A comparison of excess deaths by UK country and region during the first year of the COVID-19 pandemic.

We compare the impact of the first two waves of the COVID-19 pandemic on risk of age-standardized mortality by sex, UK country, and English region. Each wave is defined as lasting 26 weeks and are consecutive beginning in 2020 week 11. The expected rate is estimated from 2015 to 2019 mean and the projected mortality trend from the same period are used to estimate excess mortality. By both measures, excess mortality was highest and lowest in regions of England, London and the South-West, respectively. Excess mortality was consistently higher for males than females.

Should Familial Hypercholesterolaemia Be Included in the UK Newborn Whole Genome Sequencing Programme?

PURPOSE OF REVIEW: The UK National Health Service (NHS) has recently announced a Newborn Genomes Programme (NGP) to identify infants with treatable inherited disorders using whole genome sequencing (WGS). Here, we address, for familial hypercholesterolaemia (FH), the four principles that must be met for the inclusion of a disorder in the NGP. RECENT FINDINGS: Principle A: There is strong evidence that the genetic variants causing FH can be reliably detected. Principle B: A high proportion of individuals who carry an FH-causing variant are likely to develop early heart disease if left undiagnosed and not offered appropriate treatment. Principle C: Early intervention has been shown to lead to substantially improved outcomes in children with FH. Principle D: The recommended interventions are equitably accessible for all. FH meets all the Wilson and Jungner criteria for inclusion in a screening programme, and it also meets all four principles and therefore should be included in the Newborn Genomes Programme.

Type 1 diabetes in North East England and North Cumbria: patterns and time trends in 0-14-year-olds from 2012 to 2020.

Introduction: It is important to understand patterns in the epidemiology of type 1 diabetes because they may provide insight into its etiology. We examined the incidence of type 1 diabetes in children aged 0-14 years, and patient demographics and clinical parameters at presentation, over the period 2012-2020 using the North East and North Cumbria Young Persons diabetes register. Methods: Patients up to the age of 14 years with type 1 diabetes, and their families- managed in a total of 18 young persons diabetes clinics-were approached in person at the time of clinic appointments or in the days following diagnosis and they consented to their data being included in the register. Data were submitted regionally to a central unit. Descriptive statistics including crude and age-specific incidence rates were calculated. Temporal trends were analyzed using Joinpoint regression. Comparisons in incidence rates were made between age, sex and areas of higher and lower affluence as measured by the Index of Multiple Deprivation (IMD). Results: A total of 943 cases were recorded between January 2012 and December 2020. Median age at diagnosis was 8.8 years (Q1: 5.3, Q3: 11.7). There were more males than females (54% male). The median HbA1c at diagnosis was 100 mmoL/L (IQR: 39) and over one third (35%) were in ketoacidosis (pH < 7.3). Crude incidence decreased from 25.5 (95% confidence interval [CI] 20.9, 29.9) in 2012 to 16.6 (95% CI: 13.0, 20.2) per 100,000 in 2020 (5.1% per annum, 95% CI 1.1, 8.8%). During the period of the study there was no evidence of any trends in median age, HbA1c, BMI or birthweight (p = 0.18, 0.80, 0.69, 0.32) at diagnosis. Higher rates were observed in males aged 10-14 years, but similar rates were found for both sexes aged 0-9 years and there was no difference between areas of higher or lower deprivation (p = 0.22). Conclusion: The incidence of diabetes in the young may be falling in the North East of England and North Cumbria. The reasons are unclear as there were no associations identified between levels of deprivation or anthropometric measurements. Potential mechanisms include alterations in socioeconomic background or growth pattern. Further research is needed to understand the reasons behind this finding.

Context-dependent regulation of feeding behaviour by the insulin receptor, DAF-2, in Caenorhabditis elegans.

Insulin signalling plays a significant role in both developmental programmes and pathways modulating the neuronal signalling that controls adult behaviour. Here, we have investigated insulin signalling in food-associated behaviour in adult C. elegans by scoring locomotion and feeding on and off bacteria, the worm's food. This analysis used mutants (daf-2, daf-18) of the insulin signalling pathway, and we provide evidence for an acute role for insulin signalling in the adult nervous system distinct from its impact on developmental programmes. Insulin receptor daf-2 mutants move slower than wild type both on and off food and showed impaired locomotory responses to food deprivation. This latter behaviour is manifest as a failure to instigate dispersal following prolonged food deprivation and suggests a role for insulin signalling in this adaptive response. Insulin receptor daf-2 mutants are also deficient in pharyngeal pumping on food and off food. Pharmacological analysis showed the pharynx of daf-2 is selectively compromised in its response to 5-HT compared to the excitatory neuropeptide FLP-17. By comparing the adaptive pharyngeal behaviour in intact worms and isolated pharyngeal preparations, we determined that an insulin-dependent signal extrinsic to the pharyngeal system is involved in feeding adaptation. Hence, we suggest that reactive insulin signalling modulates both locomotory foraging and pharyngeal pumping as the animal adapts to the absence of food. We discuss this in the context of insulin signalling directing a shift in the sensitivity of neurotransmitter systems to regulate the worm's response to changes in food availability in the environment.

