Multiconfiguration Loads Analysis for Missions with an Uncertain Rideshare Manifest

Rideshare or “multi-manifest” missions – where several smaller “rideshare” spacecraft are launched together, usually with a larger “forward” spacecraft – are becoming increasingly common. In many cases, the properties or configuration of the rideshare spacecraft are not well-defined during initial launch manifesting and may not be finalized until a few months before launch. In this paper, a multiconfiguration loads analysis (MLA) process is presented that can enable flexibility in the mission manifesting process by allowing for uncertainty in the final rideshare configuration, including late manifest changes or swaps, without requiring additional loads analyses to those specified in the Load Cycle Process. By applying the MLA process, a set of adequately conservative loads can be generated for the forward spacecraft, launch vehicle, and potential rideshare spacecraft that account for uncertainty in the rideshare manifest and minimize the potential for issues late in the process. The MLA process will also define a mission-specific dynamic properties envelope that would allow rideshare spacecraft that “fit” within the envelope to be swapped. If all parts of the system are verified to match the models used in analysis and designed to survive the bounding loads, the launch manifest can be changed after analyses are completed, much closer to launch, without incurring increased risk

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Rhinitis associated with asthma is distinct from rhinitis alone: TARIA‐MeDALL hypothesis

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of “one-airway-one-disease,” coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the “Epithelial Barrier Hypothesis.” This review determined that the “one-airway-one-disease” concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme “allergic” (asthma) phenotype combining asthma, rhinitis, and conjunctivitis.info:eu-repo/semantics/publishedVersio

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Financial Distress and Discussing the Cost of Total Joint Arthroplasty

Background: Total joint arthroplasty is expensive. Out-of-pocket cost to patients undergoing elective total joint arthroplasty varies considerably depending on their insurance coverage but can range into the tens of thousands of dollars. The goal of this study is to evaluate the association between patient financial stress and interest in discussing costs associated with surgery. Methods: One hundred forty-one patients undergoing elective total hip and knee arthroplasty at a suburban academic medical center were enrolled and completed questionnaires about cost prior to surgery. Questions regarding if and when doctors should discuss the cost of healthcare with patients, evaluating if patients were affected by the cost of healthcare and to what extent, and financial security scores to assess current financial situation were included. The primary outcome was the answer to the question of whether a doctor should discuss cost with patients. Results: Financial stress was found to be associated with patient experience of hardship due to cost of care [P =.004], likelihood to turn down a test or treatment due to copayment [P =.029], to decline a test or treatment due to other costs [P =.003], to experience difficulty affording basic necessities [P =.008], and to have used up all or most of their savings to pay for surgery [P =.011]. In total, 84% of patients reported that they wanted to discuss surgical costs with their doctors, but 90% did not want to do so at every visit. Conclusion: Total joint arthroplasty creates considerable out-of-pocket costs that may affect patient decisions. These findings help elucidate important patient concerns that orthopedic surgeons should account for when discussing elective arthroplasty with patients

Greater Tuberosity Fractures: Does Fracture Assessment and Treatment Recommendation Vary Based on Imaging Modality?

For greater tuberosity fractures, 5-mm displacement is a commonly used threshold for recommending surgery; however, it is unclear if displacement can be assessed with this degree of precision and reliability using plain radiographs. It also is unclear if CT images provide additional information that might change decision making. We asked: (1) Does interobserver agreement for assessment of the amount and direction of fracture-fragment displacement vary based on imaging modality (radiographs only; 2-dimensional [2-D] CT images and radiographs; and 3-dimensional [3-D] and 2-D CT images and radiographs)? (2) Does the likelihood of recommending surgery vary based on imaging modality? (3) Does the level of confidence regarding the decision for treatment vary based on imaging modality? We invited 791 orthopaedic surgeons to complete a survey on greater tuberosity fractures. One hundred eighty (23%) responded and were randomized on a 1:1:1 basis in one of the three imaging modality groups and evaluated the same set of 22 fractures. We described age, sex, mechanism of injury, days between injury and imaging, and that patients had no comorbidities or signs of neurovascular damage for every case. One hundred sixty-four of the 180 respondents completed the study and there was an imbalance in noncompletion between the three groups (two of 67 [3.0%] in the radiograph only group; nine of 57 [16%] in the 2-D CT and radiograph group; and five of 56 [8.9%] in the 3-D CT, 2-D CT, and radiograph group; p = 0.043 by Fisher's exact test). Participants assessed amount (in millimeters) and direction (posterosuperior/posteroinferior/anterosuperior/anteroinferior/no displacement) of displacement; recommended treatment (surgical or nonoperative); and indicated their level of confidence regarding the recommended treatment on a scale from 0 to 10 for every case. Overall recommendation for treatment was expressed as a surgery score per surgeon by dividing the amount of cases they would operate on by the total number of cases (n = 22) and presented as a percentage. Confidence regarding the decision for treatment was calculated by averaging the confidence score per surgeon, ranging from 0 to 10. We compared interobserver agreement using kappa for categorical variables and intraclass correlation (ICC) for continuous variables. We used multivariable linear regression to assess difference in surgery score and confidence level between imaging groups, controlling for surgeon characteristics. Interobserver agreement for assessment of amount (radiographs: ICC, 0.55, 2-D CT + radiographs ICC, 0.53, 3-D CT + 2-D CT + radiographs ICC, 0.57; p values on all comparisons >0.7) and direction (radiographs: kappa, 0.30, 2-D CT + radiographs kappa, 0.43, 3-D CT + 2-D CT + radiographs kappa, 0.40; p values for all comparisons >0.096) of displacement did not vary by imaging modality. 2-D CT and radiographs (β regression coefficient [β], 3.1; p = 0.253) and 3-D CT, 2-D CT and radiographs (β, 1.6; p = 0.561) did not result in a difference in recommendation for surgery compared with radiographs alone. 2-D CT and radiographs (β, 0.40; p = 0.021) and 3-D CT, 2-D CT and radiographs (β, 0.44; p = 0.011) were associated with slightly higher levels of confidence compared with radiographs alone. Imaging modality, with the numbers evaluated, does not influence interobserver agreement of greater tuberosity fracture assessment, nor did it influence the recommendation for surgical treatment. However, surgeons did feel slightly more confident about their treatment recommendation when assessing CT images with radiographs compared with radiographs alone. Our results therefore suggest no additional value of CT scans for assessment of greater tuberosity fractures when displacement seems to be minimal on plain radiographs. CT scans could be helpful in borderline cases, or in case other fractures can be expected (eg, an occult surgical neck fracture). Level III, diagnostic stud

International Society for Quality of Life Research commentary on the draft European Medicines Agency reflection paper on the use of patient-reported outcome (PRO) measures in oncology studies

In 2014, the European Medicines Agency (EMA) released for comment a draft reflection paper on the use of patient-reported outcome (PRO) measures in oncology studies. A twelve-member International Society for Quality of Life Research (ISOQOL) taskforce was convened to coordinate the ISOQOL response. Twenty-one ISOQOL members provided detailed comments and suggestions on the paper: 81 % from academia and 19 % from industry. Taskforce members consolidated and further refined these comments and shared the recommendations with the wider ISOQOL membership. A final response was submitted to the EMA in November 2014. The impending publication of the EMA reflection paper presents a valuable opportunity for ISOQOL to comment on the current direction of EMA PRO guidance and strategy. The EMA paper, although focused on cancer, could serve as a model for using PROs in other conditions, as it provides a useful update surrounding some of the design issues common to all trial research including PRO endpoints. However, we believe there are a number of additional areas in need of greater consideration. The purpose of this commentary is therefore to highlight the strengths of this timely and potentially useful document, but also to outline areas that may warrant further discussion