No abstract available.
Osteolysis*

BACKGROUND: Reports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited. METHODS: A retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges. RESULTS: Of 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6+/-10.2 microg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2+/-1.5 microg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5+/-14.0 microg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0+/-29.1 microg/mL; all within or above); linezolid in three (mean C2hr, 11.4+/-4.1 microg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3+/-3.7 microg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 microg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations. CONCLUSION: Individual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.
Adult ; Aged ; Amikacin ; Aminosalicylic Acid ; Capreomycin ; Cohort Studies ; Cycloserine ; Drug Monitoring* ; Ethionamide ; Female ; Humans ; Pharmacokinetics ; Retrospective Studies ; Tuberculosis ; Tuberculosis, Meningeal ; Tuberculosis, Multidrug-Resistant* ; Virginia* ; Linezolid

OBJECTIVE: Pedicle-based dynamic stabilization systems, in which semi-rigid rods or cords are used to restrict or control spinal segmental motion, aim to reduce or eliminate the drawbacks associated with rigid fusion. In this study, we analyzed the two-year clinical outcomes of patients treated with the NFlex (Synthes Spine, Inc.), a pedicle-based dynamic stabilization system. METHODS: Five sites participated in a retrospective study of 72 consecutive patients who underwent NFlex stabilization. Of these 72 patients, 65 were available for 2-year follow-up. Patients were included based on the presence of degenerative disc disease (29 patients), degenerative spondylolisthesis (16 patients), lumbar stenosis (9 patients), adjacent segment degeneration (6 patients), and degenerative lumbar scoliosis (5 patients). The clinical outcome measures at each assessment were Visual Analogue Scale (VAS) to measure back pain, and Oswestry Disability Index (ODI) to measure functional status. Radiographic assessments included evidence of instrumentation failure or screw loosening. RESULTS: Sixty-five patients (26 men and 39 women) with a mean age of 54.5 years were included. Mean follow-up was 25.6 months. The mean VAS score improved from 8.1 preoperatively to 3.8 postoperatively, representing a 53% improvement, and the ODI score from 44.5 to 21.8, representing a 51% improvement. Improvements in pain and disability scores were statistically significant. Three implant-related complications were observed. CONCLUSION: Posterior pedicle-based dynamic stabilization using the NFlex system seems effective in improving pain and functional scores, with sustained clinical improvement after two years. With appropriate patient selection, it may be considered an effective alternative to rigid fusion.
Back Pain ; Constriction, Pathologic ; Follow-Up Studies ; Humans ; Male ; Outcome Assessment (Health Care) ; Patient Selection ; Retrospective Studies ; Scoliosis ; Spinal Fusion ; Spine ; Spondylolisthesis

Prompt, effective treatment is necessary following aneurysmal subarachnoid hemorrhage to prevent recurrent rupture, which is thought to double mortality. Atypical ruptured aneurysms, such as blister or dissecting pseudoaneurysms, or those that are unusually distal in the middle cerebral artery (MCA) are challenging to treat with either open or endovascular options, though the pipeline embolization device (PED) has shown promise in multiple case series. We present a case of a ruptured dissecting pseudoaneurysm in the distal MCA (distal M3/proximal M4) prefrontal division in an healthy young patient (<60 years) successfully treated with a PED. The PED was chosen both as the only vessel sparing option in the young patient as well as for its potential as a vessel sacrifice tool if the pseudoaneurysm was felt to be incompletely treated, which in this case was not necessary—though would have leveraged the thrombogenicity of the device as a therapeutic advantage.

Objective: The neutrophil to lymphocyte ratio (NLR) is a non-specific, easy-to-obtain marker of inflammation associated with morbidity and mortality in systemic, psychiatric, and age-related inflammatory conditions. Given the growing trend of substance use disorder (SUD) in older adults, and the relationship between inflammation and SUD elevated NLR may serve as a useful inflammatory biomarker of the combined burden of aging and SUD. The present study focused on cocaine use disorder (CUD) to examine if cocaine adds further inflammatory burden among older adults, by comparing NLR values between older adults with CUD and a non-cocaine using, aged-matched, nationally representative sample. Methods: The dataset included 107 (86% male) participants (aged 50−65 years) with cocaine use disorder. NLR was derived from complete blood count tests by dividing the absolute value of peripheral neutrophil concentration by lymphocyte concentration. For comparison, we extracted data from age-matched adults without CUD using the National Health and Nutrition Examination Survey. Individuals with immunocompromising conditions were excluded (e.g., rheumatoid arthritis and sexually transmitted infections such as HIV). A doubly-robust inverse probability-weighted regression adjustment (IPWRA) propensity score method was used to estimate group differences on NLR while controlling for potential confounding variables (age, gender, race, income, nicotine, marijuana and alcohol use). Results: The IPWRA model revealed that the CUD sample had significantly elevated NLR in comparison to non-cocaine users, with a moderate effect size ( weight = 0.67). Conclusion Although non-specific, NLR represents a readily obtainable inflammatory marker for SUD research. CUD may add further inflammatory burden to aging cocaine users.

Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor β-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.
Animals ; Collagen ; Collagen Type I ; Cytoskeleton ; Extracellular Matrix ; Fibrosis ; Hedgehogs ; Hepatic Stellate Cells ; Humans ; In Vitro Techniques ; Kidney ; Liver ; Liver Cirrhosis ; Lung ; Mice ; Mortality ; Myofibroblasts* ; Phenotype* ; Transcriptome ; Transforming Growth Factors

Complex structural variants(CSVs)are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.How-ever,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery com-pared with simple structural variants.Here,we systematically analyzed the multi-breakpoint con-nection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70％,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.