Validation and responsiveness of the English version of the Chemotherapy-Induced Alopecia Distress Scale (CADS) in breast cancer patients.

PURPOSE: This study aimed to validate the Chemotherapy-Induced Alopecia Distress Scale (CADS) in a diverse English-speaking population and patients with endocrine treatment-induced alopecia (EIA). OBJECTIVE: Chemotherapy and endocrine therapy commonly cause alopecia in breast cancer patients, leading to significant psychological and social challenges. The CADS was developed to assess the psychosocial impact of alopecia, but its generalizability beyond Korean patients requires further investigation. METHODS: Data from the CHANCE study (NCT02530177), which focused on non-metastatic breast cancer, was used. The cohort included 256 patients, and CADS data were collected at baseline, 6 months after chemotherapy completion, or 12 months after initiating endocrine therapy. The CADS questionnaire comprised 17 items covering physical and emotional health, daily activities, and relationships. Reliability was assessed using Cronbach's alpha, and responsiveness was measured by effect size. RESULTS: The CADS exhibited good reliability, with Cronbach's alpha of 0.91 for the overall score, indicating acceptable internal consistency in both chemotherapy (0.89) and endocrine therapy (0.86) groups. Longitudinal responsiveness was supported by an effect size of 0.49 between decreasing satisfaction with hair growth and increasing emotional distress. Cross-sectional validity was confirmed, with effect sizes of 0.91 and 0.92 for satisfaction with hair growth and emotional and activity domains, respectively. CONCLUSION: The CADS is a valid and responsive tool for assessing the psychosocial impact of chemotherapy-induced alopecia and endocrine treatment-induced alopecia in a diverse Western patient population.

The Glasgow Microenvironment Score and risk and site of recurrence in TNM I-III colorectal cancer.

BACKGROUND: Glasgow Microenvironment Score (GMS) stratifies long-term survival into three groups based on tumour phenotype: peritumoural inflammation (Klintrup-Mäkinen (KM)) and tumour stroma percentage (TSP). However, it is not known if the location of disease recurrence is influenced by the GMS category. METHODS: Seven hundred and eighty-three TNM I-III colorectal cancers (CRC) were included. GMS (GMS0-high KM; GMS1-low KM, low TSP; GMS2-low KM, high TSP) and cancer-specific survival (CSS), overall survival (OS) and disease recurrence were assessed using Cox regression analysis. RESULTS: Of the 783 patients, 221 developed CRC recurrence; 65 developed local recurrence + systemic disease. GMS was independent for CSS (HR 1.50, 95% CI 1.17-1.92, p < 0.001) and OS (HR 1.23, 1.05-1.44, p = 0.01). Higher GMS category was associated with T-stage, N-stage, emergency presentation and venous invasion. GMS was independent for local+systemic recurrence (HR 11.53, 95% CI 1.45-91.85, p = 0.04) and distant-only recurrence (HR 3.01, 95% CI 1.59-5.71, p = 0.002). GMS 2 disease did not appear to have statistically better outcomes with adjuvant chemotherapy in high-risk disease. CONCLUSION: Although confounded by a higher rate of T4 and node-positive disease, GMS 1 and 2 are associated with an increased risk of local and distant recurrence. GMS is an independent poor prognostic indicator for recurrent colorectal cancer. Higher GMS patients may benefit from enhanced postoperative surveillance.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Musculoskeletal health in newly diagnosed children with Crohn's disease.

