Utility of Diabetes Type–Specific Genetic Risk Scores for the Classification of Diabetes Type Among Multiethnic Youth

OBJECTIVEGenetic risk scores (GRS) aid classification of diabetes type in White European adult populations. We aimed to assess the utility of GRS in the classification of diabetes type among racially/ethnically diverse youth in the U.S.RESEARCH DESIGN AND METHODSWe generated type 1 diabetes (T1D)- and type 2 diabetes (T2D)-specific GRS in 2,045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes autoantibody positive or negative (DAA^+/−) and insulin sensitivity (IS) or insulin resistance (IR) and self-reported race/ethnicity (White, Black, Hispanic, and other).RESULTST1D and T2D GRS were strong independent predictors of etiologic type. The T1D GRS was highest in the DAA⁺/IS group and lowest in the DAA⁻/IR group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed differences in score distribution. Clustering by combined genetic risk showed DAA⁺/IR and DAA⁻/IS individuals had a greater probability of T1D than T2D. In DAA⁻ individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency.CONCLUSIONSDiabetes type–specific GRS are consistent predictors of diabetes type across racial/ethnic groups in a U.S. youth cohort, but future work needs to account for differences in GRS distribution by ancestry. T1D and T2D GRS may have particular utility for classification of DAA⁻ children.     

The parent trap: desire for multifetal gestation among patients treated for infertility

ObjectiveTo evaluate predictors for patient preference regarding multifetal or singleton gestation among women presenting for infertility care.DesignCross-sectional study.SettingAcademic university hospital-based infertility clinic.Patient(s)Five hundred thirty-nine female patients with infertility who presented for their initial visit.Main outcome measure(s)Demographic characteristics, infertility history, insurance coverage, desired treatment outcome, acceptability of multifetal reduction, and knowledge of the risks of multifetal pregnancies were assessed using a previously published 41-question survey. Univariate analysis was performed to assess patient factors associated with the desire for multiple births. Independent factors associated with this desire were subsequently assessed by multivariate logistic regression analysis.Result(s)Nearly a third of women preferred multiples over a singleton gestation. Nulliparity, lower annual household income, older maternal age, marital status, larger ideal family size, openness to multifetal reduction, and lack of knowledge of the maternal/fetal risks of twin pregnancies were associated with pregnancy desire. Older age (OR (95% CI) 1.66 (1.20–2.29)), nulliparity (OR (95% CI) 0.34 (0.20–0.58)), larger ideal family size (OR (95% CI) 2.34 (1.73–3.14)), and lesser knowledge of multifetal pregnancy risk (OR (95% CI) 0.67 (0.55–0.83)) were independently associated with desire.Conclusion(s)A large number of patients undergoing fertility treatment desire multifetal gestation. Although a lack of understanding of the risks associated with higher order pregnancies contributes to this desire, additional individual specific variables also contribute to this trend. Efforts to reduce the incidence of multiples should focus not only on patient education on comparative risks of multiples vs singleton pregnancies but also account for individual specific reservations.     

Innovation in Orthopaedics: Part 2—How to Translate Ideas and Research into Clinical Practice

Purpose of ReviewThis paper presents some approaches and techniques for translating an idea or research into clinical practice, considering the innovation development process.Recent FindingsInnovative tools have been a key solution for healthcare problems, such as musculoskeletal disorders, which represent a great economic burden and are among the leading causes of disability. There has been an increase in publications on this topic, but there has been no analysis of the process of innovation development. This review describes the innovation phases for translating an idea or research into clinical practice, considering the stages of discovering the opportunity, innovation creation, project specification, technology development, and innovation launch.SummaryAn analysis of the innovation development process to translate an idea or research into clinical practice, including concepts, approaches, and techniques that shows the “why”, “how”, and “what” of innovation.     

