Discovery of MDV6058 (PF-06952229), a selective and potent TGFßR1 inhibitor: Design, synthesis and optimization.

Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.

A Multicenter Study of the Clinical Utility of Nontargeted Systematic Transperineal Prostate Biopsies in Patients Undergoing Pre-Biopsy Multiparametric Magnetic Resonance Imaging.

PURPOSE: The added value of nontargeted systematic prostate biopsies when performed alongside magnetic resonance imaging targeted biopsies in men referred with a suspicion of prostate cancer is unclear. We aimed to determine the clinical utility of transperineal nontargeted systematic prostate biopsies, when performed alongside targeted systematic prostate biopsies, using pre-biopsy multiparametric magnetic resonance imaging. MATERIALS AND METHODS: Consecutive patients referred with a suspicion of prostate cancer (April 2017 to October 2019) underwent pre-biopsy multiparametric magnetic resonance imaging. A transperineal biopsy was advised if multiparametric magnetic resonance imaging PI-RADS® (v.2.0) score was 4 or 5, and score 3 required a prostate specific antigen density 0.12 ng/ml or greater. Primary threshold for clinically significant prostate cancer was defined as any Gleason 3+4 or greater. Multivariable logistic regression analysis identified pre-biopsy predictors of clinically significant prostate cancer in nontargeted systematic prostate biopsies, regardless of targeted pathology (p <0.05, R, version 3.5.1). RESULTS: A total of 1,719 men underwent a pre-biopsy multiparametric magnetic resonance imaging, with 679 (39.5%) proceeding to combined targeted systematic prostate biopsies and nontargeted systematic prostate biopsies. In these men clinically significant prostate cancer was detected in 333 (49%) and 139 (20.5%) with targeted systematic prostate biopsies and nontargeted systematic prostate biopsies, respectively. In those men with clinically significant prostate cancer in targeted systematic prostate biopsies, clinically significant prostate cancer was also present in nontargeted systematic prostate biopsies in 117 (17.2%); Gleason 3+3 was present in 50 (7.4%). In 287 men without any cancer in the targeted systematic prostate biopsies, 13 (1.9%) had clinically significant prostate cancer in nontargeted systematic prostate biopsies. In addition 18/679 (2.7%) had Gleason 3+3 disease and no Gleason greater than 4+3 was detected. Predictors associated with clinically significant prostate cancer in nontargeted systematic prostate biopsies were prostate specific antigen 5 ng/ml or greater (OR 2.05, 95% CI 1.13-3.73, p=0.02), PI-RADS score 5 (OR 2.26, 95% CI 1.51-3.38, p <0.001) and prostate volume less than 50 cc (OR 2.47, 95% CI 1.57-3.87, p <0.001). CONCLUSIONS: Detection of clinically significant prostate cancer in exclusively nontargeted transperineal systematic biopsies in a pre-biopsy multiparametric magnetic resonance imaging pathway was low (1.9%).

Threshold regulation and stochasticity from the MecA/ClpCP proteolytic system in Streptococcus mutans competence.

Many bacterial species use the MecA/ClpCP proteolytic system to block entry into genetic competence. In Streptococcus mutans, MecA/ClpCP degrades ComX (also called SigX), an alternative sigma factor for the comY operon and other late competence genes. Although the mechanism of MecA/ClpCP has been studied in multiple Streptococcus species, its role within noisy competence pathways is poorly understood. S. mutans competence can be triggered by two different peptides, CSP and XIP, but it is not known whether MecA/ClpCP acts similarly for both stimuli, how it affects competence heterogeneity, and how its regulation is overcome. We have studied the effect of MecA/ClpCP on the activation of comY in individual S. mutans cells. Our data show that MecA/ClpCP is active under both XIP and CSP stimulation, that it provides threshold control of comY, and that it adds noise in comY expression. Our data agree quantitatively with a model in which MecA/ClpCP prevents adventitious entry into competence by sequestering or intercepting low levels of ComX. Competence is permitted when ComX levels exceed a threshold, but cell-to-cell heterogeneity in MecA levels creates variability in that threshold. Therefore, MecA/ClpCP provides a stochastic switch, located downstream of the already noisy comX, that enhances phenotypic diversity.

Treating benign ureteroenteric strictures: 27-year experience comparing endourological techniques with open surgical approach.