We evaluated the impact of Crohn's disease on muscle and bone strength, mass, density, and geometry in children with newly diagnosed CD and found profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low. INTRODUCTION: Crohn's disease (CD) is an inflammatory condition of the gastrointestinal tract that can affect the musculoskeletal system. The objective of this study was to determine the prevalence of vertebral fractures and the impact of CD on muscle and bone mass, strength, density, and geometry in children with newly diagnosed CD. METHODS: Seventy-three children (26 girls) aged 7.0 to 17.7 years were examined within 35 days following CD diagnosis by lateral spine radiograph for vertebral fractures and by jumping mechanography for muscle strength. Bone and muscle mass, density, and geometry were assessed by dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT). RESULTS: Disease activity was moderate to severe in 66 (90%) patients. Mean height (Z-score -0.3, standard deviation (SD) 1.1, p = 0.02), weight (Z-score -0.8, SD 1.3, p < 0.01), body mass index (Z-score -1.0, SD 1.3, p < 0.01), lumbar spine areal bone mineral density (BMD; Z-score -1.1, SD 1.0, p < 0.01), total body bone mineral content (Z-score -1.5, SD 1.0, p < 0.01), and total body lean mass (Z-score -2.5, SD 1.1, p < 0.01) were all low for age and gender. pQCT showed reduced trabecular volumetric BMD at the tibial metaphysis, expansion of the bone marrow cavity and thin cortices at the diaphysis, and low calf muscle cross-sectional area. Jumping mechanography demonstrated low muscle power. Only one patient had a vertebral fracture. CONCLUSIONS: Children with newly diagnosed CD have profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low.

Long-term health outcomes after exposure to repeated concussion in elite level: rugby union players.

BACKGROUND: There is continuing concern about effects of concussion in athletes, including risk of the neurodegenerative disease chronic traumatic encephalopathy. However, information on long-term health and wellbeing in former athletes is limited. METHOD: Outcome after exposure to repeated brain injury was investigated in 52 retired male Scottish international rugby players (RIRP) and 29 male controls who were similar in age and social deprivation. Assessment included history of playing rugby and traumatic brain injury, general and mental health, life stress, concussion symptoms, cognitive function, disability and markers of chronic stress (allostatic load). RESULTS: The estimated number of concussions in RIRP averaged 14 (median=7; IQR 5-40). Performance was poorer in RIRP than controls on a test of verbal learning (p=0.022) and of fine co-ordination of the dominant hand (p=0.038) and not significantly different on other cognitive tests (p>0.05). There were no significant associations between number of concussions and performance on cognitive tests. Other than a higher incidence of cardiovascular disease in controls, no group differences were detected in general or mental health or estimates of allostatic load. In RIRP, persisting symptoms attributed to concussion were more common if reporting more than nine concussions (p=0.028), although these symptoms were not perceived to affect social or work functioning. CONCLUSIONS: Despite a high number of concussions in RIRP, differences in mental health, social or work functioning were not found late after injury. Subtle group differences were detected on two cognitive tests, the cause of which is uncertain. Prospective group comparison studies on representative cohorts are required.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

The Epidemiology of Liver Diseases Unique to Pregnancy in a US Community: A Population-Based Study.

BACKGROUND & AIMS: Little is known in the United States about the epidemiology of liver diseases that develop only during (are unique to) pregnancy. We investigated the incidence of liver diseases unique to pregnancy in Olmsted County, Minnesota, and long-term maternal and fetal outcomes. METHODS: We identified 247 women with liver diseases unique to pregnancy from 1996 through 2010 using the Rochester Epidemiology Project database. The crude incidence rate was calculated by the number of liver disease cases divided by 35,101 pregnancies. RESULTS: Of pregnant women with liver diseases, 134 had preeclampsia with liver dysfunction, 72 had hemolysis-associated increased levels of liver enzymes and low-platelet (HELLP) syndrome, 26 had intrahepatic cholestasis of pregnancy, 14 had hyperemesis gravidarum with abnormal liver enzymes, and 1 had acute fatty liver of pregnancy. The crude incidence of liver diseases unique to pregnancy was 0.77%. Outcomes were worse among women with HELLP or preeclampsia than the other disorders--of women with HELLP, 70% had a premature delivery, 4% had abruptio placentae, 3% had acute kidney injury, and 3% had infant death. Of women with preeclampsia, 56.0% had a premature delivery, 4% had abruptio placentae, 3% had acute kidney injury, and 0.7% had infant death. After 7 median years of follow-up (range, 0-18 years), 14% of the women developed recurrent liver disease unique to pregnancy; the proportions were highest in women with initial hyperemesis gravidarum (36%) or intrahepatic cholestasis of pregnancy (35%). Women with preeclampsia were more likely to develop subsequent hepatobiliary diseases. CONCLUSIONS: We found the incidence of liver disease unique to pregnancy in Olmsted County, Minnesota, to be lower than that reported from Europe or US tertiary referral centers. Maternal and fetal outcomes in Olmsted County were better than those reported from other studies, but fetal mortality was still high (0.7%-3.0%). Women with preeclampsia or HELLP are at higher risk for peripartum complications and subsequent development of comorbidities.

