Bacterial diversity and the antimicrobial resistome in the southwestern highlands of Saudi Arabia.

Soil is a reservoir of microbial diversity and the most supportive habitat for acquiring and transmitting antimicrobial resistance. Resistance transfer usually occurs from animal to soil and vice versa, and it may ultimately appear in clinical pathogens. In this study, the southwestern highlands of Saudi Arabia were studied to assess the bacterial diversity and antimicrobial resistance that could be affected by the continuous development of tourism in the region. Such effects could have a long-lasting impact on the local environment and community. Culture-dependent, quantitative polymerase chain reaction (qPCR), and shotgun sequencing-based metagenomic approaches were used to evaluate the diversity, functional capabilities, and antimicrobial resistance of bacteria isolated from collected soil samples. Bacterial communities in the southwestern highlands were mainly composed of Proteobacteria, Bacteroidetes, and Actinobacteria. A total of 102 antimicrobial resistance genes (ARGs) and variants were identified in the soil microbiota and were mainly associated with multidrug resistance, followed by macrolide, tetracycline, glycopeptide, bacitracin, and beta-lactam antibiotic resistance. The mechanisms of resistance included efflux, antibiotic target alteration, and antibiotic inactivation. qPCR confirmed the detection of 18 clinically important ARGs. In addition, half of the 49 identified isolates were phenotypically resistant to at least one of the 15 antibiotics tested. Overall, ARGs and indicator genes of anthropogenic activities (human-mitochondrial [hmt] gene and integron-integrase [int1]) were found in relatively lower abundance. Along with a high diversity of bacterial communities, variation was observed in the relative abundance of bacterial taxa among sampling sites in the southwestern highlands of Saudi Arabia.

Performance of an integrated multimodality image guidance and dose-planning system supporting tumor-targeted HDR brachytherapy for prostate cancer.

BACKGROUND AND PURPOSE: Advances in high-dose-rate brachytherapy to treat prostate cancer hinge on improved accuracy in navigation and targeting while optimizing a streamlined workflow. Multimodal image registration and electromagnetic (EM) tracking are two technologies integrated into a prototype system in the early phase of clinical evaluation. We aim to report on the system's accuracy and workflow performance in support of tumor-targeted procedures. MATERIALS AND METHODS: In a prospective study, we evaluated the system in 43 consecutive procedures after clinical deployment. We measured workflow efficiency and EM catheter reconstruction accuracy. We also evaluated the system's MRI-TRUS registration accuracy with/without deformation, and with/without y-axis rotation for urethral alignment at initialization. RESULTS: The cohort included 32 focal brachytherapy and 11 integrated boost whole-gland implants. Mean procedure time excluding dose delivery was 38 min (range: 21-83) for focal, and 56 min (range: 38-89) for whole-gland implants; stable over time. EM catheter reconstructions achieved a mean difference between computed and measured free-length of 0.8 mm (SD 0.8, no corrections performed), and mean axial manual corrections 1.3 mm (SD 0.7). EM also enabled the clinical use of a non or partially visible catheter in 21% of procedures. Registration accuracy improved with y-axis rotation for urethral alignment at initialization and with the elastic registration (mTRE 3.42 mm, SD 1.49). CONCLUSION: The system supported tumor-targeting and was implemented with no demonstrable learning curve. EM reconstruction errors were small, correctable, and improved with calibration and control of external distortion sources; increasing confidence in the use of partially visible catheters. Image registration errors remained despite rotational alignment and deformation, and should be carefully considered.

Management of Sacrococcygeal Chordoma: A Systematic Review and Meta-analysis of Observational Studies.

