and cost-effective methods of screening for GDM remain uncertain. Whilst treatments with lifestyle and pharmacological interventions have demonstrated short-term benefits, the long-term impact for the offspring of intrauterine exposure to antidiabetic medication remains unclear.

Early screening and treatment of gestational diabetes in high-risk women improves maternal and neonatal outcomes: A retrospective clinical audit.

AIMS: Evidence suggests that screening for gestational diabetes (GDM) occurs too late in pregnancy, when changes in glucose metabolism and fetal growth rates can already be detected. In August 2016 NHS Lothian began screening women with risk factors for GDM during early pregnancy (11-13 weeks). We hypothesised that an earlier identification and treatment of dysglycaemia would improve pregnancy outcomes compared to previous standard care. METHODS: We compared management and outcomes for singleton pregnancies with GDM delivering at Royal Infirmary Edinburgh, UK, diagnosed through routine or early screening from 01/01/2015-31/10/2017 (routine screening n = 335, early screening n = 241). RESULTS: Early screening increased the proportion of women diagnosed before 24 weeks' gestation (n = 59/335, 17.6% vs n = 103/241, 42.7%, p < 0.001) but did not change the average monthly rate of diagnosis. Early screening increased the median duration of GDM during pregnancy (71 vs 93 days of gestation, p < 0.001) with no significant changes in the pharmacological management. Early screening improved the primary composite outcome (emergency caesarean section, neonatal hypoglycaemia and macrosomia; n = 138/335, 41.2% vs n = 73/241, 30.3%, adjusted Odds Ratio [95% confidence interval] 0.62 [0.43-0.91]. CONCLUSIONS: There is a role for early screening and management of GDM however it is unclear whether this represents a cost-effective intervention.

Abnormalities of sympathetic and parasympathetic autonomic function in subjects with defaecation syncope.

UNLABELLED: Defaecation syncope is defined as blacking out at, or around, the time of defaecation. It is associated with increased mortality; however, patients rarely voluntarily report symptoms. We have examined autonomic function in a cohort of patients with defaecation syncope. METHODS: We prospectively identified all subjects referred to our unit with symptoms of defaecation syncope or presyncope on direct questioning. All subjects had autonomic function tests using beat to beat blood pressure measurement synchronized with R-R interval allowing real time assessment of autonomic function. RESULTS: Seven patients were identified who presented with defaecation syncope. Compared with age and sex matched controls, subjects had abnormalities of both sympathetic and parasympathetic autonomic function consistent with mild-moderate autonomic failure. On specific intervention syncope stopped in all subjects: 3 had culprit medication withdrawn, 3 received medication to increase blood pressure and 1 in whom cardioinhibition was demonstrated improved with permanent pacemaker insertion. Two subjects who had colonoscopy had profound haemodynamic changes during the procedure associated with syncope. CONCLUSIONS: Symptoms of syncope on defaecation are associated with autonomic failure. With appropriate therapeutic intervention our subjects all improved.