"Sandal strap" trauma and atherosclerosis are dual pathologies leading to bilateral true aneurysms of the dorsalis pedis arteries.

True aneurysm of the dorsalis pedis artery is rare. To our best knowledge, only 19 cases have been reported in the literature with one case of bilateral involvement. We describe an unusual case of simultaneous, bilateral true aneurysms of the dorsalis pedis arteries due to chronic mild trauma from dorsally positioned sandal straps with secondary atherosclerotic change. This is the first such case reported. Symptomatic aneurysms are at risk for thrombosis or embolization, and surgical management is recommended. In our case, both aneurysms were resected and repaired with interposition graft of saphenous vein. The patient was symptom free at 6-month follow-up.

SLO, SLO, quick, quick, slow: calcium-activated potassium channels as regulators of Caenorhabditis elegans behaviour and targets for anthelmintics.

Large-conductance calcium and voltage-activated potassium channels, termed SLO-1 (or BK), are pivotal players in the regulation of cell excitability across the animal phyla. Furthermore, emerging evidence indicates that these channels are key mediators of a number of neuroactive drugs, including the most recent new anthelmintic, the cyclo-octadepsipeptide emodepside. Detailed reviews of the structure, function and pharmacology of BK channels have recently been provided (Salkoff et al. in Nat Rev Neurosci 7:921-931, 2006; Ghatta et al. in Pharmacol Ther 110:103-116, 2006) and therefore these aspects will only briefly be covered here. The purpose of this review is to discuss how SLO-1 channels might function as regulators of neural transmission and network activity. In particular, we focus on the role of SLO-1 in the regulation of Caenorhabditis elegans behaviour and highlight the role of this channel as an effector for pleiotropic actions of neuroactive drugs, including emodepside. On the premise that C. elegans is a 'model nematode' with respect to many aspects of neural function, the intention is that this might inform a broader understanding of the role of these channels in the nematodes and their potential as novel anthelmintic targets.

Suppression of menstruation in adolescents with severe learning disabilities.

As girls with severe cognitive developmental delay progress into puberty and become young women with learning disabilities, concerns about menstruation are common amongst carers and health care professionals are often consulted for advice. Very little, however, has been published on this area to guide the practitioner and studies are almost exclusively confined to the gynaecological literature. We aim to give an account of the various therapeutic options available and current practice within the paediatric endocrinology unit at our institution.

The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans.

The cyclo-octadepsipeptide anthelmintic, emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug's actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of emodepside on the pharynx it remains sensitive to the inhibitory effects of emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of emodepside on locomotion. Therefore, emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca(2+)-activated K(+) channel. These mutants were highly resistant to the inhibitory effect of emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of emodepside, but are not themselves emodepside hypersensitive, favours a model whereby emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of emodepside and suggest that emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion.

Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.

CONTEXT: T(3) action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T(3) uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T(3) levels. OBJECTIVE: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3). DESIGN: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T(3) uptake, 2) T(3) metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. RESULTS: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. CONCLUSION: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.

Transporting newborn infants with suspected duct dependent congenital heart disease on low-dose prostaglandin E1 without routine mechanical ventilation.

AIM: To evaluate the safety of transporting newborn infants with suspected duct dependent congenital heart disease (CHD) treated with prostaglandin E1 (PGE1) without routine mechanical ventilation. METHODS: A retrospective population-based audit of newborn infants with suspected CHD transported on PGE1 by the New South Wales newborn and paediatric Transport Service from 1995 through 2005. RESULTS: Mechanical ventilation was not used prior to treatment with PGE1 in 94 (31%) of the 300 infants. The indications for mechanical ventilation in the remaining 206 infants (69%) included elective mechanical ventilation because of the intention to use PGE1 (n = 125) and severe hypoxaemia, acidosis or cardiorespiratory failure prior to commencing PGE1 (n = 81). 16 (17%) of the 94 infants who were not ventilated initially required mechanical ventilation before transport because of apnoea, which developed within one hour of commencing PGE1. 2 (2.6%) of the 78 infants transported without mechanical ventilation developed apnoea in transit and both were receiving >or=15 ng/kg/min of PGE1. Apnoea was more likely to occur in non-ventilated infants when the PGE1 infusion rate was >or=15 ng/kg/min compared with <15 ng/kg/min (14/33 vs 4/61, chi(2) = 15.55, p<.001). CONCLUSIONS: Newborn infants with suspected duct dependent CHD treated with low dose PGE1 (<15 ng/kg/min) may not require mechanical ventilation for safe transport.

