Intra- and Interexaminer Repeatability of Diagnostic Peri-Implant Clinical Measurement: A Pilot Study.

Despite the crucial role of examiner reliability on quality research and practice, there is still limited literature analyzing factors affecting examiner variability of peri-implant clinical measurements. The present study investigated clinical peri-implant parameters to quantify their repeatability and investigate factors that may affect their accuracy. Thirty-three implants were examined by 4 operators. Peri-implant probing depth (PD), recession (REC), and gingival index (GI) were measured for agreement and included in the analysis. Agreement was quantified using intraclass correlation coefficients (ICCs; 95% confidence interval); mixed linear and logistic regressions were used to assess additional variables. The overall interexaminer agreement was comparable between PD (0.80) and REC (0.78) but significantly worse for GI (0.45; P < .001). Similarly, the intraexaminer agreement was similar for PD (0.81) and REC (0.80) but significantly worse for GI (0.57; P < .05). The magnitude of PD did not influence the agreement. In contrast, increasing disagreement was noted for positive REC (odds ratio [OR]: 3.0), negative REC (OR: 4.8), and lower GI (OR: 4.4). The incidence of bleeding on probing and severity of GI increased for deeper PD (0.113-unit increase per millimeter). Negative and positive values of recession and lower GI were associated with increasing disagreement. Radiographic bone loss, restoration contour, and implant diameter did not affect PD accuracy in this study. In conclusion, within the limitations of the study, GI measurements presented higher variability than PD and REC did. The PD and GI were associated with one another and increased after multiple measurements.

Lognormal Distribution of Local Strain: A Universal Law of Plastic Deformation in Material.

Given the infinite diversity of microstructural inhomogeneity, the variation in spatial distribution of local strain could be infinite. However, this study finds that the statistical distribution of local strain universally follows a lognormal distribution irrespective of phase content and deformation mechanism. Moreover, this universal law is proved conditional upon the macroscopic homogeneity of deformation on the statistical window scale, equivalent to the equality between the macrostrain calculated from the displacements at the window corners and the average of the local strain. The discovery of a lognormal distribution law suggests the existence of a minimum statistical representative window (MSRW) size that is characteristic for each material. Explorations on the dependence of MSRW size on the microstructure, deformation mechanism, and strain magnitude are expected to add new dimensions to understanding of the relationship between microstructure and mechanical properties.

Limbal stem cell deficiency secondary to systemic paclitaxel (Taxol) for breast cancer: a case report.

BACKGROUND: Paclitaxel (PTX) is an antineoplastic drug widely used in treatments for ovarian, breast, and small-cell lung cancer. Although ocular effects associated with PTX have been previously described, very few studies have specifically reported systemic PTX as a contributing factor for limbal stem cell deficiency (LSCD), which is characterized by the loss of stem cell and barrier function of the limbus leading to progressive pain and reduction in visual acuity. Described here is a unique case where a patient was diagnosed with LSCD secondary to PTX use for the treatment of breast cancer, at doses of PTX far lower than what is reported in current literature. CASE PRESENTATION: A 73-year-old woman with a previous diagnosis of breast cancer with liver metastasis presented with a complaint of increasing pain in the left eye more than the right, along with decreasing visual acuity in both eyes following 3 months of PTX therapy for recurrent liver metastases. Upon examination, best-corrected visual acuity was 20/100 in the right eye and counting fingers on the left. Peripheral neovascularization, stromal scarring, and features of limbal stem cell deficiency (LSCD) were noted on the right cornea. A central neurotrophic ulcer with thinning to 50% and 360 degrees of conjunctivalization were noted on the left. After the discontinuation PTX with doxorubicin as the substitute, there was no further progression of her LSCD, and stabilization of her ocular surface was achieved. CONCLUSION: Although chemotherapy induced LSCD is a relatively rare adverse event, it is essential for clinicians starting new chemotherapy agents to consider the potential ocular toxicities that may result in their use. Ophthalmology review is recommended for patients after starting PTX therapy to assess for signs of LSCD, particularly in patients where drug toxicity can be aggravated due to impaired hepatic function.

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

BACKGROUND: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD. METHODS: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed. RESULTS: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (ß = 1.49, p value = 0.02) and MD-A (ß = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (ß = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m2) (ß = 5.32, p = 0.0002; p interaction = 0.0003). CONCLUSIONS: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.