Physical activity intensity and type 2 diabetes risk in overweight youth: a randomized trial.

BACKGROUND: The chronic effects of high-intensity endurance training on metabolic health outcomes in overweight adolescents remains poorly understood. OBJECTIVE: To test the hypothesis that high-intensity endurance training (ET) is superior to moderate-intensity ET for improving risk factors for type 2 diabetes in overweight adolescents. DESIGN AND METHODS: In this randomized trial, 106 overweight and obese adolescents (15.2 years; 76% female; 62% Caucasian) were randomly assigned to high-intensity ET (70-85% of heart rate reserve, n=38), moderate-intensity ET (40-55% heart rate reserve; n=32) or control for 6 months (n=36). The primary and secondary outcome measures were insulin sensitivity assessed using a frequently sampled intravenous glucose tolerance test and hepatic triglyceride content with magnetic resonance spectroscopy. Exploratory outcomes were cardiorespiratory fitness, physical activity and MRI and dual x-ray absorptiometry-derived measures of adiposity. RESULTS: The study had 96% retention and attendance was 61±21% and 55±24% in the high- and moderate-intensity ET arms. Intention-to-treat analyses revealed that, at follow-up, insulin sensitivity was not different between high-intensity (-1.0 mU kg(-1) min(-1); 95% confidence interval (CI): -1.6, +1.4 mU kg(-1) min(-1)) and moderate-intensity (+0.26 mU kg(-1) min(-1); 95% CI: -1.3, +1.8 mU kg(-1) min(-1)) ET arms compared with controls (interaction, P=0.97). Similarly, hepatic triglyceride at follow-up was not different in high-intensity (-1.7% fat/water (F/W); 95% CI: -7.0, +3.6% F/W) and moderate-intensity (-0.40% FW; 95% CI: -6.0, +5.3% F/W) ET compared with controls. Both high intensity (+4.4 ml per kg-FFM (fat-free mass) per minute; 95% CI: 1.7, 7.1 ml kg-FFM(-1) min(-1)) and moderate intensity (+4.4 ml kg-FFM(-1) min(-1); 95% CI: 1.6, 7.3 ml kg-FFM(-1) min(-1)) increased cardiorespiratory fitness, relative to controls (interaction P<0.001). CONCLUSIONS: ET improves cardiorespiratory fitness among obese adolescents; however, owing to lack of compliance, the influence of exercise intensity on insulin sensitivity and hepatic triglycerides remains unclear.

Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post-LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post-LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post-LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post-LT metabolic complications. Long-term follow-up is needed.

Bypass therapy assay testing as a strategy to reduce costs for treatment of haemophilia patients with inhibitors.