PURPOSE: To compare open surgical anastomotic revision with endourological techniques for the treatment of ureteroenteric strictures in patients with urinary diversions. METHODS: All records of patients treated for ureteroenteric strictures in our clinic between 1989 and 2016 were retrospectively reviewed. In 76 patients, 161 completed procedures were analyzed: 26 open revisions vs. 135 endourological treatments, including balloon dilation, Wallstent and/or laser vaporization. RESULTS: Median follow-up was 34 months. At 60 months, patency rates were 69% (95% CI 52-92%) after open vs. 27% (95% CI 19-39%) after endo-treatment (p = 0.003); median patency duration was 15.5 vs. 5 months, respectively (p = 0.014). Eventually, 15% of patients required open surgery after primary endo-treatment and 21% received endoscopic re-treatment after primary open surgery. Cox regression analysis revealed no confounding factors among the risk factors added to the model. Complication rates were higher after open surgery (27% Clavien 2, 12% Clavien 3-4 vs. 5% Clavien 1-2, 3% Clavien 3, p = 0.528). Median postoperative hospital stay was 14 days (open) vs. 2 days (endo), p < 0.001. Mean estimated glomerular filtration rate improved with + 17 (open) vs. + 8.1 (endo), p = 0.024. Renal function was compromised in 8% of patients in the open surgery group vs. 6% in the endo-treatment group. CONCLUSIONS: In these patients, in terms of patency and patency duration, open surgery was superior to endourology. Nevertheless, endourological treatments offer a safe and less-invasive alternative to delay or avoid open surgery, especially in patients who are unfit for open surgery.

Egg white hydrolysate enhances insulin sensitivity in high-fat diet-induced insulin-resistant rats via Akt activation.

Agents that block the renin-angiotensin system (RAS) improve glucoregulation in the metabolic syndrome disorder. We evaluated the effects of egg white hydrolysate (EWH), previously shown to modulate the protein abundance of RAS component in vivo, on glucose homeostasis in diet-induced insulin-resistant rats. Sprague-Dawley rats were fed a high-fat diet (HFD) for 6 weeks to induce insulin resistance. They were then randomly divided into four groups receiving HFD or HFD supplemented with different concentrations of EWH (1, 2 and 4 %) for another 6 weeks in the first trial. In the second trial, insulin-resistant rats were divided into two groups receiving only HFD or HFD+4 % EWH for 6 weeks. Glucose homeostasis was assessed by oral glucose tolerance and insulin tolerance tests. Insulin signalling and protein abundance of RAS components, gluconeogenesis enzymes and PPARγ were evaluated in muscle, fat and liver. Adipocyte morphology and inflammatory markers were evaluated. In vivo administration of EWH increased insulin sensitivity, improved oral glucose tolerance (P < 0·0001) and reduced systemic inflammation (P < 0·05). EWH potentiated insulin-induced Akt phosphorylation in muscle (P = 0·0341) and adipose tissue (P = 0·0276), but minimal differences in the protein abundance of tissue RAS components between the EWH and control groups were observed. EWH treatment also reduced adipocyte size (P = 0·0383) and increased PPARγ2 protein abundance (P = 0·0237). EWH treatment yielded positive effects on the inflammatory profile, glucose tolerance, insulin sensitivity and adipocyte differentiation in HFD-induced insulin resistance rats. The involvement of local RAS activity requires further investigation.

Predictors of disability in a childhood-onset systemic lupus erythematosus cohort: results from the CARRA Legacy Registry.

Objective Few descriptions of physical disability in childhood-onset SLE (cSLE) exist. We sought to describe disability in a large North American cohort of patients with cSLE and identify predictors of disability. Methods Sociodemographic and clinical data were obtained from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry for patients with cSLE enrolled between May 2010 and October 2014. The Childhood Health Assessment Questionnaire (CHAQ) was used to assess disability and physical functioning. Chi-square tests were used for univariate analyses, and multivariate logistic regression was used to assess predictors of disability. Results We analyzed data for 939 patients with cSLE. The median and mean CHAQ scores were 0 and 0.25, respectively, and 41% of the cohort had at least mild disability. Arthritis and higher pain scores were significantly associated with disability as compared to those without disability ( p < 0.001). In multivariate logistic regression analysis, low annual income, arthritis, and higher pain scores were associated with disability at baseline. Conclusions Disability as measured by baseline CHAQ was fairly common in cSLE patients in the CARRA Legacy Registry, and was associated with low household income, arthritis, and higher pain scores. In addition to optimal disease control, ensuring psychosocial supports and addressing pain may reduce disability in cSLE. Further study is needed of disability in cSLE.

Arthritis and use of hydroxychloroquine associated with a decreased risk of macrophage activation syndrome among adult patients hospitalized with systemic lupus erythematosus.