The Use of Amoxicillin (500 Mg) Plus Metronidazole (500 Mg) for 7 Days Adds Adjunctive Benefits for Nonsurgical Periodontal Therapy, but Limited Evidence Supports Higher/Longer Dose.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Optimal dose and duration of amoxicillin-plus-metronidazole as an adjunct to nonsurgical periodontal therapy: A systematic review and meta-analysis of randomized, placebo-controlled trials. McGowan K, McGowan T, Ivanovski S. J Clin Periodontol 2018;45:56-67. SOURCE OF FUNDING: Information not available. TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data.

Extended Solution Gate OFET-based Biosensor for Label-free Glial Fibrillary Acidic Protein Detection with Polyethylene Glycol-Containing Bioreceptor Layer.

A novel organic field effect transistor (OFET) -based biosensor is described for label-free glial fibrillary acidic protein (GFAP) detection. We report the first use of an extended solution gate structure where the sensing area and the organic semiconductor are separated, and a reference electrode is not needed. Different molecular weight polyethylene glycols (PEGs) are mixed into the bio-receptor layer to help extend the Debye screening length. The drain current change was significantly increased with the help of higher molecular weight PEGs, as they are known to reduce the dielectric constant. We also investigated the sensing performance under different gate voltage (Vg). The sensitivity increased after we decreased Vg from -5 V to -2 V, because the lower Vg is much closer to the OFET threshold voltage and the influence of attached negatively charged proteins become more apparent. Finally, the selectivity experiments toward different interferents were performed. The stability and selectivity are promising for clinical applications.

Identifying relations between imaging phenotypes and molecular subtypes of breast cancer: Model discovery and external validation.

PURPOSE: To determine whether dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) characteristics of the breast tumor and background parenchyma can distinguish molecular subtypes (ie, luminal A/B or basal) of breast cancer. MATERIALS AND METHODS: In all, 84 patients from one institution and 126 patients from The Cancer Genome Atlas (TCGA) were used for discovery and external validation, respectively. Thirty-five quantitative image features were extracted from DCE-MRI (1.5 or 3T) including morphology, texture, and volumetric features, which capture both tumor and background parenchymal enhancement (BPE) characteristics. Multiple testing was corrected using the Benjamini-Hochberg method to control the false-discovery rate (FDR). Sparse logistic regression models were built using the discovery cohort to distinguish each of the three studied molecular subtypes versus the rest, and the models were evaluated in the validation cohort. RESULTS: On univariate analysis in discovery and validation cohorts, two features characterizing tumor and two characterizing BPE were statistically significant in separating luminal A versus nonluminal A cancers; two features characterizing tumor were statistically significant for separating luminal B; one feature characterizing tumor and one characterizing BPE reached statistical significance for distinguishing basal (Wilcoxon P < 0.05, FDR < 0.25). In discovery and validation cohorts, multivariate logistic regression models achieved an area under the receiver operator characteristic curve (AUC) of 0.71 and 0.73 for luminal A cancer, 0.67 and 0.69 for luminal B cancer, and 0.66 and 0.79 for basal cancer, respectively. CONCLUSION: DCE-MRI characteristics of breast cancer and BPE may potentially be used to distinguish among molecular subtypes of breast cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1017-1027.

Automatic Estimation of Volumetric Breast Density Using Artificial Neural Network-Based Calibration of Full-Field Digital Mammography: Feasibility on Japanese Women With and Without Breast Cancer.

Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating full-field digital mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Phantom validations reached an R 2 of 0.993. Intra-patient validations ranged from R 2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R 2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

BACKGROUND: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. METHODS: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. RESULTS: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. CONCLUSIONS: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Prognostic Imaging Biomarkers in Glioblastoma: Development and Independent Validation on the Basis of Multiregion and Quantitative Analysis of MR Images.

PURPOSE: To develop and independently validate prognostic imaging biomarkers for predicting survival in patients with glioblastoma on the basis of multiregion quantitative image analysis. MATERIALS AND METHODS: This retrospective study was approved by the local institutional review board, and informed consent was waived. A total of 79 patients from two independent cohorts were included. The discovery and validation cohorts consisted of 46 and 33 patients with glioblastoma from the Cancer Imaging Archive (TCIA) and the local institution, respectively. Preoperative T1-weighted contrast material-enhanced and T2-weighted fluid-attenuation inversion recovery magnetic resonance (MR) images were analyzed. For each patient, we semiautomatically delineated the tumor and performed automated intratumor segmentation, dividing the tumor into spatially distinct subregions that demonstrate coherent intensity patterns across multiparametric MR imaging. Within each subregion and for the entire tumor, we extracted quantitative imaging features, including those that fully capture the differential contrast of multimodality MR imaging. A multivariate sparse Cox regression model was trained by using TCIA data and tested on the validation cohort. RESULTS: The optimal prognostic model identified five imaging biomarkers that quantified tumor surface area and intensity distributions of the tumor and its subregions. In the validation cohort, our prognostic model achieved a concordance index of 0.67 and significant stratification of overall survival by using the log-rank test (P = .018), which outperformed conventional prognostic factors, such as age (concordance index, 0.57; P = .389) and tumor volume (concordance index, 0.59; P = .409). CONCLUSION: The multiregion analysis presented here establishes a general strategy to effectively characterize intratumor heterogeneity manifested at multimodality imaging and has the potential to reveal useful prognostic imaging biomarkers in glioblastoma.