Effects of the novel anthelmintic emodepside on the locomotion, egg-laying behaviour and development of Caenorhabditis elegans.

Emodepside, a cyclooctadepsipeptide, is a broad-spectrum anthelmintic previously shown to paralyse body wall muscle and pharyngeal muscle in the model nematode Caenorhabditis elegans. We demonstrate that wild-type C. elegans L4 are less sensitive than adults to emodepside in two independent assays of locomotor behaviour: body bend generation on agar (adult IC(50) 3.7 nM, L4 IC(50) 13.4 nM) and thrashing behaviour in liquid (thrashing behaviour as a % of controls after 1h in 10 microM emodepside: adults 16%, L4 worms 48%). We also show that continuous exposure of wild-type C. elegans to emodepside throughout the life-cycle from egg onwards, slows worm development, an effect that is emodepside concentration-dependent. The rate of worm-hatching from eggs on agar plates containing emodepside was not significantly different from controls, suggesting that it is development post-hatching rather than hatching itself that is affected by the drug. Emodepside also inhibits wild-type C. elegans egg-laying, with acute exposure to the drug at 500 nM resulting in an almost total inhibition within the first hour. However, the rate of egg production was not inhibited and therefore emodepside-treated worms became bloated with eggs, eventually rupturing. This suggests that the effect of emodepside on reproduction is not due to an inhibition of egg production but rather a paralytic effect on the egg-laying muscles. These results, when coupled with previous research, suggest that emodepside interferes with signalling at the neuromuscular junction on the body-wall muscles (Willson et al., 2003), pharynx (Willson et al., 2004) and egg-laying muscles and thus inhibits three important physiological functions: locomotion, feeding and reproduction.

The pre-operative endocrine assessment of craniopharyngiomas.

Pre-operative endocrinopathies are common in patients presenting with craniopharyngiomas. Clinical features may not be obvious and careful pre-operative endocrine assessment is essential. Failure to recognise and address pre-operative diabetes insipidus and secondary hypoadrenalism is potentially fatal. We review the available published data on pre-operative endocrine dysfunction and suggest an approach to assessment and management before surgery.

Diabetes insipidus in craniopharyngioma: postoperative management of water and electrolyte disorders.

Pre-operative central diabetes insipidus has been reported in 8-35% of patients affected with craniopharyngioma, and in 70-90% after surgery. The management of postoperative polyuria and polydipsia can be challenging and fluid balance needs to be closely monitored. The classical triphasic pattern of endogenous vasopressin secretion--an initial phase of symptomatic diabetes insipidus occurring 24 hours after surgery; a second phase of inappropriate vasopressin secretion potentially causing hyponatraemia; and a third phase with a return to diabetes insipidus occurring up to 2 weeks later--is often complicated by cerebral salt wasting and thirst disorders. Inadequate adrenal replacement therapy and anticonvulsant agent treatment may increase the risk of life-threatening hyponatraemia in the course of desmopressin (DDAVP) treatment. Appropriate management, in order to avoid life-threatening or disabling electrolyte disturbances, requires a good grasp of the relevant pathophysiology. We review here the pathophysiology and management of the multiple fluid disorders encountered following surgery for craniopharyngiomas.

The adaptor protein soc-1/Gab1 modifies growth factor receptor output in Caenorhabditis elegans.

