Fluoroquinolones are associated with delayed treatment and resistance in tuberculosis: a systematic review and meta-analysis

SummaryBackgroundCurrent guidelines for treating community-acquired pneumonia recommend the use of fluoroquinolones for high-risk patients. Previous studies have reported controversial results as to whether fluoroquinolones are associated with delayed diagnosis and treatment of pulmonary tuberculosis (TB) and the development of fluoroquinolone-resistant Mycobacterium tuberculosis. We performed a systematic review and meta-analysis to clarify these issues.MethodsThe following databases were searched through September 30, 2010: PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, BIOSIS Previews, and the ACP Journal Club. We considered studies that addressed the issues of delay in diagnosis and treatment of TB and the development of resistance.ResultsNine eligible studies (four for delays and five for resistance issues) were included in the meta-analysis from the 770 articles originally identified in the database search. The mean duration of delayed diagnosis and treatment of pulmonary TB in the fluoroquinolone prescription group was 19.03 days, significantly longer than that in the non-fluoroquinolone group (95% confidence interval (CI) 10.87 to 27.18, p<0.001). The pooled odds ratio of developing a fluoroquinolone-resistant M. tuberculosis strain was 2.70 (95% CI 1.30 to 5.60, p=0.008). No significant heterogeneity was found among studies in the meta-analysis.ConclusionsEmpirical fluoroquinolone prescriptions for pneumonia are associated with longer delays in diagnosis and treatment of pulmonary TB and a higher risk of developing fluoroquinolone-resistant M. tuberculosis

Protein-ligand binding region prediction (PLB-SAVE) based on geometric features and CUDA acceleration

[[abstract]]Background Protein-ligand interactions are key processes in triggering and controlling biological functions within cells. Prediction of protein binding regions on the protein surface assists in understanding the mechanisms and principles of molecular recognition. In silico geometrical shape analysis plays a primary step in analyzing the spatial characteristics of protein binding regions and facilitates applications of bioinformatics in drug discovery and design. Here, we describe the novel software, PLB-SAVE, which uses parallel processing technology and is ideally suited to extract the geometrical construct of solid angles from surface atoms. Representative clusters and corresponding anchors were identified from all surface elements and were assigned according to the ranking of their solid angles. In addition, cavity depth indicators were obtained by proportional transformation of solid angles and cavity volumes were calculated by scanning multiple directional vectors within each selected cavity. Both depth and volume characteristics were combined with various weighting coefficients to rank predicted potential binding regions. Results Two test datasets from LigASite, each containing 388 bound and unbound structures, were used to predict binding regions using PLB-SAVE and two well-known prediction systems, SiteHound and MetaPocket2.0 (MPK2). PLB-SAVE outperformed the other programs with accuracy rates of 94.3% for unbound proteins and 95.5% for bound proteins via a tenfold cross-validation process. Additionally, because the parallel processing architecture was designed to enhance the computational efficiency, we obtained an average of 160-fold increase in computational time. Conclusions In silico binding region prediction is considered the initial stage in structure-based drug design. To improve the efficacy of biological experiments for drug development, we developed PLB-SAVE, which uses only geometrical features of proteins and achieves a good overall performance for protein-ligand binding region prediction. Based on the same approach and rationale, this method can also be applied to predict carbohydrate-antibody interactions for further design and development of carbohydrate-based vaccines. PLB-SAVE is available at http://save.cs.ntou.edu.tw.[[booktype]]電子

Clinical Effects and Differences in Neural Function Connectivity Revealed by MRI in Subacute Hemispheric and Brainstem Infarction Patients With Dysphagia After Swallowing Therapy

Background: Early detection and intervention for post-stroke dysphagia could reduce the incidence of pulmonary complications and mortality. The aims of this study were to investigate the benefits of swallowing therapy in swallowing function and brain neuro-plasticity and to explore the relationship between swallowing function recovery and neuroplasticity after swallowing therapy in cerebral and brainstem stroke patients with dysphagia.Methods: We collected 17 subacute stroke patients with dysphagia (11 cerebral stroke patients with a median age of 76 years and 6 brainstem stroke patients with a median age of 70 years). Each patient received swallowing therapies during hospitalization. For each patient, functional oral intake scale (FOIS), functional dysphagia scale (FDS) and 8-point penetration-aspiration scale (PAS) in videofluoroscopy swallowing study (VFSS), and brain functional magnetic resonance imaging (fMRI) were evaluated before and after treatment.Results: FOIS (p = 0.003 in hemispheric group and p = 0.039 in brainstem group) and FDS (p = 0.006 in hemispheric group and p = 0.028 in brainstem group) were both significantly improved after treatment in hemispheric and brainstem stroke patients. In hemispheric stroke patients, changes in FOIS were related to changes of functional brain connectivity in the ventral default mode network (vDMN) of the precuneus in brain functional MRI (fMRI). In brainstem stroke patients, changes in FOIS were related to changes of functional brain connectivity in the left sensorimotor network (LSMN) of the left postcentral region characterized by brain fMRI.Conclusion: Both hemispheric and brainstem stroke patients with different swallowing difficulties showed improvements after swallowing training. For these two dysphagic stroke groups with corresponding etiologies, swallowing therapy could contribute to different functional neuroplasticity