Published studies suggest that bypass therapy assay testing can be used to predict treatment response and dosing requirements for haemophilia patients with inhibitors. The aim of this study was to evaluate the costs of utilizing and not utilizing bypass therapy assay testing before treating mild-to-moderate bleeding episodes on-demand in haemophilia patients with inhibitors from a US third-party payer perspective. In our exploratory decision tree model, the average patient was assumed to be an adult weighing 75 kg. Based on existing head-to-head clinical trials, the efficacy of activated prothrombin complex (aPCC) and recombinant factor VIIa (rFVIIa) was assumed to be equivalent and based on expert opinion of the haematologist in our study it was conservatively assumed that assay testing improves the efficacy of both the bypassing agents by 10%. Probabilistic and one-way sensitivity analyses were used to determine the robustness of the results. Cost savings per bleeding episode were estimated at $6886 (95% CI = $4310-7978) for aPCC and $7647 (95% CI = $3134-10 388) for rFVIIa treatment. This translates in potential cost savings of 24.8% (95% CI = 15.5-28.8%) for aPCC use and 18.2% (95% CI = 8-24.7%) for rFVIIa use. Furthermore, if testing successfully predicts the optimum dose for concomitant therapy at the onset of bleeding, significant cost savings were observed compared with rFVIIa and aPCC therapies alone. Use of bypass therapy assay testing before treatment administration in haemophilia inhibitor patients can potentially reduce treatment costs significantly while optimizing dose and therapy response.

Structure and magnetic properties of Cu3Ni2SbO6 and Cu3Co2SbO6 Delafossites with honeycomb lattices.

The crystal structures of two Delafossites, Cu3Ni2SbO6 and Cu3Co2SbO6, are determined by high-resolution synchrotron powder X-ray diffraction. The Ni and Co are ordered with respect to Sb in the layer of edge sharing octahedra, forming magnetic layers with honeycomb geometry. High-resolution electron microscopy confirms ordering, and selected-area electron diffraction patterns identify examples of the stacking polytypes. Low temperature synthetic treatments result in disordered stacking of the layers, but heating just below their melting points results in nearly fully ordered stacking variants. The major variant in both cases is a monoclinic distortion of a 6-layer Delafossite polytype, but a significant amount of a 2-layer polytype is also present for the Ni case. The antiferromagnetic ordering with transitions, at 22.3 and 18.5 K for Ni and Co variants, respectively, is investigated by temperature and field dependent magnetization, as well as specific heat. The sharp magnetic transitions support the presence of well developed 2:1 ordering of the Co:Sb or Ni:Sb ions in the honeycomb layers. Neutron diffraction measurements at 4 K are used to determine the magnetic structures. For both the Ni and Co phases, the propagation vector is k = [100], and can be described as alternating ferromagnetic chains in the metal-oxide plane giving an overall antiferromagntic "zigzag" alignment. While orientation of the magnetic moments of the Co is along the b-axis, the Ni moments are in the ac plane, approximately parallel to the stacking direction. Bulk magnetization properties are discussed in terms of their magnetic structures.

Local elastic response measured near the colloidal glass transition.

We examine the response of a dense colloidal suspension to a local force applied by a small magnetic bead. For small forces, we find a linear relationship between the force and the displacement, suggesting the medium is elastic, even though our colloidal samples macroscopically behave as fluids. We interpret this as a measure of the strength of colloidal caging, reflecting the proximity of the samples' volume fractions to the colloidal glass transition. The strain field of the colloidal particles surrounding the magnetic probe appears similar to that of an isotropic homogeneous elastic medium. When the applied force is removed, the strain relaxes as a stretched exponential in time. We introduce a model that suggests this behavior is due to the diffusive relaxation of strain in the colloidal sample.

Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis.

We have administered a recombinant adenovirus vector (AdCFTR) containing the normal human CFTR cDNA to the nasal and bronchial epithelium of four individuals with cystic fibrosis (CF). We show that this vector can express the CFTR cDNA in the CF respiratory epithelium in vivo. With doses up to 2 x 10(9) pfu, there was no recombination/complementation or shedding of the vector or rise of neutralizing antibody titres. At 2 x 10(9) pfu, a transient systemic and pulmonary syndrome was observed, possibly mediated by interleukin-6. Follow-up at 6-12 months demonstrated no long term adverse effects. Thus, it is feasible to use an adenovirus vector to transfer and express the CFTR cDNA in the respiratory epithelium of individuals with CF. Correction of the CF phenotype of the airway epithelium might be achieved with this strategy.

Validation and Responsiveness of the English version of the Chemotherapy-Induced Alopecia Distress Scale (CADS) in Breast Cancer Patients.