Background Macrophage activation syndrome (MAS) is an uncommon but serious complication of systemic lupus erythematosus (SLE). We aimed to identify factors associated with MAS among adult hospitalized SLE patients. Methods Within the Brigham and Women's Hospital (BWH) Lupus Center Registry, we identified adult SLE patients > age 17 who had been hospitalized from 1970 to 2016, with either ferritin > 5000 ng/ml during admission or "macrophage activation syndrome" or "MAS" in discharge summary. We confirmed MAS by physician diagnosis in medical record review. We matched each hospitalized SLE patient with MAS to four SLE patients hospitalized without MAS (by SLE diagnosis date ±1 year). We employed conditional logistic regression models to identify clinical factors associated with MAS among hospitalized SLE patients. Results Among 2094 patients with confirmed SLE, we identified 23 who had a hospitalization with MAS and compared them to 92 hospitalized without MAS. Cases and controls had similar age at SLE diagnosis (29.0 vs. 30.5, p = 0.60), and hospital admission (43.0 vs. 38.3, p = 0.80), proportion female (78% vs. 84%, p = 0.55), and time between SLE diagnosis and hospitalization (1971 vs. 1732 days, p = 0.84). Arthritis (OR 0.04 (95% CI 0.004-0.35)) and hydroxychloroquine use (OR 0.18 (95% CI 0.04-0.72)) on admission were associated with decreased MAS risk. Admission Systemic Lupus Erythematosus Disease Activity Index scores (30 vs. 19, p = 0.002) and lengths of stay (16 days vs. 3 days, p < 0.0001) were much higher among cases. Death during hospitalization was 19% among cases and 3% among controls ( p = 0.03). Conclusions In this case-control study of hospitalized adult SLE patients, arthritis and hydroxychloroquine use at hospital admission were associated with decreased MAS risk. Further studies are needed to validate these factors associated with lowered MAS risk.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.

Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient-derived induced pluripotent stem cells.

AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses. RESULTS: The expression profiles of LK2GS were distinct from those of wild-type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD-specific hNESs and hIOs by microarray and qRT-PCR analysis. CONCLUSION: We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.

Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR.

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.

Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).

The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

Trajectories in quality of life of patients with a fracture of the distal radius or ankle using latent class analysis.

PURPOSE: This prospective study aimed to identify the different trajectories of quality of life (QOL) in patients with distal radius fractures (DRF) and ankle fractures (AF). Secondly, it was examined if subgroups could be characterized by sociodemographic, clinical, and psychological variables. METHODS: Patients (n = 543) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref), the pain, coping, and cognitions questionnaire, NEO-five factor inventory (neuroticism and extraversion), and the state-trait anxiety inventory (short version) a few days after fracture (i.e., pre-injury QOL reported). The WHOQOL-Bref was also completed at three, six, and 12 months post-fracture. Latent class trajectory analysis (i.e., regression model) including the Step 3 method was performed in Latent Gold 5.0. RESULTS: The number of classes ranged from three to five for the WHOQOL-Bref facet and the four domains with a total variance explained ranging from 71.6 to 79.4%. Sex was only significant for physical and psychological QOL (p < 0.05), whereas age showed significance for overall, physical, psychological, and environmental QOL (p < 0.05). Type of treatment or fracture type was not significant (p > 0.05). Percentages of chronic comorbidities were 1.8 (i.e., social QOL) to 4.5 (i.e., physical QOL) higher in the lowest compared to the highest QOL classes. Trait anxiety, neuroticism, extraversion, pain catastrophizing, and internal pain locus of control were significantly different between QOL trajectories (p < 0.05). CONCLUSIONS: The importance of a biopsychosocial model in trauma care was confirmed. The different courses of QOL after fracture were defined by several sociodemographic and clinical variables as well as psychological characteristics. Based on the identified characteristics, patients at risk for lower QOL may be recognized earlier by health care providers offering opportunities for monitoring and intervention.

Exploiting whole genome sequence data to fine map and characterize candidate genes within a quantitative trait loci region affecting androstenone on porcine chromosome 5.

Male piglets are routinely castrated to eliminate boar taint. However, this treatment is undesirable, and alternative approaches, including genetic strategies to reduce boar taint, are demanded. Androstenone is one of the causative agents of boar taint, and a QTL region affecting this pheromone has previously been reported on SSC5: 22.6-24.8 Mb in Duroc. The QTL region is one of the few reported for androstenone that does not simultaneously affect levels of other sex steroids. The main objective of this study was to fine map this QTL. Whole genome sequence data from 23 Norwegian Duroc boars were analyzed to detect new polymorphisms within the QTL region. A subset of 161 SNPs was genotyped in 834 Duroc sires and analyzed for association with androstenone in adipose tissue and testosterone, estrone sulphate and 17ß-estradiol in blood plasma. Our results revealed 100 SNPs significantly associated with androstenone levels in fat (P < 0.001) with 94 of the SNPs being in strong linkage disequilibrium in the region 23.03-24.27 Mb. This haplotype block contains at least four positional candidate genes (HSD17B6, SDR9C7, RDH16 and STAT6) involved in androstenone biosynthesis. No significant associations were found between any of the SNPs and levels of testosterone and estrogens, confirming previous findings. The amount of phenotypic variance explained by single SNPs within the haplotype block was as high as 5.4%. As the SNPs in this region significantly affect levels of androstenone without affecting levels of other sex steroids, they are especially interesting as genetic markers for selection against boar taint.

Disease activity and transition outcomes in a childhood-onset systemic lupus erythematosus cohort.

Objective The chronicity and severity of childhood-onset systemic lupus erythematosus (cSLE) necessitate effective transition from pediatric to adult providers. We studied transition outcomes in a cSLE cohort. Methods We identified patients at an adult lupus clinic diagnosed with SLE ≤ 18 years who had been followed by a pediatric rheumatologist. Data extracted from the first three years in adult care ("post-transition period") included: sociodemographics, depression, anxiety, SLE manifestations, SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/ACR Damage Index for SLE (SLICC) scores, non-adherence, and gaps in care (no appointments in the recommended time frame). Multivariable logistic regression analyses for predictors of: (1) time between pediatric and adult providers, (2) gaps in care, (3) unscheduled utilization (emergency department visits and admissions) (4) depression and/or anxiety were performed, as was a multivariable Poisson regression analysis for number of missed appointments. Results In 50 patients, SLEDAI scores were stable (mean 5.7 ± 5.0 at start vs. 4.7 ± 4.8 at year 3, p = 0.2), but SLICC scores increased (0.46 ± 0.84, vs. 0.78 ± 1.25, p = 0.01). Depression and anxiety increased significantly (10% vs. 26%, p = 0.02). Mean time from last pediatric to first adult provider visit was almost nine months (253 ± 392 days). Nearly 75% of patients had ≥ 1 gap in care. White race, low education level and non-adherence were significantly associated with missed appointments. Conclusion Despite moderate disease activity in this cSLE transition cohort, prolonged time between pediatric and adult providers and gaps in care in the post-transition period occurred. Anxiety and depression were frequently reported. Future work should identify methods to improve transition.

Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide.

Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.

Clinical indication and timing of antenatal corticosteroid administration at a single centre.

OBJECTIVE: To determine how well antenatal corticosteroids (ACS) were timed, based on the indication for administration for women delivering preterm. DESIGN: Retrospective cohort study. SETTING: Tertiary medical centre. POPULATION: Six hundred and thirty women who had singleton preterm births between 24 and 34 weeks' gestational age. METHODS: Charts from 2006 to 2011 were reviewed for indications for ACS administration, which included premature rupture of membranes, threatened preterm labour, risk factors for spontaneous preterm birth such as short ultrasound cervical length, positive fetal fibronectin, and hypertensive disorders of pregnancy. Charts were reviewed for timing of ACS administration in relation to delivery. MAIN OUTCOME MEASURES: The primary outcome was optimal timing, defined as administration of ACS ≥ 24 hours to ≤ 7 days prior to delivery. RESULTS: Of 630 women who delivered preterm, 589 (93%) received ACS prior to delivery. ACS timing was optimal in 40% (238 of 589) of cases. Women with hypertensive disorders were most likely to have steroids optimally timed (62%). Asymptomatic women at increased risk for preterm delivery were less likely to receive optimally timed ACS (12%). The majority of women who received steroids >2 weeks prior to delivery (57%) received a second course. CONCLUSION: A majority of women who delivered preterm did not receive optimally timed ACS. Diagnostic tools that identified women at risk for preterm birth were not able to identify patients for appropriate steroid timing. Given the range of clinical scenarios in which patients are at increased risk for preterm delivery, further research is needed to assist clinicians in optimising steroid administration. TWEETABLE ABSTRACT: Optimal timing of antenatal steroids prior to delivery does not occur in most cases.

The course of health status and (health-related) quality of life following fracture of the lower extremity: a 6-month follow-up study.

