Idols you can make: The player as auteur in Japan’s media mix

Japan has recently seen an upsurge in idol ikusei (nurturing) games: networked mobile games where one nurtures and produces an idol pop group. These games are a significant part of Japan’s contemporary ‘media mix’, influenced both by virtual pet games and by discourses of nurturing surrounding the production of ‘real’ girl idol groups by male producer-auteur figures. Previous analyses have considered affection for simulated or virtual girl idol figures as a detached longing for stylised characteristics (moe). This article uses a case study of a mobile game at the centre of the Love Live! girl idol-nurturing simulation franchise to suggest that we cannot only speak of players’ affection for nurturing games’ characters in terms of postmodern disembodiment; we must also consider how in playing idol-nurturing games, players take the place of real male producer-auteur figures in Japanese popular music production, where discourses of gendered nurturing abound

LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank

Background: Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in LDLR, APOB, PCSK9, and APOE. Some mutation-negative patients have a polygenic cause for elevated LDL-C due to a burden of common LDL-C-raising alleles, as demonstrated in people of White British (WB) ancestry using a 12-single nucleotide polymorphism (SNP) score. This score has yet to be evaluated in people of South Asian (SA), and Black and Caribbean (BC) ethnicities. Objectives: 1) Compare the LDL-C and 12-SNP score distributions across the three major ethnic groups in the United Kingdom: WB, SA, and BC individuals; 2) compare the association of the 12-SNP score with LDL-C in these groups; 3) evaluate ethnicity-specific and WB 12-SNP score decile cut-off values, applied to SA and BC ethnicities, in predicting LDL-C concentrations and hypercholesterolaemia (LDL-C>4.9 mmol/L). Methods: The United Kingdom Biobank cohort was used to analyse the LDL-C (adjusted for statin use) and 12-SNP score distributions in self-reported WB (n = 353,166), SA (n = 7,016), and BC (n = 7,082) participants. To evaluate WB and ethnicity-specific 12-SNP score deciles, the total dataset was split 50:50 into a training and testing dataset. Regression analyses (logistic and linear) were used to analyse hypercholesterolaemia (LDL-C>4.9 mmol/L) and LDL-C. Findings: The mean (±SD) measured LDL-C differed significantly between the ethnic groups and was highest in WB [3.73 (±0.85) mmol/L], followed by SA [3.57 (±0.86) mmol/L, p < 2.2 × 10−16], and BC [3.42 (±0.90) mmol/L] participants (p < 2.2 × 10−16). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25), p < 2.2 × 10−16], and WB and SA participants [0.86 (±0.19), p < 2.2 × 10−16]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [R2 (95% CI): WB = 0.067 (0.065–0.069), BC = 0.080 (0.063–0.097), SA = 0.027 (0.016–0.038)]. The odds ratio and the area under the curve for hypercholesterolaemia were not statistically different when applying ethnicity-specific or WB deciles in all ethnic groups. Interpretation: We provide information on the differences in LDL-C and the 12-SNP score distributions in self-reported WB, SA, and BC individuals of the United Kingdom Biobank. We report the association between the 12-SNP score and LDL-C in these ethnic groups. We evaluate the performance of ethnicity-specific and WB 12-SNP score deciles in predicting LDL-C and hypercholesterolaemia

Lipid lowering and Alzheimer disease risk: A mendelian randomization study.

OBJECTIVE: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics. METHODS: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls). RESULTS: Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition. INTERPRETATION: We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39

Identifying patients at risk of emergency admission for colorectal cancer.

BACKGROUND: Patients whose colorectal cancer is treated after an emergency admission tend to have late-stage cancer and a poor prognosis. We identified risk factors for an emergency admission by linking data from the National Bowel Cancer Audit (NBCA) and the English Hospital Episode Statistics (HES), an administrative database of all admissions to English National Health Service hospitals, which includes data on mode of admission. METHODS: We identified all adults included in the NBCA with a primary diagnosis of bowel cancer, excluding cancer of the appendix, between August 2007 and July 2011 whose record could be linked to HES. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) for an emergency admission for colorectal cancer. All risk factors were adjusted for cancer site and calendar year. RESULTS: 97,909 adults were identified with a primary diagnosis of bowel cancer and 82,777 patients could be linked to HES. Patients who were older, female, of a non-white ethnic background, and more socioeconomically deprived, and those with dementia or cardiac, neurologic and liver disease had an increased risk of presenting as an emergency admission. The strongest risk factors were age (90 compared with 70 years: OR 2.99, 95% CI 2.84 to 3.15), dementia (OR 2.46, 2.18 to 2.79), and liver disease (OR 1.87, 1.69 to 2.08). CONCLUSIONS: Our study identifies risk factors that may impair health-seeking behaviour and access to healthcare. An earlier recognition of symptoms in patients with these risk factors may contribute to better outcomes

The use of tumour markers CEA, CA-195 and CA-242 in evaluating the response to chemotherapy in patients with advanced colorectal cancer.

