Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated ...regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Patients treated for cervical cancer exhibit large inter and intra-fraction anatomical changes. The Unity MR-Linac (MRL) can image these patients with MR prior to and during treatment which enables ...daily plan adaptation. However, the MRL has a limited treatment field in the sup/inf direction of 22 cm which can restrict the treatment of patients who require longer treatment fields. Here we explore potential adaptive workflows in combination with a dual isocentre approach, to widen the range of cervix patients that can benefit from this treatment.
Ten cervical cancer patients were retrospectively planned with a dual isocentre technique to deliver 45 Gy in 25 fractions. 5 node-negative and 5 node-positive patients were planned using the EMBRACE II protocol. A 2 cm overlap region between the two isocentres was positioned entirely in the nodal region. A treatment workflow was simulated to account for inter-fraction anatomical change. Isocentre shifts of 3 and 6 mm were applied to investigate the effect of intra-fraction motion.
Dual isocentre adapted plans ensured significantly better coverage than non-adapted (recalculated) plans with a larger benefit seen for the node-negative cases. The difference to the reference plan for the V4275 cGy to the ITV was -0.8 cGy and -8.2 cGy for the adapted and recalculated plans respectively. Movements superiorly did not affect the coverage of the ITV by more than 1%, but shifting it inferiorly caused the ITV coverage on the plan to reduce by ∼2.4% per mm.
A dual isocentre technique for cervical cancer treatments and adaptive workflows have been demonstrated to recover the required plan quality for inter-fraction changes. This illustrates the feasibility of a dual isocentre technique for the MRL.
Thresholds for defining a positive biomarker in a clinical trial, and what constitutes a positive biomarker, are not standardised. ...companion assays are co-developed with a drug, as determined by ...the pharmaceutical company in collaboration with the company contracted to produce the assay, without regard to the other assays being developed for the same biomarker. ...PD-L1 assay kits are approved by the FDA in 15 different cancer types but the PD-L1 staining patterns, scoring methods, and positivity thresholds are different in almost all of these cancer types. ...the various assays and scoring systems are not equivalent, despite being matched to the same specific drug. In 2019, considering the results of the IMpassion130 trial, the FDA approved the Ventana PD-L1 (SP142) assay (Ventana Medical Systems, Tucson, AZ, USA) and cut-point (1% of tumour-infiltrating immune cells) to assess PD-L1 in patients with triple-negative breast cancer treated with atezolizumab.1 However, following the Keynote 355 breast cancer trial,2 the results of which were publicised in 2020, investigating pembrolizumab in the same patient population, the FDA is likely to approve the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA) and its combined positivity score-scoring system to assess PD-L1.
We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N giraulti, and N. longicomis. Parasitoids are important regulators of ...arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specifk genes including diverse venoms; lateral gene transfers among Pox viruses, WolbacMa, and Nasonia; and the rapid evolution of genes involved in nuclearmitochondrial interactions that are implicated in spedation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
The current study aimed to examine whether the prevalence and risk factors for suicidal ideation and attempts differ when comparing two American Indian reservation samples to the U.S. general ...population. Data were from the baseline nationally representative National Comorbidity Survey (N = 5,877) and the representative American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP; N = 3,084). Face-to-face interviews were conducted using the fully structured World Health Organization Composite International Diagnostic Interview. American Indians from these Northern Plains and Southwest tribes appeared significantly less likely to have suicidal thoughts in their lifetime when compared with the general population, odds ratio (OR) of 0.49 (99% CI 0.36, 0.66) and 0.36 (99% CI 0.25, 0.51), respectively. However, members of the Northern Plains tribe were more likely to have attempted suicide in their lifetime compared with the general population (OR = 1.96, 99% CI 1.45, 2.65). Suicide attempts without suicidal ideation were more common in the two American Indian samples than in the general population. In contrast, correlates of suicidal behavior appear quite similar when comparing the groups. Increased attention is needed to determine why rates of ideation and attempts may differ in American Indians when compared with the general population.
Childhood mental, behavioral, and developmental disorders (MBDDs) are associated with adverse outcomes that can persist into adulthood (1,2). Pediatric clinical settings are important for identifying ...and treating MBDDs (3). Early identification and treatment of MBDDs can promote healthy development for all children (4), especially those living in poverty who are at increased risk for MBDDs (3,5) but might have reduced access to care (6). CDC analyzed data from the 2016 National Survey of Children's Health (NSCH) on MBDDs, risk factors, and use of federal assistance programs (e.g., Supplemental Nutrition Assistance Program SNAP) to identify points to reach children in poverty. In line with previous research (3,6), compared with children in higher-income households, those in lower-income households more often had ever received a diagnosis of an MBDD (22.1% versus 13.9%), and less often had seen a health care provider in the previous year (80.4% versus 93.8%). Among children living below 200% of the federal poverty level (FPL) who did not see a health care provider in the previous year, seven of 10 were in families receiving at least one public assistance benefit. Public assistance programs might offer collaboration opportunities to provide families living in poverty with information, co-located screening programs or services, or connection to care.
To compare insulin sensitivity (M/I) and β-cell responses in youth versus adults with impaired glucose tolerance (IGT) or drug-naïve, recently diagnosed type 2 diabetes.
In 66 youth (80.3% with IGT) ...and 355 adults (70.7% IGT), hyperglycemic clamps were used to measure
) M/I,
) acute (0-10 min first phase) C-peptide (ACPR
) and insulin (AIR
) responses to glucose,
) steady-state C-peptide and insulin concentrations at plasma glucose of 11.1 mmol/L, and
) arginine-stimulated maximum C-peptide (ACPR
) and insulin (AIR
) responses at plasma glucose >25 mmol/L. The fasting C-peptide-to-insulin ratio was used as an estimate of insulin clearance.
Insulin sensitivity was 46% lower in youth compared with adults (
< 0.001), and youth had greater acute and steady-state C-peptide (2.3- and 1.3-fold, respectively; each
< 0.001) and insulin responses to glucose (AIR
3.0-fold and steady state 2.2-fold; each
< 0.001). Arginine-stimulated C-peptide and insulin responses were also greater in youth (1.6- and 1.7-fold, respectively; each
< 0.001). After adjustment for insulin sensitivity, all β-cell responses remained significantly greater in youth. Insulin clearance was reduced in youth (
< 0.001). Participants with diabetes had greater insulin sensitivity (
= 0.026), with lesser C-peptide and insulin responses than those with IGT (all
< 0.001) but similar insulin clearance (
= 0.109).
In people with IGT or recently diagnosed diabetes, youth have lower insulin sensitivity, hyperresponsive β-cells, and reduced insulin clearance compared with adults. Whether these age-related differences contribute to declining β-cell function and/or impact responses to glucose-lowering interventions remains to be determined.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological ...disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.