PURPOSE: The aim of this prospective study was to describe the course of health status (HS), health-related quality of life, and quality of life (QOL) in patients with lower extremity fractures (LEF) up to 6 months post-fracture. METHODS: Patients (n = 171; age range 18-100 years) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref) and the Short Musculoskeletal Function Assessment questionnaire (SMFA) at time of diagnosis (i.e., pre-injury status), 1 week, and 6 months post-fracture. Linear mixed modeling was performed. RESULTS: Interaction effects of time with treatment were detected for the WHOQOL-Bref facet Overall QOL and General health (p = .002) and Physical health (p = .003). Patients did not return to their pre-injury Physical health, Psychological health, and Environment 6 months post-fracture (p < .05). No effects were found for Social relationships. The SMFA subscale Lower extremity dysfunction showed main effects for time and treatment (p < .0001) with full recovery at 6 months (p = .998). An interaction effect of time with treatment was found for Daily life consequences (p < .0001) with nonoperatively treated patients showing full recovery (p = 1.00), whereas surgically treated patients did not (p = .002). CONCLUSIONS: Six months after LEF, patients still experienced impaired physical and psychological health on the WHOQOL-Bref compared to their pre-injury status. However, patients showed full recovery on SMFA Lower extremity dysfunction, indicating that the choice of the questionnaire influences the derived conclusions. LEF did not affect satisfaction with social relationships.

Major Esophageal Dilation After Laparoscopic Adjustable Gastric Banding in Symptomatic Patients: Does It Prevent Effective Weight Loss and How Should It be Treated?

INTRODUCTION: Esophageal dilation (ED) has been described as a long-term complication following laparoscopic adjustable gastric banding (LAGB) with an incidence of 0.5-50%. The purpose of this study was to evaluate the effect of major ED on weight loss and find methods to diagnose ED and possible treatment strategies based on a classification. MATERIALS AND METHODS: We performed a retrospective analysis of all patients undergoing LAGB between 2004 and 2008 in three community-based hospitals. ED was classified in four stages of dilation using gastrografin swallow. We report body mass index (BMI), failure rates and reoperations among these patients, with a mean follow-up period of 6.7 years. RESULTS: Nineteen (18.4%) of 103 patients who underwent LAGB presented with esophageal dilation. Band deflation failed for all nine patients (8.7%) with major ED. The mean BMI at LAGB (BMI 1), revision (BMI 2), and 1 year after conversion (BMI 3) were 45.9±3.2, 42.8±4.9 and 30.3±5.5 kg/m2, respectively. No significant difference was found comparing BMI 1 and BMI 2 (p=0,065, EWL1: 14.2±21.7 kg/m2). In contrast, the weight loss after the revision surgery was significant (p=0.001, EWL2: 67.1±30 kg/m2). No significant difference was found concerning age, gender, ASA, preoperative (LAGB) weight, and mean interval between LAGB and revision comparing patients with major ED (IV) to patients with milder forms (ED I-III). CONCLUSION: ED is a serious long-term complication after LAGB and seems to prevent effective weight loss in stage IV. Furthermore, untreated dilation could cause long-term damage to the esophagus. Therefore, we suggest routine radiographic follow-up after LAGB even in asymptomatic patients and a treatment based on a classification with an early surgical revision for major ED.

Psychometric properties of the Dutch Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with a fracture of the upper or lower extremity.

PURPOSE: This prospective study examined the psychometric properties of the adapted Dutch translation of the Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with isolated unilateral lower fracture (LEF) or upper extremity fracture (UEF). METHODS: Patients (N = 458) completed the SMFA, WHOQOL-BREF, and the RAND-36 at time of diagnosis (i.e. pre-injury status), 1, and 2 weeks post-fracture. Principal axis factoring was performed, and Cronbach's alpha coefficients (α) and intra-class correlation coefficients (ICC) were calculated. Furthermore, Pearson's product-moment correlations (r), paired t tests, and standardized response means (SRM) were calculated. RESULTS: A three-factor structure was found: Lower extremity dysfunction, Upper extremity dysfunction, and Daily life consequences. This structure was different for patients with LEF versus UEF. ICCs ranged from .68 to .90, and α varied from .81 to .95. The correlations between the SMFA and, respectively, the RAND-36 and WHOQOL-BREF were small to large depending on the SMFA factor combined with fracture location. Responsiveness was confirmed (p < .0001; SRM ranging from .28 to 1.71). CONCLUSIONS: The SMFA has good psychometric properties in patients with fractures. Patients with UEF and LEF could not be regarded as a homogenous group. The development of separate SMFA modules should be considered.