Previous genetic analysis has shown that dos/soc-1/Gab1 functions positively in receptor tyrosine kinase (RTK)-stimulated Ras/Map kinase signaling through the recruitment of csw/ptp-2/Shp2. Using sensitized assays in Caenorhabditis elegans for let-23/Egfr and daf-2/InsR (insulin receptor-like) signaling, it is shown that soc-1/Gab1 inhibits phospholipase C-gamma (PLCgamma) and phosphatidylinositol 3'-kinase (PI3K)-mediated signaling. Furthermore, as well as stimulating Ras/Map kinase signaling, soc-1/Gab1 stimulates a poorly defined signaling pathway that represses class 2 daf-2 phenotypes. In addition, it is shown that SOC-1 binds the C-terminal SH3 domain of SEM-5. This binding is likely to be functional as the sem-5(n2195)G201R mutation, which disrupts SOC-1 binding, behaves in a qualitatively similar manner to a soc-1 null allele in all assays for let-23/Egfr and daf-2/InsR signaling that were examined. Further genetic analysis suggests that ptp-2/Shp2 mediates the negative function of soc-1/Gab1 in PI3K-mediated signaling, as well as the positive function in Ras/Map kinase signaling. Other effectors of soc-1/Gab1 are likely to inhibit PLCgamma-mediated signaling and stimulate the poorly defined signaling pathway that represses class 2 daf-2 phenotypes. Thus, the recruitment of soc-1/Gab1, and its effectors, into the RTK-signaling complex modifies the cellular response by enhancing Ras/Map kinase signaling while inhibiting PI3K and PLCgamma-mediated signaling.

Influence of socio-economic deprivation on outcomes for patients diagnosed with gastric cancer.

OBJECTIVE: Socio-economic deprivation has an influence on the outcome for patients diagnosed with breast, colorectal and bronchial cancer, but there are few data on its association with gastric cancer. The aim of this study was to determine the influence of socio-economic deprivation on outcomes for patients with gastric cancer. MATERIAL AND METHODS: Three hundred and thirty consecutive patients with gastric adenocarcinoma presenting to a single hospital between 1 October 1995 and 30 June 2004 were studied prospectively and deprivation scores calculated using the National Assembly for Wales Indices of Multiple Deprivation. The patients were subdivided into quintiles for analysis. RESULTS: Inhabitants of the most deprived areas (quintile 5) were younger at presentation (median 70 years versus 74 years, p=0.007), and experienced longer delays in diagnosis (18 weeks versus 9 weeks, p=0.02) when compared with patients from the least deprived areas (quintile 1). Operative mortality was 3-fold higher for patients from the most deprived areas when compared with patients from less deprived areas (15% versus 5%, p=0.03). There was no correlation between stage of disease and socio-economic deprivation. For patients undergoing potentially curative surgery, the 5-year survival for patients from the most deprived areas was 32%, compared with 66% for patients from the least deprived areas (p=0.03). CONCLUSIONS: Socio-economic deprivation was associated with younger age at diagnosis, longer diagnostic delay, greater operative mortality and a shorter duration of survival following R0 gastrectomy. These poorer outcomes were not explained by the stage of disease at diagnosis.

LET-60 RAS modulates effects of insulin/IGF-1 signaling on development and aging in Caenorhabditis elegans.

The DAF-2 insulin/insulin-like growth factor 1 (IGF-1) receptor signals via a phosphatidylinositol 3-kinase (PI3K) pathway to control dauer larva formation and adult longevity in Caenorhabditis elegans. Yet epistasis analysis suggests signal bifurcation downstream of DAF-2. We have used epistasis analysis to test whether the Ras pathway (which plays a role in signaling from mammalian insulin receptors) acts downstream of DAF-2. We find that an activated Ras mutation, let-60(n1046gf), weakly suppresses constitutive dauer diapause in daf-2 and age-1 (PI3K) mutants. Moreover, increased Ras pathway signaling partially suppresses the daf-2 mutant feeding defect, while reduced Ras pathway signaling enhances it. By contrast, activated Ras extends the longevity induced by mutation of daf-2, while reduced Ras pathway signaling partially suppresses it. Thus, Ras pathway signaling appears to act with insulin/IGF-1 signaling during larval development, but against it during aging.

Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans.

In Caenorhabditis elegans, numerous 'synMuv' (synthetic multivulval) genes encode for chromatin-associated proteins involved in transcriptional repression, including an orthologue of Rb and components of the NuRD histone deacetylase complex. These genes antagonize Ras signalling to prevent erroneous adoption of vulval fate. To identify new components of this mechanism, we performed a genome-wide RNA interference (RNAi) screen. After RNAi of 16 757 genes, we found nine new synMuv genes. Based on predicted functions and genetic epistasis experiments, we propose that at least four post-translational modifications converge to inhibit Ras-stimulated vulval development: sumoylation, histone tail deacetylation, methylation, and acetylation. In addition, we demonstrate a novel role for sumoylation in inhibiting LIN-12/Notch signalling in the vulva. We further show that many of the synMuv genes are involved in gene regulation outside the vulva, negatively regulating the expression of the Delta homologue lag-2. As most of the genes identified in this screen are conserved in humans, we suggest that similar interactions may be relevant in mammals for control of Ras and Notch signalling, crosstalk between these pathways, and cell proliferation.