Purpose: This study aimed to validate the chemotherapy-induced alopecia distress scale (CADS) in a diverse English-speaking population and patients with endocrine treatment- induced alopecia (EIA). Objective: Chemotherapy and endocrine therapy commonly cause alopecia in breast cancer patients, leading to significant psychological and social challenges. The CADS was developed to assess the psychosocial impact of alopecia, but its generalizability beyond Korean patients requires further investigation. Methods: Data from the CHANCE study ( NCT02530177 ), which focused on non-metastatic breast cancer, was used. The cohort included 256 patients, and CADS data were collected at baseline, six months after chemotherapy completion, or 12 months after initiating endocrine therapy. The CADS questionnaire comprised 17 items covering physical and emotional health, daily activities, and relationships. Reliability was assessed using Cronbach's alpha, and responsiveness was measured by effect size. Results: The CADS exhibited good reliability, with a Cronbach's alpha of 0.91 for the overall score, indicating acceptable internal consistency in both chemotherapy (0.89) and endocrine therapy (0.86) groups. Longitudinal responsiveness was supported by an effect size of 0.49 between decreasing satisfaction with hair growth and increasing emotional distress. Cross-sectional validity was confirmed, with effect sizes of 0.91 and 0.92 for satisfaction with hair growth and emotional and activity domains, respectively. Conclusion: The CADS is a valid and responsive tool for assessing the psychosocial impact of chemotherapy-induced alopecia and endocrine treatment-induced alopecia in a diverse Western patient population.

Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation.

Drug-induced liver injury (DILI) is increasingly being recognized as a common cause of acute hepatitis. The clinical impact of DILI after liver transplantation (LT) is not known. The aim of this study was to describe the frequency, clinical presentation, and outcomes of DILI in LT recipients. LT recipients with possible DILI were identified with electronic pathology records and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Twenty-nine of 1689 LT recipients (1.7%) were identified with DILI. The mean age was 52 years, and 52% were women. The major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). The severity of DILI was mild or moderate in 92% of the cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at the time of diagnosis. The mean biochemistry values were as follows: alanine aminotransferase, 204 ± 263 U/L; aspartate aminotransferase, 108 ± 237 U/L; alkaline phosphatase, 469 ± 689 U/L; and total bilirubin, 1.9 ± 10.3 mg/dL. The median duration of medication use until the diagnosis of DILI was 57 days, and the major agent classes were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%). Trimethoprim-sulfamethoxazole was the most common implicated agent (n = 11). Serum liver enzymes improved within a median time of 34 days (range = 5-246 days) after drug withdrawal. Hepatic retransplantation or death did not occur. Among the 50 cases with possible DILI explained by other causes, 13 individuals (26%) had no alternative diagnosis despite histological findings compatible with DILI. In conclusion, DILI is a rare yet underrecognized event among LT recipients. The majority of cases are not clinically severe, and they resolve after drug cessation without hepatic retransplantation or death.

Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome.

SUMMARY: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.

Persistence of sugars used for intestinal permeability measures in an in vitro rumen environment.