STUDY DESIGN: Systematic review and meta-analysis of observational studies. OBJECTIVE: The aim of the study is to evaluate different treatment modalities in the management of sacrococcygeal chordoma. SUMMARY OF BACKGROUND DATA: Chordomas are primary malignant bone tumors associated with considerable morbidity and mortality. METHODS: We searched MEDLINE, EMBASE, Cochrane Central-Register of Controlled Trials, and Scopus from inception to July 2015. Eligible studies included patients with sacrococcygeal chordoma treated exclusively with surgery, radiotherapy, or both. Two reviewers independently assessed the eligibility of potential studies, risk of bias, and extracted data. Outcomes of interest were all-cause mortality, progression-free survival, and metastases. We analyzed further surgical outcomes by resection margin. All outcomes were assessed at 60 months and more than 60 months following intervention. RESULTS: We included 33 noncomparative studies reporting on 501 patients (mean age 57 years). Overall mortality rate was (16%) after surgical resection with adjuvant radiotherapy and (28%) after surgical resection, and (43%) after radiotherapy (P = 0.28). All-cause mortality following wide surgical resection was (32%) compared to (40%) after marginal resection (P = 0.51). Overall progression-free survival rate was (58%) after surgical resection with adjuvant radiotherapy and (55%) after surgery (P = 0.92). However, at more than 60 months follow-up, progression-free survival rates were significantly higher (P = 0.024) following surgical resection with adjuvant radiotherapy (74%) in comparison to surgery (55%) and radiotherapy (36%). Overall progression-free survival rates were nonsignificantly higher after wide surgical resection (66%) than marginal resection (33%) (P = 0.16). However, at 60 months follow-up, progression-free survival rates were significantly higher following wide surgical resection (73%) than marginal resection (33%) (P = 0.047). CONCLUSION: Sacrococcygeal chordoma is a difficult to treat disease entity. Until comparative studies become available, wide surgical resection and multidisciplinary management are the recommended approaches to improve patient outcomes. LEVEL OF EVIDENCE: 3.

Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.

The deregulation of serine protease activity is a common feature of neurological injury, but little is known regarding their mechanisms of action or whether they can be targeted to facilitate repair. In this study we demonstrate that the thrombin receptor (Protease Activated Receptor 1, (PAR1)) serves as a critical translator of the spinal cord injury (SCI) proteolytic microenvironment into a cascade of pro-inflammatory events that contribute to astrogliosis and functional decline. PAR1 knockout mice displayed improved locomotor recovery after SCI and reduced signatures of inflammation and astrogliosis, including expression of glial fibrillary acidic protein (GFAP), vimentin, and STAT3 signaling. SCI-associated elevations in pro-inflammatory cytokines such as IL-1ß and IL-6 were also reduced in PAR1-/- mice and co-ordinate improvements in tissue sparing and preservation of NeuN-positive ventral horn neurons, and PKCγ corticospinal axons, were observed. PAR1 and its agonist's thrombin and neurosin were expressed by perilesional astrocytes and each agonist increased the production of IL-6 and STAT3 signaling in primary astrocyte cultures in a PAR1-dependent manner. In turn, IL-6-stimulated astrocytes increased expression of PAR1, thrombin, and neurosin, pointing to a model in which PAR1 activation contributes to increased astrogliosis by feedforward- and feedback-signaling dynamics. Collectively, these findings identify the thrombin receptor as a key mediator of inflammation and astrogliosis in the aftermath of SCI that can be targeted to reduce neurodegeneration and improve neurobehavioral recovery.

Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury.

Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression-spinal cord injury (SCI) compared to wild type littermates. Molecular profiling of the injury epicenter, and spinal segments above and below, demonstrated that mice lacking PAR2 had significantly attenuated elevations in key hallmarks of astrogliosis (glial fibrillary acidic protein (GFAP), vimentin and neurocan) and in expression of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1 beta (IL-1ß)). SCI in PAR2-/- mice was also accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons and reductions in GFAP-immunoreactivity, expression of the pro-apoptotic marker BCL2-interacting mediator of cell death (BIM), and in signal transducer and activator of transcription 3 (STAT3). The potential mechanistic link between PAR2, STAT3 and astrogliosis was further investigated in primary astrocytes to reveal that the SCI-related serine protease, neurosin (kallikrein 6) promotes IL-6 secretion in a PAR2 and STAT3-dependent manner. Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling. IL-6 promotes expression of GFAP, vimentin, additional IL-6 and robust increases in both neurosin and PAR2, thereby driving the PAR2-signaling circuit forward. Given the significant reductions in astrogliosis and inflammation as well as superior neuromotor recovery observed in PAR2 knockout mice after SCI, we suggest that this receptor and its agonists represent new drug targets to foster neuromotor recovery.