Associations of Amylin with Inflammatory Markers and Metabolic Syndrome in Apparently Healthy Chinese

BACKGROUND: Cellular and animal studies implicate multiple roles of amylin in regulating insulin action, glucose and lipid metabolisms. However, the role of amylin in obesity related metabolic disorders has not been thoroughly investigated in humans. Therefore, we aimed to evaluate the distribution of circulating amylin and its association with metabolic syndrome (MetS) and explore if this association is influenced by obesity, inflammatory markers or insulin resistance in apparently healthy Chinese. METHODS: A population-based sample of 1,011 Chinese men and women aged 35-54 years was employed to measure plasma amylin, inflammatory markers (C-reactive protein [CRP] and interleukin-6 [IL-6]), insulin, glucose and lipid profiles. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. RESULTS: Plasma amylin concentrations were higher in overweight/obese participants than normal-weight counterparts (P<0.001) without sex difference. Circulating amylin was positively associated with CRP, IL-6, BMI, waist circumference, blood pressure, fasting glucose, insulin, amylin/insulin ratio, HOMA-IR, LDL cholesterol and triglycerides, while negatively associated with HDL cholesterol (all P<0.001). After multiple adjustments, the risk of MetS was significantly higher (odds ratio 3.71; 95% confidence interval: 2.53 to 5.46) comparing the highest with the lowest amylin quartile. The association remained significant even further controlling for BMI, inflammatory markers, insulin or HOMA-IR. CONCLUSIONS: Our study suggests that amylin is strongly associated with inflammatory markers and MetS. The amylin-MetS association is independent of established risk factors of MetS, including obesity, inflammatory markers and insulin resistance. The causal role of hyperamylinemia in the development of MetS needs to be confirmed prospectively

Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo-controlled trial

Background: Chronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology. Methods: We performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762. Findings: Participants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group. Interpretation: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology. Funding: National Institute for Health Research

Statistical significance of cis-regulatory modules

BACKGROUND: It is becoming increasingly important for researchers to be able to scan through large genomic regions for transcription factor binding sites or clusters of binding sites forming cis-regulatory modules. Correspondingly, there has been a push to develop algorithms for the rapid detection and assessment of cis-regulatory modules. While various algorithms for this purpose have been introduced, most are not well suited for rapid, genome scale scanning. RESULTS: We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites. CONCLUSION: The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM) and MODSTORM software

The Secret Life of the Anthrax Agent Bacillus anthracis: Bacteriophage-Mediated Ecological Adaptations

Ecological and genetic factors that govern the occurrence and persistence of anthrax reservoirs in the environment are obscure. A central tenet, based on limited and often conflicting studies, has long held that growing or vegetative forms of Bacillus anthracis survive poorly outside the mammalian host and must sporulate to survive in the environment. Here, we present evidence of a more dynamic lifecycle, whereby interactions with bacterial viruses, or bacteriophages, elicit phenotypic alterations in B. anthracis and the emergence of infected derivatives, or lysogens, with dramatically altered survival capabilities. Using both laboratory and environmental B. anthracis strains, we show that lysogeny can block or promote sporulation depending on the phage, induce exopolysaccharide expression and biofilm formation, and enable the long-term colonization of both an artificial soil environment and the intestinal tract of the invertebrate redworm, Eisenia fetida. All of the B. anthracis lysogens existed in a pseudolysogenic-like state in both the soil and worm gut, shedding phages that could in turn infect non-lysogenic B. anthracis recipients and confer survival phenotypes in those environments. Finally, the mechanism behind several phenotypic changes was found to require phage-encoded bacterial sigma factors and the expression of at least one host-encoded protein predicted to be involved in the colonization of invertebrate intestines. The results here demonstrate that during its environmental phase, bacteriophages provide B. anthracis with alternatives to sporulation that involve the activation of soil-survival and endosymbiotic capabilities

Exercise is medicine in oncology: Engaging clinicians to help patients move through cancer