High-Entropy Borides under Extreme Environment of Pressures and Temperatures

The high-entropy transition metal borides containing a random distribution of five or more constituent metallic elements offer novel opportunities in designing materials that show crystalline phase stability, high strength, and thermal oxidation resistance under extreme conditions. We present a comprehensive theoretical and experimental investigation of prototypical high-entropy boride (HEB) materials such as (Hf, Mo, Nb, Ta, Ti)B₂ and (Hf, Mo, Nb, Ta, Zr)B₂ under extreme environments of pressures and temperatures. The theoretical tools include modeling elastic properties by special quasi-random structures that predict a bulk modulus of 288 GPa and a shear modulus of 215 GPa at ambient conditions. HEB samples were synthesized under high pressures and high temperatures and studied to 9.5 GPa and 2273 K in a large-volume pressure cell. The thermal equation of state measurement yielded a bulk modulus of 276 GPa, in excellent agreement with theory. The measured compressive yield strength by radial X-ray diffraction technique in a diamond anvil cell was 28 GPa at a pressure of 65 GPa, which is a significant fraction of the shear modulus at high pressures. The high compressive strength and phase stability of this material under high pressures and high temperatures make it an ideal candidate for application as a structural material in nuclear and aerospace fields.     

Treatment Options for Patellofemoral Arthritis

Purpose of ReviewTo present a synthesis of recent literature regarding the treatment of patellofemoral arthritisRecent FindingsRisk factors of PFJ OA include patella malalignment or maltracking, injury to supportive structures including the MPFL, dysfunction of hamstring and quadriceps coordination, lower limb alignment, trochlear dysplasia, patellar trauma, or ACL surgery. Special physical exam maneuvers include patellar grind test, apprehension test, and lateral patellar tilt angle. Radiographs that should be obtained first-line include weight bearing bilateral AP, lateral, and Merchant views. CT and MRI are used to assess trochlear dysplasia, excessive patellar height, and TT-TG distance. Non-operative management options discussed include non-pharmacologic treatment (patient education, self-management, physical therapy, weight loss), ESWT, cold therapy, taping, bracing, and orthotics. Pharmacologic management options discussed include NSAIDs, acetaminophen, oral narcotics, and duloxetine. Injection therapies include glucocorticoids, hyaluronic acid, PRP, and other regenerative therapies (BMAC, adipose, or mesenchymal stem cells). Other treatment options include radiofrequency ablation and botulinum toxin. The algorithm for the surgical treatment of PFJ OA can begin with arthroscopic assessment of the PF articular cartilage to address mechanical symptoms and to evaluate/treat lateral soft tissue with or without overhanging lateral osteophytes. If patients fail to have symptomatic improvement, a TTO can be considered in those patients less than 50 years of age or active patients >50 years old. In patients with severe PFJ OA, refractory to the above treatments, PFA should be considered. While early PFA design and technique were less than encouraging, more recent implant design and surgical technique have demonstrated robust results in the literature.SummaryPatellofemoral osteoarthritis is a challenging orthopedic problem to treat, in that it can often affect younger patients, with otherwise well-functioning knees. It is a unique entity compared to TF OA with distinct epidemiology, biomechanics and risk factors and treatment options.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Radical cystectomy in septuagenarian patients with bladder cancer

Introduction: Clinical results of radical cystectomy performed on elderly bladder cancer patients over 70 years old were assessed to determine whether age is one of the critical points for the application of this type of surgery. Materials: From January 1992 to December 2002, 41 radical cystectomy performed in septuagenarian population were compared with 197 performed in patients less than 70 years of age. Results: The early and late complication rate for septuagenarians was 29.7% and 12%, compared with 26.9% and 9.6% for patients younger than 70 years respectively. The overall mortality rate for septuagenarians was 4.9%, compared with 8.6% for patients younger than 70 years. There was no significant difference between the two groups with regard to pathologic stage or length of hospital stay. The 5-year overall survival rate for septuagenarians was 53% compared with 59% for patients younger than 70 years. Conclusions: When indicated after adequate preoperative assessment and optimization of the patient, radical cystectomy is a safe procedure in the septuagenarians and patient should not be denied surgery dependent on chronologic age.     

Defects in processing and trafficking of the AE1 Cl<Superscript>−</Superscript>/HCO3<Superscript>−</Superscript> exchanger associated with inherited distal renal tubular acidosis

Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl^?/HCO₃ ^? exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity.