Clinical and technical factors in endoscopic skull base surgery associated with reconstructive success.

BACKGROUND: In this study, we identified key discrete clinical and technical factors that may correlate with primary reconstructive success in endoscopic skull base surgery (ESBS). METHODS: ESBS cases with intraoperative cerebrospinal fluid (CSF) leaks at four tertiary academic rhinology programs were retrospectively reviewed. Logistic regression identified factors associated with surgical outcomes by defect subsite (anterior cranial fossa [ACF], suprasellar [SS], purely sellar, posterior cranial fossa [PCF]). RESULTS: Of 706 patients (50.4% female), 61.9% had pituitary adenomas, 73.4% had sellar or SS defects, and 20.5% had high-flow intraoperative CSF leaks. The postoperative CSF leak rate was 7.8%. Larger defect size predicted ACF postoperative leaks; use of rigid reconstruction and older age protected against sellar postoperative leaks; and use of dural sealants compared to fibrin glue protected against PCF postoperative leaks. SS postoperative leaks occurred less frequently with the use of dural onlay. Body-mass index, intraoperative CSF leak flow rate, and the use of lumbar drain were not significantly associated with postoperative CSF leak. Meningitis was associated with larger tumors in ACF defects, nondissolvable nasal packing in SS defects, and high-flow intraoperative leaks in PCF defects. Sinus infections were more common in sellar defects with synthetic grafts and nondissolvable nasal packing. CONCLUSIONS: Depending on defect subsite, reconstructive success following ESBS may be influenced by factors, such as age, defect size, and the use of rigid reconstruction, dural onlay, and tissue sealants.

Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity.

BACKGROUND: Hypersensitivity reactions to etoposide have been reported and patients have been safely transitioned to etoposide phosphate for continued therapy. However, the safety and efficacy of substituting etoposide phosphate for etoposide has not been well established in pediatric orthopedic malignancies. The aim of this study is to determine whether etoposide phosphate can be substituted for etoposide in pediatric orthopedic malignancies. METHODS: A chart review of pediatric patients who developed hypersensitivity reactions to etoposide while being treated for orthopedic malignancies was performed at a large academic medical center. Three patients were identified, two with Ewing sarcoma and one with an osteosarcoma. All three patients experienced hypersensitivity reactions to their first doses of etoposide and were switched to etoposide phosphate for further therapy. RESULTS: After premedication, all three patients tolerated full doses of etoposide phosphate without a graded dose challenge or desensitization. Two of the patients were premedicated with diphenhydramine alone, while the third received diphenhydramine and dexamethasone. CONCLUSIONS: Etoposide phosphate is a potentially safe alternative for pediatric patients with orthopedic malignancies who experience etoposide hypersensitivity. However, caution is needed as there are cases of etoposide phosphate hypersensitivity.

Clinical presentation of hereditary angioedema.

Hereditary angioedema (HAE) is a rare, autosomal dominant disease caused by a deficiency in the C1-inhibitor protein. It is characterized by recurrent episodes of nonpruritic, nonpitting, subcutaneous or submucosal edema that typically involves the extremities or the gastrointestinal tract. However, the genitourinary tract, face, oropharynx, and/or larynx may be affected as well. Symptoms often begin in childhood, worsen at puberty, and persist throughout life, with unpredictable severity. Patients who are untreated may have frequent attacks, with intervals that can range from every few days to rare episodes. Minor trauma and stress are frequent precipitants of swelling episodes, but many attacks occur without clear triggers. HAE attacks may be preceded by a prodrome and/or be accompanied by erythema marginatum. The swelling typically worsens over the first 24 hours, before gradually subsiding over the subsequent 48 to 72 hours. Although oropharyngeal swelling is less frequent, more than half of patients have had at least one episode of laryngeal angioedema during their lifetime. Attacks may start in one location and spread to another before resolving. HAE attacks that involve the abdomen or oropharynx have been associated with significant morbidity and mortality. Abdominal attacks can cause severe abdominal pain, nausea, and vomiting. Bowel sounds are often diminished or silent, and guarding and rebound tenderness may be present on physical examination. These findings may lead to unnecessary abdominal imaging and procedures. Fluid shifts into the interstitial space or peritoneal cavity can cause clinically significant hypotension. Laryngeal edema poses the greatest risk for patients with HAE. Although prompt diagnosis and treatment improves outcomes, the variable presentation of HAE can make it difficult to diagnose.

Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

The APOB loss-of-function mutation of Holstein dairy cattle does not cause a deficiency of cholesterol but decreases the capacity for cholesterol transport in circulation.

The loss-of-function mutation of the apolipoprotein (APO) B gene (APOB) in Holstein cattle accounts for increased losses in calves that are homozygous for this mutation. Heterozygous carriers of the APOB mutation are clinically healthy but show decreased concentrations of plasma cholesterol and lipoproteins. So far, the metabolic effects of the mutation have only been investigated in heterozygous calves, bulls, and nonlactating females. In high-yielding dairy cows, a marked decrease in cholesterol concentration in plasma during early lactation is part of the usual metabolic changes. Given the essential role of cholesterol in fatty acid and lipid metabolism, a specific effect of the APOB mutation on metabolism and performance in dairy cows is expected. Therefore, the aim of the present study was to investigate the effects of different APOB genotypes on metabolic parameters, hepatic metabolism, and lactation and reproductive performance. Twenty pairs of full siblings with similar age, performance, and calving were investigated. Both animals of each pair were kept on the same farm and consisted of a heterozygous carrier (CDC) and a noncarrier (CDF) of the APOB mutation associated with cholesterol deficiency. Blood samples were taken in early (25.5 ± 4.7 d in milk) and mid lactation (158.2 ± 11.1 d in milk; mean ± SD), and analyzed for nonesterified fatty acids, ß-hydroxybutyrate, glucose, insulin-like growth factor-1, aspartate aminotransferase and gamma-glutamyltransferase activity, total cholesterol, free cholesterol, triacylglycerols, high density lipoprotein-cholesterol, and phospholipids. The evaluation of milk production, milk gross composition, and lactation persistency was based on official Dairy Herd Improvement Association recordings. Cholesterol and lipoprotein concentrations were lower in CDC cows than in CDF cows in early and mid lactation. Metabolic parameters, triacylglycerol concentration in plasma, and lactation and reproductive performance did not differ between CDC cows and CDF cows. The low cholesterol concentrations associated with the APOB mutation in heterozygous carriers are not because of a primary deficiency of cholesterol at a cellular level, as the term "cholesterol deficiency" suggests, but rather a consequence of reduced capacity for its transport in circulation. Overall, the data of the present study suggest that, despite the presence of the APOB mutation, cholesterol is not limiting for animals' metabolic adaptation and performance in heterozygous Holstein cows.

Genome-wide mapping of the dominance effects based on breed ancestry for semen traits in admixed Swiss Fleckvieh bulls.

Heterosis is the beneficial deviation of crossbred progeny from the average of parental lines for a particular trait. Heterosis is due to nonadditive genetic effects with dominance and epistatic components. Recent advances in genotyping technology have encouraged researchers to estimate and scan heterosis components for a range of traits in crossbred populations, applying various definitions of such components. In this study, we defined the intralocus (dominance) component of heterosis using local genetic ancestry and performed genome-wide association analysis for admixed Swiss Fleckvieh bulls and their parental populations, Red Holstein Friesian and Swiss Simmental, for semen traits. A linear mixed model for 41,824 SNP, including SNP additive genetic, breed additive, and breed dominance effects on 1,178 bulls (148 Red Holstein Friesian, 213 Swiss Simmental, and 817 Swiss Fleckvieh) with a total of 43,782 measurements was performed. In total, 19 significant regions for breed dominance were identified for volume (2 regions on Bos taurus autosome 10 and 22) and percentage of live spermatozoa (17 regions on Bos taurus autosome 3, 4, 5, 7, 13, 14, and 17), and genes associated with spermatogenesis, sperm motility, and male fertility traits were located there. No significant region for breed dominance was detected for total number of spermatozoa. The signals for breed dominance were relatively wide, most likely due to limited numbers of recombination events in a small number of generations (10-15 generations) of crossbreeding in the recent Swiss Fleckvieh composite.

Effects of breed proportion and components of heterosis for semen traits in a composite cattle breed.

The aim of this study was to estimate the non-additive genetic effects of the dominance component of heterosis as well as epistatic loss on semen traits in admixed Swiss Fleckvieh, a composite of Simmental (SI) and Red Holstein Friesian (RHF) cattle. Heterosis is the additional gain in productivity or fitness of cross-bred progeny over the mid-purebred parental populations. Intralocus gene interaction usually has a positive effect, while epistatic loss generally reduces productivity or fitness due to lack of evolutionarily established interactions of genes from different breeds. Genotypic data on 38,205 SNP of 818 admixed, as well as 148 RHF and 213 SI bulls as the parental breeds were used to predict breed origin of alleles. The genomewide locus-specific breed ancestries of individuals were used to calculate effects of breed difference as well as the dominance component of heterosis, while proxies for two definitions of epistatic loss were derived from 100,000 random pairs of loci. The average Holstein Friesian ancestry in admixed bulls was estimated 0.82. Results of fitting different linear mixed models showed including the dominance component of heterosis considerably improved the model adequacy for three of the four traits. Inclusion of epistatic loss increased the accuracy of the models only for our new definition of the epistatic effect for two traits, while the other definition was so highly correlated with the dominance component that statistical separation was impossible.

Liver transcriptome analysis reveals important factors involved in the metabolic adaptation of the transition cow.

During early lactation, dairy cows experience a severe metabolic load often resulting in the development of various diseases. The inevitable deficiency in nutrients and energy at the onset of lactation requires an optimal adaptation of the hepatic metabolism to overcome metabolic stress. We conducted a whole-liver transcriptome analysis for the transition cow to identify novel factors crucial for metabolic adaptation. Liver samples were obtained from 6 Red Holstein dairy cows (parity 2 to 7, mean ± standard deviation: 3.7 ± 2.3) at 3 time points: T1 = 22 ± 4 d antepartum, T2 = 10 ± 2 d postpartum, and T3 = 17 ± 2 d postpartum. Using RNA sequencing (RNA-seq), we studied the transcriptomic profile of the transition cow before and after parturition. We performed a differential gene expression analysis (DGEA) and gene-set enrichment analysis (GSEA) for biological processes (gene ontology, GO) and pathways (Kyoto Encyclopedia of Genes and Genomes, KEGG). Among the 10,186 expressed genes, we discovered 1,063 differentially expressed genes (false discovery rate = 5%). The GSEA revealed 16 biological processes and 7 pathways significantly (false discovery rate = 5%) associated with the hepatic changes of the transition cow. Our results confirm that major hepatic changes are related to energy mobilization after parturition; in particular, they are related to fatty acid oxidation/metabolism, cholesterol metabolism, and gluconeogenesis. Using the STRING database (https://string-db.org/), we investigated interactions between significant genes and identified 9 key genes (CYP7A1, APOA1, CREM, LOC522146, CYP2C87, HMGCR, FDFT1, SGLE, and CYP26A1) through which the different processes involved in the metabolic adaptation interact. Comparing our main results with the literature, we could identify further genes that have not yet been associated with the transition period (e.g., CPT1B, ADIPOR2, LEPR, CREB3L3, and CCND1) and that are mainly involved in processes controlled by AMP-activated protein kinase, an important regulator of energy homeostasis.

A reaction norm sire model to study the effect of metabolic challenge in early lactation on the functional longevity of dairy cows.

Due to the discrepancy of the high energy demand for rapidly increasing milk production and limited feed intake in the transition period around parturition, dairy cows require considerable metabolic adaptations. We hypothesize that some cows are genetically less suited to cope with these metabolic needs than others, leading to adverse follow-up effects on longevity. To test this, we designed a reaction norm model in which functional lifetime was linked to the metabolic challenge in the beginning of the first lactation. As challenge variables, we used either the sum of milk yield or the accumulated fat-to-protein ratio of the first 3 test-days (<120 d in milk), pre-adjusted for herd-test-day variance. We defined a random regression sire model, in which a random slope was estimated for each sire to assess whether a bull had robust (neutral or positive slopes) or non-robust (negative slopes) daughters. We fitted the model to data of ∼580,000 daughters of ∼5,000 Brown Swiss bulls with suitable observations available (≥10 daughters per bull). To validate our proposed model and assess the reliability of the estimated (co)variance components, we conducted an extensive bootstrap approach. For both challenge variables, we found the sire variance for the slope of the random regression to be significantly different from zero, suggesting a genetic component for metabolic adaptability. The results of the study show that the ability to cope with metabolic stress in the transition period has a genetic component, which can be used to breed metabolically robust dairy cows.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations.

BACKGROUND: In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS: Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. RESULTS: Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. CONCLUSIONS: Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

A systematic approach to predicting the risk of unicompartmental knee arthroplasty revision.

OBJECTIVE: Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA. DESIGN: We collected all revision cases available (n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model. RESULTS: Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA. CONCLUSIONS: The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future.

Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was ≥8.0% 12 months after randomization. Baseline and 12-month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c ≥8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61-0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37-0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40-0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c ≥8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above-target HbA1c concentration after 12 months on the standard protocol.

The association of calcium supplementation and incident cardiovascular events in the Multi-ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Many US adults use calcium supplements to address inadequate dietary intake and improve bone health. However, recent reports have suggested that use of calcium supplements may elevate cardiovascular disease (CVD) risk. In this study, we examined associations between baseline calcium supplement use and incident myocardial infarction (MI) (n = 208 events) and CVD events (n = 641 events) over 10.3 years in men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 6236), with dietary calcium intake at baseline also examined as a supplementary objective. METHODS AND RESULTS: Using Cox proportional hazards models, no compelling associations between calcium intake from supplements or diet and incident CVD events were observed upon multivariate adjustment for potential confounders. An association with lower MI risk was observed comparing those with low levels of calcium supplement use (1-499 mg) to those using no calcium supplements (hazard ratio 0.69, 95% CI 0.48, 0.98, p = 0.039). Relationships were homogeneous by gender, race/ethnicity, or chronic kidney disease. Results were also similar when the analysis was limited to postmenopausal women only. CONCLUSION: Analysis of incident MI and CVD events in the MESA cohort does not support a substantial association of calcium supplement use with negative cardiovascular outcomes.

A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle.

Cholesterol deficiency, a new autosomal recessive inherited genetic defect in Holstein cattle, has been recently reported to have an influence on the rearing success of calves. The affected animals show unresponsive diarrhea accompanied by hypocholesterolemia and usually die within the first weeks or months of life. Here, we show that whole genome sequencing combined with the knowledge about the pedigree and inbreeding status of a livestock population facilitates the identification of the causative mutation. We resequenced the entire genomes of an affected calf and a healthy partially inbred male carrying one copy of the critical 2.24-Mb chromosome 11 segment in its ancestral state and one copy of the same segment with the cholesterol deficiency mutation. We detected a single structural variant, homozygous in the affected case and heterozygous in the non-affected carrier male. The genetic makeup of this key animal provides extremely strong support for the causality of this mutation. The mutation represents a 1.3kb insertion of a transposable LTR element (ERV2-1) in the coding sequence of the APOB gene, which leads to truncated transcripts and aberrant splicing. This finding was further supported by RNA sequencing of the liver transcriptome of an affected calf. The encoded apolipoprotein B is an essential apolipoprotein on chylomicrons and low-density lipoproteins, and therefore, the mutation represents a loss of function mutation similar to autosomal recessive inherited familial hypobetalipoproteinemia-1 (FHBL1) in humans. Our findings provide a direct gene test to improve selection against this deleterious mutation in Holstein cattle.

Structure-function analysis of SAP97, a modular scaffolding protein that drives dendrite growth.

Activation of AMPA receptors assembled with the GluA1 subunit can promote dendrite growth in a manner that depends on its direct binding partner, SAP97. SAP97 is a modular scaffolding protein that has at least seven recognizable protein-protein interaction domains. Several complementary approaches were employed to show that the dendrite branching promoting action of full length SAP97 depends on ligand(s) that bind to the PDZ3 domain. Ligand(s) to PDZ1, PDZ2 and I3 domains also contribute to dendrite growth. The ability of PDZ3 ligand(s) to promote dendrite growth depends on localization at the plasma membrane along with GluA1 and SAP97. These results suggest that the assembly of a multi-protein complex at or near synapses is vital for the translation of AMPA-R activity into dendrite growth.

Metabolic adaptation recorded during one lactation does not allow predicting longevity in dairy cows.

INTRODUCTION: Metabolic and health disorders account distinctly for culling in dairy cows. This study investigated if metabolic status obtained once in life during a negative energy balance in early lactation allows to predict age and lifetime performance animals achieved at culling. Metabolically stressed cows entering at least their 3rd lactation (n = 200, parity: 5.0 ± 2.1, mean ± SD) were selected from a field study conducted in Switzerland. Age of cows at culling ranged from 4.7 to 20.2 years with parities from 3 to 17. From cows with known reasons of culling, 28.4% were culled because of fertility, 16.4% due to udder health, 15.5% due to high age and 10.4% because of claw health/lameness. A retrospective classification of the one-time recorded metabolic adaptation in week 4 post partum did not differ between animals of different parities at culling. Furthermore, there was no relationship neither between the metabolic adaptation recorded in a preceding lactation and the number of lactations achieved, nor to the lifetime milk production. Contrary to the wide spread assumptions, an inadequate adaptation due to a high metabolic load in early lactation may not result in an earlier culling of dairy cows, although they are more prone to metabolic disorders.

INTRODUCTION: Les problèmes métaboliques ainsi que d'autres pathologies jouent un rôle important dans les causes de réforme des vaches laitières. Dans la présente étude, on a cherché à savoir si le statut métabolique, qui a été noté une fois durant un bilan énergétique négatif au début de la lactation, permettait de tirer des conclusions quant à l'âge et à la performance de vie au moment de la sortie de l'exploitation. On a choisi, dans le cadre d'une étude de terrain effectuée en Suisse, des vache surchargées métaboliquement à partir de la troisième lactation (n = 200, numéro de lactation: 5.0 ± 2.1, moyenne ± déviation standard). L'âge des vaches lors de la réforme variait entre 4.7 et 20.2 ans et ces vaches comptaient entre 3 et 17 lactations. Chez les vaches dont on connaissait la cause de réforme, celle-ci était pour 28.4% des troubles de fertilité, pour 16.4% des problèmes de mamelle, pour 15.5% un âge avancé et pour 10.4% des affections des onglons ou des boiteries. Une classification rétrospective basée sur la charge métabolique dans la quatrième semaine de lactation n'a pas montré de différence quant au nombre de lactations atteint ni quant à la performance de vie. Contrairement à l'idée répandue, on a pu montrer qu'une adaptation insuffisante due à une charge métabolique élevée en début de lactation ne conduisait pas forcément à une réforme précoce, bien que de telles vaches soient soumises à un risque plus élevé d'affections métaboliques.

The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study.

BACKGROUND: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. OBJECTIVE: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). METHODS: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. RESULTS: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (≥ 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. CONCLUSION: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

Detecting signals in pharmacogenomic genome-wide association studies.

In a common pharmacogenomic scenario, outcome measures are compared for treated and untreated subjects across genotype-defined subgroups. The key question is whether treatment benefit (or harm) is particularly strong in certain subgroups, and therefore the statistical analysis focuses on the interaction between treatment and genotype. However, genome-wide analysis in such scenarios requires careful statistical thought as, in addition to the usual problems of multiple testing, the marker-defined sample sizes, and therefore power, vary across the individual genotypes being evaluated. The variability in power means that the usual practice of using a common P-value threshold across tests has difficulties. The reason is that the use of a fixed threshold, with variable power, implies that the costs of type I and type II errors vary across tests in a manner that is implicit rather than dictated by the analyst. In this paper we discuss this problem and describe an easily implementable solution based on Bayes factors. We pay particular attention to the specification of priors, which is not a straightforward task. The methods are illustrated using data from a randomized controlled clinical trial in which homocysteine levels are compared in individuals receiving low and high doses of folate supplements and across marker subgroups. The method we describe is implemented in the R computing environment with code available from http://faculty.washington.edu/jonno/cv.html.

Lens of controllable optical field with thin film metallic glasses for UV-LEDs.

In the exposure process of photolithography, a free-form lens is designed and fabricated for UV-LED (Ultraviolet Light-Emitting Diode). Thin film metallic glasses (TFMG) are adopted as UV reflection layers to enhance the irradiance and uniformity. The Polydimethylsiloxane (PDMS) with high transmittance is used as the lens material. The 3-D fast printing is attempted to make the mold of the lens. The results show that the average irradiance can be enhanced by 6.5~6.7%, and high uniformity of 85~86% can be obtained. Exposure on commercial thick photoresist using this UV-LED system shows 3~5% dimensional deviation, lower than the 6~8% deviation for commercial mercury lamp system. This current system shows promising potential to replace the conventional mercury exposure systems.