Tumour markers CEA, CA-195 and CA-242 were measured in 33 patients undergoing chemotherapy for advanced colorectal cancer. The aim was to determine whether they could be used to accurately monitor the course of the disease, and reduce the need for imaging. Treatment with a 5-fluorouracil based regimen resulted in a partial response in nine patients (27%), whereas the remainder either had disease stabilisation or suffered from progression. Before treatment the CEA was elevated in 85% of patients and the CA-195 and CA-242 in 78%. All three markers were elevated in 70% and at least one elevated in 93%. CA-195 and CA-242 appeared to be co-expressed, by contrast with the CEA. When compared to the results of serial CT scanning the CEA correlated best with the course of the disease, the positive predictive value being 54% for a partial response, 77% for minor and partial responses combined and 100% for progressive disease. The corresponding values for CA-195 were 46%, 62% and 100% respectively and for CA-242, 50%, 67% and 100% respectively. Thus, although falling levels of markers overestimate the number of responses demonstrated by imaging, rising tumour markers invariably herald progressive disease. This was often evident up to 16 weeks before progression was observed on scanning. CEA is the most useful of the three markers in the monitoring of patients being treated for advanced colorectal cancer, but other markers may prove valuable if the CEA is normal. The use of tumour markers should reduce the need for regular scanning

***TEST SUBMISSION*** BMJ-15: Acceptance within last 3 months (01/03/2020); Online publication within 12 months (10/12/2020); Embargo (10/09/2021) less than 12 months from pub date; VoR

From UAT Test publisher via Jisc Publications RouterHistory: accepted 2020-03-01, epub 2020-12-10Article version: VoRPublication status: PublishedAbstract: TEST: THIS IS A PUBLICATIONS ROUTER TEST SUBMISSION. Objectives: To quantify post-colonoscopy colorectal cancer (PCCRC) rates in England by using recent World Endoscopy Organisation guidelines, compare incidence among colonoscopy providers, and explore associated factors that could benefit from quality improvement initiatives. Design: Population based cohort study. Setting: National Health Service in England between 2005 and 2013. Population: All people undergoing colonoscopy and subsequently diagnosed as having colorectal cancer up to three years after their investigation (PCCRC-3yr). Main outcome measures: National trends in incidence of PCCRC (within 6-36 months of colonoscopy), univariable and multivariable analyses to explore factors associated with occurrence, and funnel plots to measure variation among providers. Results: The overall unadjusted PCCRC-3yr rate was 7.4% (9317/126 152), which decreased from 9.0% in 2005 to 6.5% in 2013 (P<0.01). Rates were lower for colonoscopies performed under the NHS bowel cancer screening programme (593/16 640, 3.6%), while they were higher for those conducted by non-NHS providers (187/2009, 9.3%). Rates were higher in women, in older age groups, and in people with inflammatory bowel disease or diverticular disease, in those with higher comorbidity scores, and in people with previous cancers. Substantial variation in rates among colonoscopy providers remained after adjustment for case mix. Conclusions: Wide variation exists in PCCRC-3yr rates across NHS colonoscopy providers in England. The lowest incidence was seen in colonoscopies performed under the NHS bowel cancer screening programme. Quality improvement initiatives are needed to address this variation in rates and prevent colorectal cancer by enabling earlier diagnosis, removing premalignant polyps, and therefore improving outcomes

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

Background: Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention. Objective: To evaluate the performance of two-stage adult population screening for FH. Design: Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants inLDLR, APOB, PCSK9andAPOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood. Setting: UK Biobank. Participants: 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence. Main outcome measures: For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing. Results: We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of &gt;4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected throughtwo-generationcascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden. Conclusions: Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement

Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

BACKGROUND: There has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. METHOD: We employed two-sample Mendelian randomization (MR) to investigate: (1) the causal role of genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels and MS risk and severity; and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n =7,069). RESULTS: The results of MR using the inverse variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway, (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. MR results also show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. CONCLUSION: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk via a cholesterol-independent pathway (i.e., RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk

Intracerebroventricular administration of chondroitinase ABC reduces acute edema after traumatic brain injury in mice

Background Brain edema is a significant challenge facing clinicians managing severe traumatic brain injury (TBI) in the acute period. If edema reaches a critical point, it leads to runaway intracranial hypertension that, in turn, leads to severe morbidity or death if left untreated. Clinical data on the efficacy of standard interventions is mixed. The goal of this study was to validate a novel therapeutic strategy for reducing post-traumatic brain edema in a mouse model. Prior in vitro work reported that the brain swells due to coupled electrostatic and osmotic forces generated by large, negatively charged, immobile molecules in the matrix that comprises brain tissue. Chondroitinase ABC (ChABC) digests chondroitin sulfate proteoglycan, a molecule that contributes to this negative charge. Therefore, we administered ChABC by intracerebroventricular (ICV) injection after controlled cortical impact TBI in the mouse and measured associated changes in edema. Results Almost half of the edema induced by injury was eliminated by ChABC treatment. Conclusions ICV administration of ChABC may be a novel and effective method of treating post-traumatic brain edema in the acute period