Classification of breed combinations for slaughter pigs based on genotypes-modeling DNA samples of crossbreeds as fuzzy sets from purebred founders.

In pig production, the production animals are generally three- or four-way crossbreeds. Reliable information regarding the breed of origin of slaughtered pigs is useful, even a prerequisite, for a number of purposes, e.g., evaluating potential breed effects on carcass grading. Genetic data from slaughtered pigs can easily be extracted and used for crossbreed classification. In the current study, four classification methods, namely, random forest (RF), ADMIXTURE, partial least squares regression (PLSR), and partial least squares together with quadratic discriminant analysis (PLS-QDA) were evaluated on simulated (n = 7,500) genomic data of crossbreeds. The derivation of the theory behind PLS-QDA is a major part of the current study, whereas RF and ADMIXTURE are known and well-described in the literature. Classification success (CS) rate, square loss (SL), and Kullback-Leibler (KL) divergence loss for the simulated data were used to compare methods. Overall, PLS-QDA performed best with 99%/0.0018/0.002 (CS/SL/KL) vs. 97%/0.0084/0.051, 97%/0.0087/0.0623, and 17%/0.068/0.39 for PLSR, ADMIXTURE, and RF, respectively. PLS-QDA and ADMIXTURE, as the most relevant methods, were used on a real dataset (n = 1,013) from Norway where the two largest classes contained 532 and 192 (PLS-QDA), and 531 and 193 (ADMIXTURE) individuals, respectively. These two classes were expected to be dominating a priori. The Bayesian nature of PLS-QDA enables inclusion of desirable features such as a separate class "unknown breed combination" and informative priors for crossbreeds, making this a preferable method for the classification of breed combination in the industry.

Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors.

Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the discovery and profiling of a novel series of N-acylpyrazoles, which act as selective, covalent, reversible, non-competitive inhibitors of thrombin. We describe in vitro stability issues associated with this chemotype and, importantly, demonstrate that N-acylpyrazoles successfully act in vivo as anticoagulants in basic thrombotic animal models. Crucially, this anticoagulant nature is unaccompanied by the higher bleeding risk profile that has become an undesirable characteristic of the DTIs and factor Xa inhibitors. We propose that the N-acylpyrazole chemotype shows intriguing promise as next-generation oral anticoagulants.

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.

All-inside arthroscopic anterior cruciate ligament reconstruction with internal brace Ligament Augmentation using semitendinosus tendon autograft: A case series.

Introduction and importance: Anterior Cruciate Ligament (ACL) reconstruction surgery has been proven to be closely related to the graft healing process, which can last up to 12 months after surgery. In recent years, through various biomechanical and clinical studies, Internal Brace Ligament Augmentation (IBLA) has been shown to protect the graft during these early postoperative stages and improve the outcome of ACL reconstruction. We present this case series of all-inside arthroscopic anterior cruciate ligament reconstruction with IBLA using semitendinosus tendon autografts, with the goal of evaluating postoperative clinical and patient-reported outcomes. Case presentation: A total of 37 patients who underwent all-inside arthroscopic anterior cruciate ligament reconstruction with IBLA using only semitendinosus tendon autografts, were evaluated, in terms of patient reported outcome and clinical assessment, during the 3, 6 and 12 months post-operative follow-up. Results: The mean Lysholm Knee score at the final follow-up was 94,03 +- 3,65 with a difference of 34,59 +- 5,52 to the baseline level. International Knee Documentation Committee (IKDC) classification rated 30 cases of grade A and 7 cases of grade B. In terms of clinical tests and knee's range of motion, all patients have returned to normal, and no cases of re-rupture or other severe complications were found. Clinical discussion: Early follow-up patient reported outcomes have provided good to great results for the 37 patients who underwent all-inside arthroscopic anterior cruciate ligament reconstruction with IBLA using semitendinosus tendon autografts and no cases of graft failure or other notable complication has been discovered. Clinical findings suggest improved knee's integrity and range of movement during the early stages, which may promote early rehabilitation, however future long-term comparative studies are needed. Conclusion: IBLA with all-inside ACL reconstructions using only semitendinosus autograft has provided good to great results however, future long-term comparative studies are needed.

Diagnostic value of clinical tests and Mri for meniscal injury in patients with anterior cruciate ligament injury: Case series study.