The clinical impact of immediate on-site cytopathology evaluation during endoscopic ultrasound-guided fine needle aspiration of pancreatic masses: a prospective multicenter randomized controlled trial.

OBJECTIVES: Observational data on the impact of on-site cytopathology evaluation (OCE) during endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of pancreatic masses have reported conflicting results. We aimed to compare the diagnostic yield of malignancy and proportion of inadequate specimens between patients undergoing EUS-FNA of pancreatic masses with and without OCE. METHODS: In this multicenter randomized controlled trial, consecutive patients with solid pancreatic mass underwent randomization for EUS-FNA with or without OCE. The number of FNA passes in the OCE+ arm was dictated by the on-site cytopathologist, whereas seven passes were performed in OCE- arm. EUS-FNA protocol was standardized, and slides were reviewed by cytopathologists using standardized criteria for cytologic characteristics and diagnosis. RESULTS: A total of 241 patients (121 OCE+, 120 OCE-) were included. There was no difference between the two groups in diagnostic yield of malignancy (OCE+ 75.2% vs. OCE- 71.6%, P=0.45) and proportion of inadequate specimens (9.8 vs. 13.3%, P=0.31). Procedures in OCE+ group required fewer EUS-FNA passes (median, OCE+ 4 vs. OCE- 7, P<0.0001). There was no significant difference between the two groups with regard to overall procedure time, adverse events, number of repeat procedures, costs (based on baseline cost-minimization analysis), and accuracy (using predefined criteria for final diagnosis of malignancy). There was no difference between the two groups with respect to cytologic characteristics of cellularity, bloodiness, number of cells/slide, and contamination. CONCLUSIONS: Results of this study demonstrated no significant difference in the diagnostic yield of malignancy, proportion of inadequate specimens, and accuracy in patients with pancreatic mass undergoing EUS-FNA with or without OCE.

Effects of tofacitinib on lymphocyte sub-populations, CMV and EBV viral load in patients with plaque psoriasis.

BACKGROUND: Plaque psoriasis is a debilitating skin condition that affects approximately 2% of the adult population and for which there is currently no cure. Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. METHODS: The design of this study has been reported previously (NCT00678210). Patients with moderate to severe chronic plaque psoriasis received tofacitinib (2 mg, 5 mg, or 15 mg) or placebo, twice daily, for 12 weeks. Lymphocyte sub-populations, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured at baseline and up to Week 12. RESULTS: Tofacitinib was associated with modest, dose-dependent percentage increases from baseline in median B cell count at Week 4 (24-68%) and Week 12 (18-43%) and percentage reductions from baseline in median natural killer cell count at Week 4 (11-40%). The proportion of patients with detectable CMV and EBV DNA (defined as >0 copies/500 ng total DNA) increased post-baseline in tofacitinib-treated patients. However, multivariate analyses found no relationship between changes in CMV or EBV viral load and changes in lymphocyte sub-populations or tofacitinib treatment. CONCLUSIONS: Twelve weeks of treatment with tofacitinib had no clinically significant effects on CMV or EBV viral load, suggesting that lymphocyte sub-populations critical to the response to chronic viral infections and viral reactivation were not significantly affected. Replication of these findings during long-term use of tofacitinib will allow confirmation of this observation.

Improved efficacy of endobronchial ultrasound-guided fine-needle aspiration biopsy in comparison to endobronchial ultrasound-guided miniforceps biopsy.