Case report: Infective endocarditis caused by Brevundimonas vesicularis

BACKGROUND: There are few reports in the literature of invasive infection caused by Brevundimonas vesicularis in patients without immunosuppression or other predisposing factors. The choice of antimicrobial therapy for bacteremia caused by the pathogen requires more case experience to be determined. CASE PRESENTATION: The case of a 40-year-old previously healthy man with subacute endocarditis proposed to be contributed from an occult dental abscess is described. The infection was found to be caused by B. vesicularis on blood culture results. The patient recovered without sequelae after treatment with ceftriaxone followed by subsequent ciprofloxacin therapy owing to an allergic reaction to ceftriaxone and treatment failure with ampicillin/sulbactam. CONCLUSION: To our knowledge, this is the first report of B. vesicularis as a cause of infective endocarditis. According to an overview of the literature and our experience, we suggest that third-generation cephalosporins, piperacillin/tazobactam, and ciprofloxacin are effective in treating invasive B. vesicularis infections, while the efficacy of ampicillin-sulbactam needs further evaluation

Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy

Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis

Detection and Alignment of 3D Domain Swapping Proteins Using Angle-Distance Image-Based Secondary Structural Matching Techniques

This work presents a novel detection method for three-dimensional domain swapping (DS), a mechanism for forming protein quaternary structures that can be visualized as if monomers had “opened” their “closed” structures and exchanged the opened portion to form intertwined oligomers. Since the first report of DS in the mid 1990s, an increasing number of identified cases has led to the postulation that DS might occur in a protein with an unconstrained terminus under appropriate conditions. DS may play important roles in the molecular evolution and functional regulation of proteins and the formation of depositions in Alzheimer's and prion diseases. Moreover, it is promising for designing auto-assembling biomaterials. Despite the increasing interest in DS, related bioinformatics methods are rarely available. Owing to a dramatic conformational difference between the monomeric/closed and oligomeric/open forms, conventional structural comparison methods are inadequate for detecting DS. Hence, there is also a lack of comprehensive datasets for studying DS. Based on angle-distance (A-D) image transformations of secondary structural elements (SSEs), specific patterns within A-D images can be recognized and classified for structural similarities. In this work, a matching algorithm to extract corresponding SSE pairs from A-D images and a novel DS score have been designed and demonstrated to be applicable to the detection of DS relationships. The Matthews correlation coefficient (MCC) and sensitivity of the proposed DS-detecting method were higher than 0.81 even when the sequence identities of the proteins examined were lower than 10%. On average, the alignment percentage and root-mean-square distance (RMSD) computed by the proposed method were 90% and 1.8Å for a set of 1,211 DS-related pairs of proteins. The performances of structural alignments remain high and stable for DS-related homologs with less than 10% sequence identities. In addition, the quality of its hinge loop determination is comparable to that of manual inspection. This method has been implemented as a web-based tool, which requires two protein structures as the input and then the type and/or existence of DS relationships between the input structures are determined according to the A-D image-based structural alignments and the DS score. The proposed method is expected to trigger large-scale studies of this interesting structural phenomenon and facilitate related applications

Impaired Small-World Network Efficiency and Dynamic Functional Distribution in Patients with Cirrhosis

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome and a major complication of liver cirrhosis. Dysmetabolism of the brain, related to elevated ammonia levels, interferes with intercortical connectivity and cognitive function. For evaluation of network efficiency, a ‘small-world’ network model can quantify the effectiveness of information transfer within brain networks. This study aimed to use small-world topology to investigate abnormalities of neuronal connectivity among widely distributed brain regions in patients with liver cirrhosis using resting-state functional magnetic resonance imaging (rs-fMRI). Seventeen cirrhotic patients without HE, 9 with minimal HE, 9 with overt HE, and 35 healthy controls were compared. The interregional correlation matrix was obtained by averaging the rs-fMRI time series over all voxels in each of the 90 regions using the automated anatomical labeling model. Cost and correlation threshold values were then applied to construct the functional brain network. The absolute and relative network efficiencies were calculated; quantifying distinct aspects of the local and global topological network organization. Correlations between network topology parameters, ammonia levels, and the severity of HE were determined using linear regression and ANOVA. The local and global topological efficiencies of the functional connectivity network were significantly disrupted in HE patients; showing abnormal small-world properties. Alterations in regional characteristics, including nodal efficiency and nodal strength, occurred predominantly in the association, primary, and limbic/paralimbic regions. The degree of network organization disruption depended on the severity of HE. Ammonia levels were also significantly associated with the alterations in local network properties. Results indicated that alterations in the rs-fMRI network topology of the brain were associated with HE grade; and that focal or diffuse lesions disturbed the functional network to further alter the global topology and efficiency of the whole brain network. These findings provide insights into the functional changes in the human brain in HE