INTRODUCTION AND IMPORTANCE: Meniscal tear is one of the most common knee injuries and knee surgery procedures. It is frequently associated with an anterior cruciate ligament (ACL) injury. We conducted this study, on patients with ACL reconstruction surgeries, which were occasionally accompanied by meniscal tears, in order to determine the diagnostic value of clinical examinations for meniscal tear, both individually and in combination, in correlations to magnetic resonance imaging (MRI) scans, with the goal of improving clinical diagnosis for patients with meniscal injuries in particular, as well as meniscal injuries associated with cruciate ligament knee injuries. CASE PRESENTATION: 50 patients were thoroughly clinically examined, using Joint line tenderness, Thessaly test, McMurray's test, Apley's test followed by MRI, before their scheduled ACL reconstruction arthroscopic surgeries. The meniscal tears were then identified during the procedure, and were treated, if necessary. The data before and after the surgery was taken into calculating, with arthroscopic findings serving as the gold standard. RESULTS: the sensitivity, specificity and accuracy of each clinical tests and MRI scans respectively were: for medial meniscus, Joint line tenderness (70%; 53,3%; 60%); McMurray's test (80%; 73,3%: 76%); Apley's test (65%; 70%; 68%); Thessaly test(70%; 76,7%; 74%); MRI (90%; 83,3%; 86%); lateral meniscus: Joint line tenderness (73%; 66,7%; 70%); McMurray's test (69,2%; 75%: 72%); Apley's test (69,2%; 70,8%; 70%); Thessaly test (73,1%; 75%; 74%); MRI (88,5%; 87,5%; 88%). However, when combining at least two positive tests into a single composite test, the diagnostic value is considerably enhanced with sensitivity, specificity and accuracy of 85%, 73,3%, 78% for medial meniscus, 92,3%, 87,5%, 90% for lateral meniscus. CLINICAL DISCUSSION: Clinical tests are essential for diagnosis of meniscal tears, although inconsistent. A composite test consisting of at least two positive tests can considerably enhance the diagnostic value, even comparable to MRI scans. However, after the clinical examination, MRI is still necessary for the diagnostic process of meniscal injuries in particular, as well as meniscal injuries associated with cruciate ligament knee injuries. CONCLUSION: The combination of clinical tests and MRI images will give a precise diagnosis as well as surgical indication for meniscus injury in patients with anterior cruciate ligament tear.

Irreducible Traumatic Radial Head Dislocation Due to Annular Ligament Interposition in a Child with Ulnar Plastic Deformation: A Case Report.

BACKGROUND: The traumatic dislocation of the radial head in children is commonly treated by closed reduction. Sometimes, however, this strategy of treatment may not be effective due to the location of soft tissues in the radio-shoulder joint. The literature presents a few cases of the irreducible radial head dislocation with ulnar plastic deformation. Because it is a relatively rare condition, such a traumatic dislocation can be easily missed. Neglected injuries can lead to unwanted complications and unpredictable surgical outcomes. CASE PRESENTATION: This study presents a relatively rare case of traumatic radial head dislocation with ulnar plastic deformation in a 3-year-old child, which was successfully treated by open reduction. The examined case did not require osteotomy and ligamentous reconstruction. The initial attempt of closed reduction failed due to annular ligament interposition, which has been detected on MRI. After 3 months of treatment, the range of motion of the operated arm gradually improved. At the 6-month follow-up, the Mayo elbow-performance score indicated an excellent treatment outcome. CONCLUSIONS: The delayed treatment of radial head dislocation with ulnar plastic deformation can hinder the supination and pronation of the forearm, resulting in elbow/forearm deformity. The earlier this condition is detected, the easier it will be to treat it and the better the treatment outcome will be. The examined case of irreversible traumatic dislocation, successfully treated by open reduction, may help to treat radial head dislocation better.

MR compatibility, safety and accuracy of the redesigned UMC Utrecht single needle implant device.

Purpose. The Utrecht single needle implant device (SNID) was redesigned to increase needle insertion velocity. The purpose of this study is to evaluate the magnetic resonance compatibility, safety and accuracy of the implant device preparing its application in a patient study to investigate the feasibility of inserting a brachytherapy needle into the prostate to a defined tumor target point.Methods. Several experiments were performed to evaluate the mechanical and radiofrequency safety of the needle system, the magnetic field perturbation, the calibration of the implant device in the MR coordinate system, functioning of the implant device during imaging and accuracy of needle insertion.Results. Endurance experiments showed the mechanical safety of the needle system. Magnetic field perturbation was acceptable with induced image distortions smaller than 0.5 mm for clinical MR sequences. Calibration of the implant device in the MR coordinate system was reproducible with average error (mean±standard deviation) of 0.2 ± 0.4 mm, 0.1 ± 0.3 mm and 0.6 ± 0.6 mm in thex,y- andz- direction, respectively. The RF safety measurement showed for clinical MR imaging sequences maximum temperature rises of 0.2 °C at the entry and tip points of the needle. Simultaneous functioning of the implant device and imaging is possible albeit with some intensity band artifacts in the fast field echo images. Finally, phantom measurements showed deviations amounting 2.5-3.6 mm measured as target-to-needle distance at a depth of 12 cm.Conclusions. This preclinical evaluation showed that the MR compatibility, safety and accuracy of the redesigned UMC Utrecht SNID allow its application in a patient study on the feasibility of inserting a brachytherapy needle into the prostate to a defined tumor target point.

Occupational symptoms due to exposure to volatile organic compounds among female Vietnamese nail salon workers in Danang city.

OBJECTIVES: Nail workers are exposed to many hazardous chemicals. Despite many warnings about health problems among nail workers in other countries, data concerning exposure to chemical hazards among nail workers is still limited in Vietnam. In this study, we aimed to identify exposure to volatile organic compounds and their relationship with occupational symptoms among Vietnamese female nail salon workers. METHODS: A cross-sectional study was conducted in Danang, Vietnam, from January 2019 to September 2019. Total 42 personal passive samplers were collected to evaluate 12 substances from 21 nail workers (15 salons) twice a week. We chose one representative worker from each of the nine salons with less than six workers and two representative workers from each of the six salons with over five workers for personal sampling based on the principle of similar exposure groups. We interviewed a total of 100 nail workers in 15 salons and 100 office workers in offices adjacent to the salons to compare occupational symptoms among them. RESULTS: The commonly detected compounds in nail salons were acetone (97.6%), butyl acetate (83.3%), and ethyl acetate and ethyl methacrylate (78%). The concentration of total target VOCs was related to the number of serviced customers, the concentration of CO2 , and general ventilation used. The subjective symptoms were significantly higher for the nail workers than for the comparison subjects, that is, headache, nausea, nose irritation, skin irritation, shortness of breath, and confusion. Among 100 nail workers, nose irritation was significantly higher for nail workers who were exposed to acetone at levels exceeding the Vietnam occupational exposure limit (VOEL) adjusted with the Brief-Scala model. CONCLUSIONS: Exposure to VOCs such as acetone in nail salons results in occupational symptoms among workers.

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%).

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.

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.

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.

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.

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.

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.

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.

The relationship between physical and psychological complaints and quality of life in severely injured patients.

PURPOSE: The purpose of this study was two-fold. The first goal was to investigate which variables were associated with the remaining physical limitations of severely injured patients after the initial rehabilitation phase. Second, we investigated whether physical limitations were attributable to the association between psychological complaints and quality of life in this patient group. METHODS: Patients who were 18 years or older and who had an injury severity score (ISS)>15 completed a set of questionnaires at one time-point after their rehabilitation phase (15-53 months after their trauma). The Short Musculoskeletal Function Assessment (SMFA) questionnaire was used to determine physical limitations. The Hospital Anxiety and Depression Scale, the Dutch Impact of Event Scale and the Cognitive Failure Questionnaire were used to determine psychological complaints, and the World Health Organization Quality of Life assessment instrument-BREF was used to measure general Quality of Life (QOL). Differences in physical limitations were investigated for several trauma- and patient-related variables using non-parametric independent-sample Mann-Whitney U tests. Multiple linear regression was performed to investigate whether the decreased QOL of severely injured patients with psychological complaints could be explained by their physical limitations. RESULTS: Older patients, patients with physical complaints before the injury, patients with higher ISS scores, and patients who had an injury of the spine or of the lower extremities reported significantly more physical problems. Additionally, patients with a low education level, patients who were living alone, and those who were unemployed reported significantly more long-term physical problems. Severely injured patients without psychological complaints reported significantly less physical limitations than those with psychological complaints. The SMFA factor of Lower extremity dysfunction was a confounder of the association between psychological complaints and QOL in all QOL domains. CONCLUSIONS: Long-term physical limitations were mainly reported by patients with psychological complaints. The decreased QOL of severely injured patients with psychological complaints can partially be explained by physical limitations, particularly those involving lower extremity function. Experienced physical limitations were significantly different for some trauma and patient characteristics. These characteristics may be used to select patients for whom a rehabilitation programme would be useful.

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.

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.