OBJECTIVE: Endobronchial ultrasound-guided fine-needle aspiration (EBUS-FNA) cytology and EBUS-miniforceps biopsy (MFB) have emerged as less invasive tools for evaluating mediastinal lymph nodes and pulmonary lesions. The aim of this study is to compare the diagnostic yields of EBUS-FNA cytology to EBUS-MFB. STUDY DESIGN: A retrospective cohort study was performed by reviewing the database at our institution between December 12, 2010, and August 10, 2012. A total of 476 consecutive cases were identified. Of these, 227 patients had concurrent FNA and MFB taken during the procedure. The results and diagnostic yields of both techniques are calculated. RESULTS: Of the 476 cases, the mean age was 62 ± 14 years with 53% being males. In 453 of the total cases, the less invasive FNA technique alone produced enough diagnostic cytology material negating the need for concurrent MFB. Of these FNA cases, 280 were diagnosed as malignant neoplasms. The diagnostic yield of EBUS-FNA cytology was comparable to EBUS-MFB (95% FNA and 94% MFB). There were discordant diagnoses between cytology and histology in 19 of the 227 (∼8.4%) cases. CONCLUSIONS: EBUS-FNA cytology is a more efficacious diagnostic modality compared to EBUS-MFB.

Utilization of p40 (ΔNp63) with p63 and cytokeratin 5/6 immunohistochemistry in non-small cell lung carcinoma fine-needle aspiration biopsy.

OBJECTIVE: Specific subclassification of pulmonary non-small cell carcinoma (NSCCA) is clinically necessary, and the aim of this study is to examine the utilization of p40 (ΔNp63) in fine-needle aspiration (FNA) biopsy for lung NSCCA. STUDY DESIGN: Database files of the Washington University Medical Center were searched. Patients who underwent endobronchial ultrasound and CT FNA of a primary lung neoplasia were selected and immunohistochemistry (IHC) was performed. A panel of markers was utilized, including p40, p63, cytokeratin (CK) 5/6, thyroid transcription factor, and napsin. RESULTS: One hundred patients were identified and comprised 38 squamous cell carcinomas (SCCA), 46 adenocarcinomas (AdCA), and 16 NSCCA. For SCCA, p40 was positive in 34/38 cases (89%) and negative in 4/38 cases (11%); p63 was positive in 33/38 cases (87%) and negative in 5/38 cases (13%); CK5/6 was positive in 38/38 cases. For AdCA cases, p40 was negative, p63 was positive in 2 cases (5%) and CK5/6 was negative in 43/46 cases (92%). CONCLUSION: For NSCCA, p40 had 89% sensitivity and 100% specificity compared to p63 with 86% sensitivity and 96% specificity and CK5/6 with 100% sensitivity and 96% specificity. In the evaluation of FNA biopsy for pulmonary NSCCA, p40 is a useful IHC marker for neoplastic subclassification, with better specificity in comparison to p63.

An Appraisal of Immunohistochemical Stain Use in Hepatic Metastasis Highlights the Effectiveness of the Individualized, Case-Based Approach: Analysis of Data From a Tertiary Care Medical Center.

CONTEXT.­: Liver biopsy plays an important role in the clinical management of metastases and often requires workup using immunohistochemical (IHC) markers, but the approach varies among institutions. OBJECTIVE.­: To evaluate the utility of a morphologic pattern-based, individualized approach in the workup of hepatic metastases. DESIGN.­: All liver biopsies with metastasis between 2015 and 2018 were identified from our institutional database and were reviewed. The morphologic pattern of the metastasis and IHC markers used in each case were recorded. The final identification of primary site of the tumor was assessed based on all the available clinicopathologic data. The academic ranking and practice pattern of the pathologist signing out the case were also recorded. RESULTS.­: A total of 406 liver biopsies with metastasis were identified, and the cases were classified as adenocarcinoma (253 of 406; 62%), carcinoma not otherwise specified (12 of 406; 3%), neuroendocrine neoplasm (54 of 406; 13%), poorly differentiated carcinoma (43 of 406; 11%), nonepithelial tumor (24 of 406; 6%), and squamous cell carcinoma (20 of 406; 5%). The primary site was unknown in 39% (158 of 406) at the time of liver biopsy. A primary site was determined in 97% (395 of 406) of all cases, and only 3% (11 of 406) remained true carcinoma of unknown primary. The average number of IHC markers/case in patients with known primary was 2.6, compared with 5.9 with an initial unknown primary and 9.5 in cases of true carcinoma of unknown primary. CONCLUSIONS.­: An individualized, case-based approach seems to be highly cost-effective and uses fewer IHC markers compared with preset panels that often comprise 10 or more IHC markers.

Optimising Medications in Older Vascular Surgery Patients Through Geriatric Co-management.