Effect of metal ion irradiation on hard coating synthesis by physical vapor deposition

The aim of this thesis is to understand and control how the ions in the plasma influence the film growth during thin film deposition processes. Two physical vapor deposition (PVD) techniques are investigated, namely magnetron sputtering and cathodic arc evaporation. For magnetron sputtering, the unconventional hybrid high-power impulse and direct current magnetron cosputtering (HiPIMS/DCMS) configuration is used in this work. By synchronizing the substrate bias pulses with the HiPIMS pulses by a time offset and duration, the metal ions from the target material can be selected to impinge the growing film, whereas the contribution of the working gas ions can be effectively reduced. Two aspects are explored, low-mass ion subplantation and heavy-mass ion irradiation. The thesis begins with establishing the correlation between N2 pressure and plasma properties of the cathodic arc evaporation process using Ti0.5Al0.5 target. The results show Ti ions are the dominant species, followed by Al+. On the other hand, due to the shorter mean free path of the species with increasing N2 pressure, the ion energies and the effective electron temperature decrease while electron density increases. Consequently, comparing the TiAlN coatings grown at lower and higher N2 pressures, the crystallographic textures changes from cubic 220 to 111 along the growth direction, and the residual stress reduces from compressive (-3.4 GPa) to almost stress-free (0.6 GPa). The rest of the thesis addresses the influence of ionized species on microstructures, with a focus on tuning film properties by ions in the plasma. Ti1-x(AlySi1-y)xN coatings (0.38 &lt; x &lt; 0.76 and 0.68 ≤ y ≤ 1.00) were deposited with an AlSi-HiPIMS/Ti-DCMS with synchronized substrate bias setup. The results show that the coatings deposited by this method have higher Al and Si solubilities in NaCl-structured TiN than other PVD techniques due to low mass ion subplantations. Additionally, a range of films with different compositions display a combination of high hardness (~ 30 GPa) and low residual stress (s &lt; 0.5 GPa), which highlights the benefits of minimizing the Ar+ incorporation by synchronizing substrate bias to the Al+/Si+-rich portion of the HiPIMS pulses. The selected TiAlSiN coatings were then studied for the crater wear resistance of high-speed cutting performance on ball bearing steel (100Cr6). The effects of phase contents and microstructures on cutting performance are evaluated. This is further extended by a study of the influence of neutral and ion fluxes overlap and the subplantation range of low-mass ions. This is accomplished by introducing the 1-fold substrate table rotation, different target-to-substrate distances, and substrate bias voltage in a AlSi-HiPIMS/Ti-DCMS hybrid deposition process. The microstructure and phase analysis show the necessity of overlap between HiPIMS and DCMS fluxes to deposit TiAlSiN solid solutions. The compositional variation of the multilayers can be controlled by the applied substrate bias and table rotational speed. Rotation during deposition may yield coatings comparable in hardness to the ones without rotation at the expense of higher compressive stress. The effectiveness of controlling heavy ion irradiation is investigated by replacing external heating with high-mass W+ irradiation to grow dense and hard titanium tungsten carbide (TiWC) coatings by WC-HiPIMS/TiC-DCMS with synchronized bias technique. The ionization degree of W+ are controlled by the peak current density (0.27 ≤ JT ≤ 1.36 A/cm2). The results show that W+ irradiation effectively densified TiWC coatings without external heating. The total energy consumption per hour is reduced by 77% using the HiPIMS/DCMS setup without external heating, yet this TiWC coating is 10 GPa harder than similar coating grown by self-bias DCMS with heating

Dense and hard TiWC protective coatings grown with tungsten ion irradiation using WC-HiPIMS/TiC-DCMS co-sputtering technique without external heating

Titanium tungsten carbide (TiWC) coatings are deposited by a combined high-power impulse and dc magnetron co-sputtering (HiPIMS/DCMS) technique. No external heating is applied during deposition phase, instead, the thermally driven adatom mobility is substituted by heavy ion irradiation. DCMS sources equipped with titanium carbide targets provide constant neutral fluxes to establish the predominant coating structures, whereas tungsten carbide target in HiPIMS mode serves as the source of heavy metal-ions. Substrate bias of −60 V is synchronized to W+ ion-rich time domains of HiPIMS pulses to minimize the contribution from working gas ions. The influence of W+ ion flux intensity, controlled by varying peak target current density (JT), on film properties is investigated. X-ray photoelectron spectroscopy reveals the presence of over stoichiometric carbon forming an amorphous phase, the amount of which can be fine-tuned by varying JT. Changes in film composition as a function of JT are explained based on the in-situ ion mass spectroscopy analyses. Dense TiWC coatings by hybrid process exhibit hardness higher than 30 GPa, which are comparable to TiWC films deposited by DCMS with dc substrate bias and external heating. The relative energy consumption in the hybrid process is reduced by 77 % as compared to high-temperature DCMS processing