A compelling evidence base supports exercise as a safe, effective intervention to improve many cancer related health outcomes among cancer patients and survivors. Oncology clinicians play a key role in encouraging their patients to move more. Therefore, the oncology clinical care team is urged to do the following at regular intervals: ASSESS exercise levels, ADVISE patients to become more active, and REFER patients to specific exercise programming. It is recommended that a process be developed to incorporate these steps into the standard care of oncology patients. A simple, straightforward approach is recommended to discern whether patients should be referred to outpatient rehabilitation versus community based exercise programming. The exponential growth of exercise oncology research has driven the need for revised cancer exercise guidelines and a roadmap for oncology clinicians to follow to improve physical and psychological outcomes from cancer diagnosis and for the balance of life. This paper serves as a call to action and details pathways for exercise programming (clinical, community and self-directed) tailored to the different levels of support and intervention needed by a given cancer patient or survivor. Preserving activity and functional ability is integral to cancer care and oncology clinicians are key to providing these referrals

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Avaliação comparativa do espaçamento anterior em nipo-brasileiros e leucodermas, na dentição decídua Comparative assessment of anterior spacing in Japanese-Brazilian and white children in the primary dentition

OBJETIVO: avaliar comparativamente a prevalência das características de espaçamento anterior em nipo-brasileiros e leucodermas, na dentição decídua. MÉTODOS: duas amostras de crianças com 2 a 6 anos de idade foram selecionadas: 405 nipo-brasileiros de 36 escolas do estado de São Paulo e 510 leucodermas de 11 instituições públicas da cidade de São Paulo. As variantes oclusais foram classificadas em quatro categorias, nas arcadas superior e inferior: espaçamento generalizado; somente espaços primatas; ausência de espaços; e apinhamento. Foi aplicada regressão logística para análise do efeito dos fatores idade, sexo e grupo étnico sobre a prevalência das características oclusais (&#945; = 0,05). RESULTADOS: em nipo-brasileiros, o espaçamento generalizado foi a característica mais prevalente nas arcadas superior (46,2%) e inferior (53,3%). A frequência dos espaços primatas foi maior na arcada superior (28,2% versus 15,3%). Para a ausência de espaços (21,7-26,4%) e o apinhamento (4,0-4,9%), a variação entre as arcadas foi relativamente pequena. Em leucodermas, a ausência de espaços e a presença exclusiva dos primatas evidenciaram distribuição similar à observada nos nipo-brasileiros. O espaçamento generalizado foi diagnosticado em aproximadamente 50% das arcadas. A prevalência de apinhamento foi maior na arcada inferior (12,8% versus 3,9%). O único modelo de regressão logística que apresentou algum fator significativo foi o ajustado para a prevalência de apinhamento. Apenas o fator racial foi significativo (p < 0,001). CONCLUSÃO: sugere-se que as características de espaçamento anterior, na dentição decídua, não estariam condicionadas à idade ou ao sexo. Contudo, leucodermas teriam chances 2,8 vezes maiores de apresentar apinhamento na arcada inferior, em comparação aos nipo-brasileiros.<br>OBJECTIVE: To carry out a comparative evaluation of the prevalence of anterior spacing characteristics in Japanese-Brazilian and white children in primary dentition. METHODS: Two selected samples of children aged 2-6 years were: 405 Japanese-Brazilians from 36 schools in the State of São Paulo and 510 white children from 11 public institutions in São Paulo city. The spacing features in the maxillary and mandibular arches were assigned to four categories: generalized spacing; only primate spaces; no spacing; and crowding. Logistic regression was used to analyze the effect of age, gender and ethnic group on the prevalence of the occlusal characteristics (&#945;=0.05). RESULTS: In Japanese-Brazilians, generalized spacing was the most prevalent trait in the maxillary (46.2%) and mandibular (53.3%) arches. The frequency of primate spaces was higher in the maxillary arch (28.2% versus 15.3%). Concerning no spacing (21.7-26.4%) and crowding (4.0-4.9%), the variation between arches was relatively small. In white children, no spacing and exclusive presence of primate spaces showed distributions similar to that observed in Japanese-Brazilians. Generalized spacing was diagnosed in approximately 50% of the arches. Crowding prevalence was higher in the mandibular arch (12.8% versus 3.9%). The regression model adjusted for crowding prevalence was the only significant one. Only racial factor was significant (p<0.001). CONCLUSION: It may be suggested that anterior spacing features in primary dentition would not be influenced by age or gender. Nevertheless, white children would have 2.8 times more chances of presenting crowding in the mandibular arch, in comparison with Japanese-Brazilians