BACKGROUND: Prescribing of potentially inappropriate medications and under-prescribing of guideline-recommended medications for cardiovascular risk modification have both been associated with negative outcomes in older adults. Hospitalisation represents an important opportunity to optimise medication use and may be achieved through geriatrician-led interventions. OBJECTIVE: We aimed to evaluate whether implementation of a novel model of care called Geriatric Comanagement of older Vascular (GeriCO-V) surgery patients is associated with improvements in medication prescribing. METHODS: We used a prospective pre-post study design. The intervention was a geriatric co-management model, where a geriatrician delivered comprehensive geriatric assessment-based interventions including a routine medication review. We included consecutively admitted patients to the vascular surgery unit at a tertiary academic centre aged ≥ 65 years with an expected length of stay of ≥ 2 days and who were discharged from hospital. Outcomes of interest were the prevalence of at least one potentially inappropriate medication as defined by the Beers Criteria at admission and discharge, and rates of cessation of at least one potentially inappropriate medication present on admission. In the subgroup of patients with peripheral arterial disease, the prevalence of guideline-recommended medications on discharge was determined. RESULTS: There were 137 patients in the pre-intervention group (median [interquartile range] age: 80.0 [74.0-85.0] years, 83 [60.6%] with peripheral arterial disease) and 132 patients in the post-intervention group (median [interquartile range] age: 79.0 (73.0-84.0) years, 75 [56.8%] with peripheral arterial disease). There was no change in the prevalence of potentially inappropriate medication use from admission to discharge in either group (pre-intervention: 74.5% on admission vs 75.2% on discharge; post-intervention: 72.0% vs 72.7%, p = 0.65). Forty-five percent of pre-intervention group patients had at least one potentially inappropriate medication present on admission ceased, compared with 36% of post-intervention group patients (p = 0.11). A higher number of patients with peripheral arterial disease in the post-intervention group were discharged on antiplatelet agent therapy (63 [84.0%] vs 53 [63.9%], p = 0.004) and lipid-lowering therapy (58 [77.3%] vs 55 [66.3%], p = 0.12). CONCLUSIONS: Geriatric co-management was associated with an improvement in guideline-recommended antiplatelet agent prescribing aimed at cardiovascular risk modification for older vascular surgery patients. The prevalence of potentially inappropriate medications was high in this population, and was not reduced with geriatric co-management.

Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone.

A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 µM).

Modifying quinolone antibiotics yields new anxiolytics.

Patients taking fluoroquinolone antibiotics such as norfloxacin exhibit a low incidence of convulsions and anxiety. These side effects probably result from antagonism of the neurotransmitter gamma-aminobutyric acid (GABA) at the brain GABA(A) receptor complex (GRC). Modification of norfloxacin yields molecules such as compound 4 that potentiate GABA action with alpha(2) subunit selectivity. Compound 4 is anxiolytic but does not cause sedation, and may represent a new class of ligands that have anxiolytic activity without sedative liability.

Calibrated uncertainty estimation for interpretable proton computed tomography image correction using Bayesian deep learning.

Integrated-type proton computed tomography (pCT) measures proton stopping power ratio (SPR) images for proton therapy treatment planning, but its image quality is degraded due to noise and scatter. Although several correction methods have been proposed, techniques that include estimation of uncertainty are limited. This study proposes a novel uncertainty-aware pCT image correction method using a Bayesian convolutional neural network (BCNN). A DenseNet-based BCNN was constructed to predict both a corrected SPR image and its uncertainty from a noisy SPR image. A total 432 noisy SPR images of 6 non-anthropomorphic and 3 head phantoms were collected with Monte Carlo simulations, while true noise-free images were calculated with known geometric and chemical components. Heteroscedastic loss and deep ensemble techniques were performed to estimate aleatoric and epistemic uncertainties by training 25 unique BCNN models. 200-epoch end-to-end training was performed for each model independently. Feasibility of the predicted uncertainty was demonstrated after applying two post-hoc calibrations and calculating spot-specific path length uncertainty distribution. For evaluation, accuracy of head SPR images and water-equivalent thickness (WET) corrected by the trained BCNN models was compared with a conventional method and non-Bayesian CNN model. BCNN-corrected SPR images represent noise-free images with high accuracy. Mean absolute error in test data was improved from 0.263 for uncorrected images to 0.0538 for BCNN-corrected images. Moreover, the calibrated uncertainty represents accurate confidence levels, and the BCNN-corrected calibrated WET was more accurate than non-Bayesian CNN with high statistical significance. Computation time for calculating one image and its uncertainties with 25 BCNN models is 0.7 s with a consumer grade GPU. Our model is able to predict accurate pCT images as well as two types of uncertainty. These uncertainties will be useful to identify potential cause of SPR errors and develop a spot-specific range margin criterion, toward elaboration of uncertainty-guided proton therapy.