Orally administered synthetic sugars are routinely used as markers of intestinal permeability in nonruminants and young calves, but not adult ruminants, likely because of uncertainty surrounding degradation of such sugar markers (e.g., d-mannitol, sucralose, lactulose) in the rumen. The objective was to evaluate persistence of d-mannitol, sucralose, and lactulose in a closed in vitro rumen fermentation system over 48 h. The null hypothesis was that sugar concentration would not be affected by time. Rumen contents were collected and processed under anerobic conditions a total of 12 times from a ruminally cannulated lactating Holstein cow. These 12 rumen samplings reflect 4 in vitro experiments (d-mannitol, sucralose, lactulose, and d-glucose as a positive methodological control), each replicated 3 times. For each replication, filtered rumen contents and rumen buffer (1:3; vol/vol) were added to a series of six 500-mL flasks, each containing 3 filter bags. Each filter bag contained 500 mg of ground total mixed ration (94.2% dry matter; 15.2% crude protein, 40.9% neutral detergent fiber, 3.9% fat, and 6.2% ash, dry matter basis) and three 5-mm glass beads. The 6 flasks represented 0, 6, 12, 24, and 48 h time points, and a 48-h negative control flask. A single sugar was tested during each experimental replicate. Final flask concentrations of each sugar were 4.07 mg/mL d-glucose, 1.99 mg/mL d-mannitol, 2.17 mg/mL sucralose, or 3.10 mg/mL lactulose. Flasks were incubated under anerobic conditions at 39°C where they remained undisturbed until the designated time of removal (0, 6, 12, 24, or 48 h). At removal, an aliquot of each flask was removed and sugar concentration was quantified by HPLC-mass spectrometry. Data for each experiment were analyzed using an ANOVA model that included the single fixed effect of time (0, 6, 12, 24, or 48 h); flask within replicate was the random term. Lactulose was not resolved in any samples due to interfering components within the sample matrix; no lactulose data are presented. As expected, positive methodological control of glucose decreased to negligible concentrations by 6 h of in vitro incubation. d-Mannitol followed the same pattern as glucose, which was different from our hypothesis. The interpretation is that d-mannitol is degraded in the in vitro rumen culture system and, by extension, is therefore not a viable choice to use in in vivo intestinal permeability tests in adult ruminants when dosed orally. As hypothesized, sucralose concentration did not change over 48 h of incubation in a closed in vitro rumen fermentation system. This suggests feasibility of orally dosed sucralose in adult ruminants as a rumen-inert marker of intestinal permeability with subsequent analysis of biological samples (e.g., urine, blood) by HPLC-mass spectrometry.

SNAREs and NSF in targeted membrane fusion.

A major current issue in vesicle trafficking is whether NSF (N-ethylmaleimide-sensitive factor) and alpha-SNAP (alpha-soluble NSF attachment protein) are required prior to SNARE (SNAP receptor) complex formation to allow vesicle docking, or after docking at a step close to membrane fusion. Recent studies of yeast vacuolar fusion indicated that the requirement for ATP, NSF and alpha-SNAP could be completely satisfied prior to SNARE docking complex assembly; however, the universality of a predocking role for these factors remains to be established. The vacuolar fusion system has also been used to directly demonstrate a requirement for SNARE proteins on both fusing membranes, verifying a central postulate of current fusion models.

Economical comparison of APCC vs. rFVIIa for mild-to-moderate bleeding episodes in haemophilia patients with inhibitors.

To construct a cost-minimization model comparing activated prothrombin complex concentrates (APCC) vs. recombinant factor VIIa (rFVIIa) in haemophilia patients with inhibitors from a US third party payer perspective. A literature-based decision model was used to model inhibitor treatment costs and outcomes. As existing clinical trials fail to demonstrate differences in the relative efficacy or safety of APCC vs. rFVIIa, we assumed the same efficacy for both products in the base-case. Regimens of APCC (75 IU kg⁻¹ × 2 doses) and rFVIIa (90 µg kg⁻¹× 3 doses) were assumed according to manufacturer recommendations. If the first-line treatment failed, patients chose to continue the current treatment or switch to another drug. All costs were adjusted to 2009 US dollars. Sensitivity analyses on the infusion frequency, efficacy, unit price, switch rate, re-bleed rate and body weight were performed to assess model robustness. In the base-case, the total medical cost to treat a bleed with APCC or rFVIIa as first-line medication was US$25,969 and US$35,838, respectively. One-way sensitivity analyses showed that results were insensitive to the efficacy of rFVIIa, unit price of APCC or rFVIIa, switch rate, re-bleed rate or body weight. The rFVIIa will reach cost neutrality when the efficacy of APCC is as low as 60%, or rFVIIa is infused only twice for each line, or APCC is infused three times for each line. Two-way sensitivity analyses showed that results were quite sensitive to the assumed infusion frequency for both products. First-line APCC compared with rFVIIa can be a cost-saving alternative for home treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors.