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Background Chronic cough (CC) of 8 weeks or more affects about 10% of adults and may lead to expensive treatments and reduced quality of life. Incomplete diagnostic coding complicates identifying CC in electronic health records (EHRs). Natural language processing (NLP) of EHR text could improve detection. Research Question Can NLP be used to identify cough in EHRs, and to characterize adults and encounters with CC? Study Design and Methods A Midwestern EHR system identified patients aged 18 to 85 years during 2005 to 2015. NLP was used to evaluate text notes, except prescriptions and instructions, for mentions of cough. Two physicians and a biostatistician reviewed 12 sets of 50 encounters each, with iterative refinements, until the positive predictive value for cough encounters exceeded 90%. NLP, International Classification of Diseases, 10th revision, or medication was used to identify cough. Three encounters spanning 56 to 120 days defined CC. Descriptive statistics summarized patients and encounters, including referrals. Results Optimizing NLP required identifying and eliminating cough denials, instructions, and historical references. Of 235,457 cough encounters, 23% had a relevant diagnostic code or medication. Applying chronicity to cough encounters identified 23,371 patients (61% women) with CC. NLP alone identified 74% of these patients; diagnoses or medications alone identified 15%. The positive predictive value of NLP in the reviewed sample was 97%. Referrals for cough occurred for 3.0% of patients; pulmonary medicine was most common initially (64% of referrals). Limitations Some patients with diagnosis codes for cough, encounters at intervals greater than 4 months, or multiple acute cough episodes may have been misclassified. Interpretation NLP successfully identified a large cohort with CC. Most patients were identified through NLP alone, rather than diagnoses or medications. NLP improved detection of patients nearly sevenfold, addressing the gap in ability to identify and characterize CC disease burden. Nearly all cases appeared to be managed in primary care. Identifying these patients is important for characterizing treatment and unmet needs.

Purpose: Pretreating the kidney with 100 low-energy shock waves (SWs) with a time pause before delivering a clinical dose of SWs (Dornier HM-3, 2000 SWs, 24 kV, and 120 SWs/min) has been shown to significantly reduce the size of the hemorrhagic lesion produced in that treated kidney, compared to a protocol without pretreatment. It has been assumed that a similar reduction in injury will occur with lithotripters other than the HM-3, but experiments to confirm this assumption are lacking. In this study, we sought to verify that the lesion protection phenomenon also occurs in a lithotripter using an electromagnetic shock source and dry-head coupling. Materials and Methods: Eleven female pigs were placed in a Dornier Compact S lithotripter where the left kidney of each animal was targeted for lithotripsy treatment. Some kidneys received 2500 SWs at power level (PL) = 5 (120 SWs/min) while some kidneys were pretreated with 100 SWs at PL = 1, with a 3-minute time pause, followed immediately by 2500 SWs at PL = 5 (120 SWs/min). Lesion size analysis was performed to assess the volume of hemorrhagic tissue injury created by each treatment regimen (% functional renal volume). Results: Lesion size fell by 85% (p = 0.01) in the 100 SW pretreatment group compared to the injury produced by a regimen without pretreatment. Conclusions: The results suggest that the treatment pause protection phenomenon occurs with a Dornier Compact S, a machine distinctly different from the Dornier HM-3. This result also suggests that this phenomenon may be observed generally in SW lithotripters.

Objective: Our goals were to validate stone comminution with an investigational burst wave lithotripsy (BWL) system in patient-relevant conditions and to evaluate the use of ultrasonic propulsion to move a stone or fragments to aid in observing the treatment endpoint. Materials and Methods: The Propulse-1 system, used in clinical trials of ultrasonic propulsion and upgraded for BWL trials, was used to fragment 46 human stones (5–7 mm) in either a 15-mm or 4-mm diameter calix phantom in water at either 50% or 75% dissolved oxygen level. Stones were paired by size and composition, and exposed to 20-cycle, 390-kHz bursts at 6-MPa peak negative pressure (PNP) and 13-Hz pulse repetition frequency (PRF) or 7-MPa PNP and 6.5-Hz PRF. Stones were exposed in 5-minute increments and sieved, with fragments >2 mm weighed and returned for additional treatment. Effectiveness for pairs of conditions was compared statistically within a framework of survival data analysis for interval censored data. Three reviewers blinded to the experimental conditions scored ultrasound imaging videos for degree of fragmentation based on stone response to ultrasonic propulsion. Results: Overall, 89% (41/46) and 70% (32/46) of human stones were fully comminuted within 30 and 10 minutes, respectively. Fragments remained after 30 minutes in 4% (1/28) of calcium oxalate monohydrate stones and 40% (4/10) of brushite stones. There were no statistically significant differences in comminution time between the two output settings (p = 0.44), the two dissolved oxygen levels (p = 0.65), or the two calyx diameters (p = 0.58). Inter-rater correlation on endpoint detection was substantial (Fleiss' kappa = 0.638, p

Purpose This study provides an overview of the prognosis of intravascular large B cell lymphoma (IVLBCL) over the past 10 years and analyzes the possible relevant factors. Patients and methods We conducted a literature search of case reports, case series, and retrospective studies of IVLBCL published from January 2008 to July 2018. After excluding inappropriate data, 103 publications were selected for the analysis. Statistical analyses of different treatment modalities, the effect of blood-brain barrier (BBB)-penetrating drugs, and prognostic factors for outcomes were performed. Results In total, 182 pathologically confirmed cases of IVLBCL were included in our study. The results revealed that the 1- and 3-year overall survival rates were 42.3 and 11.5%, respectively, whereas the median overall survival was 340 days. Overall survival (450 days vs 180 days) and progression-free survival (420 days vs 150 days) were significantly longer in patients who received rituximab-containing regimens than in those treated with other regimens. For IVLBCL involving the CNS, regimens containing BBB-penetrating drugs failed to provide an additional survival benefit. In addition, lactic dehydrogenase levels ≥700 U/L, CNS involvement, and hemophagocytic syndrome were identified as unfavorable risk factors in patients with IVLBCL, whereas skin involvement appeared to be a protective factor. Conclusion Rituximab-containing chemotherapy can improve the outcomes of patients with IVLBCL, but the prognosis remains unsatisfactory. Treatment regimens containing BBB-penetrating drugs failed to improve outcomes in patients with CNS-involved IVLBCL. Several factors affect the prognosis of patients with IVLBCL, and further research on the underlying mechanisms is needed.

Background: The association between pre-existing diabetes mellitus (DM) and subsequent increased incidence of breast cancer (BC), as well as worse survival after BC diagnosis, is well described. However, the reverse relationship of BC or metastases to development of new onset DM is unknown. Preclinical evidence suggests that increased bone destruction due to bone metastases or endocrine therapy impairs insulin secretion via TGFβ-mediated oxidation of the ryanodine receptor in pancreatic β- cells, predisposing patients to development of new onset DM. This analysis describes the prevalence and new onset of DM in metastatic BC compared to matched, unaffected controls and non-metastatic BC. Methods: This retrospective study collected data on women from the Indiana Network for Patient Care (INPC, a multi-health system electronic health record data warehouse), and the Indiana State Department of Health Cancer Registry from 2015 to 2017. Diagnosis of BC and metastases were established using ICD codes from INPC and confirmed in the cancer registry. DM was defined using a combination of ICD codes, diabetic medication prescriptions, and hemoglobin A1c >6.5%. Controls without BC were matched to all BC cases by birth year and race. The prevalence of DM before, or < 30 days after, BC diagnosis is described for non- cancer controls, all patients with BC, and subgroups without metastases, any metastases, and with bone metastases. In patients without evidence of DM prior to or < 30 days after BC diagnosis, the incidence of new onset DM was compared to matched controls over the same time period. The occurrence of new DM was evaluated both including and excluding the first 6 months after BC diagnosis to account for potential DM diagnosis simply due to medical attention. Prevalence and subsequent incidence of DM was compared between cases and controls using Pearson’s chi-square tests. Variables including demographics, comorbidities, BC treatment, A1c values, and DM treatments were also collected. Results: Any DM diagnosis, pre-existing DM, and new onset DM were higher in breast cancer cases compared to controls (Table). While pre-existing DM was similar between those with metastatic and non-metastatic DM (35.0% vs. 32.2%, p=0.22), new onset DM was higher in metastatic disease compared to non-metastatic BC (14.4% vs. 7.0%, p Conclusions: Diabetes is highly prevalent in this Indiana BC cohort. Incidence of new onset DM after BC is higher in those with metastatic BC compared to both controls and BC cases without metastatic disease. Hemoglobin A1c was highest in those with bone metastases, further supporting the hypothesis that bone turnover may influence insulin secretion and glucose metabolism. Additional investigation will analyze the influence of medications (chemo-, endocrine, and bone protective therapy) on development of DM. As more patients live longer with metastatic BC, identification and management of DM will be imperative given its impact on BC survival, treatment delivery, healthcare costs, and quality of life. ControlsBreast cancer (BC) casesAllNon-metAll metBone metNon-bone metTotal n10212102129760452236216Any DM, n (%)2464 (24.1)4406 (43.1)3823 (39.2)223 (49.3)111 (47.0)112 (51.9)p-value2 6 months after BC1, n (%)336 (3.3)621 (6.1)565 (5.8)56 (12.4)27 (11.4)29 (13.4)p-value2 Citation Format: Tarah Ballinger, Sarah El-Azab, Ziyue Liu, Theresa Guise, Erik Imel. High prevalence and incidence of new onset diabetes in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-11.

INTRODUCTION AND OBJECTIVE:The purpose of the study is to test whether removing small, asymptomatic stones from the kidneys of patients being treated for kidney or ureteral stones will reduce recur...

Purpose: Ultrasonic propulsion is an investigative modality to noninvasively image and reposition urinary stones. Our goals were to test safety and effectiveness of new acoustic exposure conditions from a new transducer, and to use simultaneous ureteroscopic and ultrasonic observation to quantify stone repositioning. Materials and Methods: During operation, ultrasonic propulsion was applied transcutaneously, whereas stone targets were visualized ureteroscopically. Exposures were 350 kHz frequency, ≤200 W/cm(2) focal intensity, and ≤3-second bursts per push. Ureteroscope and ultrasound (US) videos were recorded. Video clips with and without stone motion were randomized and scored for motion ≥3 mm by independent reviewers blinded to the exposures. Subjects were followed with telephone calls, imaging, and chart review for adverse events. Results: The investigative treatment was used in 18 subjects and 19 kidneys. A total of 62 stone targets were treated ranging in size from a collection of “dust” to 15 mm. Subjects received an average of 17 ± 14 propulsion bursts (per kidney) for a total average exposure time of 40 ± 40 seconds. Independent reviewers scored at least one stone movement ≥3 mm in 18 of 19 kidneys (95%) from the ureteroscope videos and in 15 of 19 kidneys (79%) from the US videos. This difference was probably because of motion out of the US imaging plane. Treatment repositioned stones in two cases that would have otherwise required basket repositioning. No serious adverse events were observed with the device or procedure. Conclusions: Ultrasonic propulsion was shown to be safe, and it effectively repositioned stones in 95% of kidneys despite positioning and access restrictions caused by working in an operating room on anesthetized subjects.

BACKGROUND: X-linked hypophosphatemia (XLH) causes rickets, osteomalacia, skeletal deformities and growth impairment, due to elevated fibroblast growth factor 23 and hypophosphatemia. Conventional therapy requires high doses of phosphate salts combined with active vitamin D analogues. Risks of this regimen include nephrocalcinosis and secondary hyperparathyroidism or progression to tertiary (hypercalcemic) hyperparathyroidism. METHODS: The primary goals were to estimate the prevalence of hyperparathyroidism and to characterize parathyroidectomy outcomes regarding hypercalcemia among XLH patients. XLH patients attending our center from 1/2000 to 12/2017 were included in a retrospective chart review. Prevalence of nephrocalcinosis and eGFR

BACKGROUND: IPMNs are cystic pancreatic lesions with variable malignant potential. Thrombospondin-2 (THBS2)—an endogenous, anti-angiogenic matrix glycoprotein—may modulate tumor progression. We hypothesized that circulating levels of THBS2 could aid in preoperative prediction of malignant IPMN. METHODS: Preoperative serum/plasma samples were procured from patients undergoing surgery. Circulating levels of THBS2 were measured (enzyme-linked immunosorbent assay) and compared to surgical pathology IPMN dysplastic grade. RESULTS: 164 patients underwent THBS2 testing (100 Low/Moderate-IPMN; 64 High-Grade/Invasive-IPMN). Circulating THBS2 (mean±SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6±12.7ng/mL vs. 20.4±8.2ng/mL; P

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a powerful tool to assess bone health. To determine how an individual's or population of interest's HR-pQCT outcomes compare to expected, reference data are required. This study provides reference data for HR-pQCT measures acquired in a population of White adults.PURPOSE: To provide age- and sex-specific reference data for high-resolution peripheral quantitative computed tomography (HR-pQCT) measures of the distal and diaphyseal radius and tibia acquired using a second-generation scanner and percent-of-length offsets proximal from the end of the bone.METHODS: Data were acquired in White adults (aged 18-80 years) living in the Midwest region of the USA. HR-pQCT scans were performed at the 4% distal radius, 30% diaphyseal radius, 7.3% distal tibia, and 30% diaphyseal tibia. Centile curves were fit to the data using the LMS approach.RESULTS: Scans of 867 females and 317 males were included. The fitted centile curves reveal HR-pQCT differences between ages, sexes, and sites. They also indicate differences when compared to data obtained by others using fixed length offsets. Excel-based calculators based on the current data were developed and are provided to enable computation of subject-specific percentiles, z-scores, and t-scores and to plot an individual's outcomes on the fitted curves. In addition, regression equations are provided to convert estimated failure load acquired with the conventional criteria utilized with first-generation scanners and those specifically developed for second-generation scanners.CONCLUSION: The current study provides unique data and resources. The combination of the reference data and calculators provide clinicians and investigators an ability to assess HR-pQCT outcomes in an individual or population of interest, when using the described scanning and analysis procedure. Ultimately, the expectation is these data will be expanded over time so the wealth of information HR-pQCT provides becomes increasingly interpretable and utilized.

Background Previous narrative reviews have concluded that dietary nitrate (NO3−) improves maximal neuromuscular power in humans. This conclusion, however, was based on a limited number of studies, and no attempt has been made to quantify the exact magnitude of this beneficial effect. Such information would help ensure adequate statistical power in future studies and could help place the effects of dietary NO3− on various aspects of exercise performance (i.e., endurance vs. strength vs. power) in better context. We therefore undertook a systematic review and individual participant data meta-analysis to quantify the effects of NO3− supplementation on human muscle power. Methods The literature was searched using a strategy developed by a health sciences librarian. Data sources included Medline Ovid, Embase, SPORTDiscus, Scopus, Clinicaltrials.gov, and Google Scholar. Studies were included if they used a randomized, double-blind, placebo-controlled, crossover experimental design to measure the effects of dietary NO3− on maximal power during exercise in the non-fatigued state and the within-subject correlation could be determined from data in the published manuscript or obtained from the authors. Results Nineteen studies of a total of 268 participants (218 men, 50 women) met the criteria for inclusion. The overall effect size (ES; Hedge’s g) calculated using a fixed effects model was 0.42 (95% confidence interval (CI) 0.29, 0.56; p = 6.310 × 10− 11). There was limited heterogeneity between studies (i.e., I2 = 22.79%, H2 = 1.30, p = 0.3460). The ES estimated using a random effects model was therefore similar (i.e., 0.45, 95% CI 0.30, 0.61; p = 1.064 × 10− 9). Sub-group analyses revealed no significant differences due to subject age, sex, or test modality (i.e., small vs. large muscle mass exercise). However, the ES in studies using an acute dose (i.e., 0.54, 95% CI 0.37, 0.71; p = 6.774 × 10− 12) was greater (p = 0.0211) than in studies using a multiple dose regimen (i.e., 0.22, 95% CI 0.01, 0.43; p = 0.003630). Conclusions Acute or chronic dietary NO3− intake significantly increases maximal muscle power in humans. The magnitude of this effect–on average, ~ 5%–is likely to be of considerable practical and clinical importance. Supplementary Information The online version contains supplementary material available at 10.1186/s12970-021-00463-z.

Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression free survival (mPFS), with secondary objectives including median overall survival (mOS), safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically-defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.

Background Depression is associated with an increased risk of cardiovascular disease in human immunodeficiency virus (HIV). We hypothesized that reducing depressive symptoms would improve HIV-related cardiovascular risk. Methods We conducted a single-center, randomized (1:1), controlled, parallel-group, assessor-blinded, pilot trial comparing Beating the Blues US (BtB)—an evidence-based, 8-session, internet cognitive-behavioral therapy for depression—with usual care (UC) in HIV-positive participants receiving virologically suppressive antiretroviral therapy and with Patient Health Questionnaire (PHQ)-9 scores ≥10. The primary endpoint was change in brachial artery flow-mediated dilation (FMD) at 12 weeks. Secondary endpoints were FMD change at 24 weeks and inflammation, coagulation, and metabolic biomarker changes at 12 and 24 weeks. Results Fifty-four participants were randomized (27 in each arm). Mean reductions in PHQ-9 scores were significantly greater with BtB versus UC at 12 weeks (−5.60 vs −1.52; P = .007) and 24 weeks (−6.00 vs −1.38; P = .008); reductions in the Hopkins Symptom Checklist Depression Scale-20 scores were also significantly greater with BtB versus UC at 24 weeks (−0.72 vs −0.35; P = .029). Changes in FMD between arms were not significantly different at 12 or 24 weeks. Significantly larger reductions in soluble (s)CD14 and sCD163 with BtB versus UC were found at 12 and 24 weeks, respectively. Conclusions Compared with UC, internet cognitive-behavioral therapy using BtB resulted in greater improvements in depressive symptoms and monocyte activation markers but did not improve FMD in this pilot trial. These data support performing larger studies to determine the potential salutatory effects of behavioral therapies for depression on HIV-related inflammation., In this pilot randomized trial, we found that internet cognitive-behavioral therapy, compared with usual care, improved depressive symptoms and monocyte activation, but not endothelial function, in HIV-positive patients.

In recent years, the increase of aging population in developed countries has become a significant social problem. There are not a few accidents caused by their low walking ability. The improvement of the walking ability for the elderly and post recovery patients is the main concern of this paper. For this purpose, it is necessary to analyze and estimate their walking posture. In this paper, we propose a posture analysis and estimation method and a gait index acquisition method using a monocular wearable camera. The idea of this paper is to employ an ego-camera mounted on a user. His/her walking posture is analyzed by the frontal view video provided from the camera. This idea intends that the proposed system will be used on a daily basis in the future by those who want to improve their walking posture to keep a healthy life.

INTRODUCTION AND OBJECTIVE:Our goals were to validate stone comminution with an investigative clinical burst wave lithotripsy (BWL) system and to evaluate the use of ultrasonic propulsion to move t...

BACKGROUND Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P

Introduction: Studies suggest that the width of the acoustic shadow on ultrasound (US) more accurately reflects true stone size than the stone width in US images. We evaluated the need for training in the adoption of the acoustic shadow sizing technique by clinical providers. Methods: Providers without shadow sizing experience were recruited and assigned in a stratified, alternating manner to receive a training tutorial (“trained”) or no intervention (“control”). Each conducted a baseline assessment of 24 clinical US images; where present, shadow width was measured using custom calipers. The trained group subsequently completed a standardized training module on shadow sizing. All subjects repeated measurements after ∼1 week. Group demographics were compared using Fisher's exact test. Measurements were compared to clinically reported stone sizes on corresponding CT and US using mixed-effects models. One millimeter concordance between shadow and CT size was compared using a generalized linear mixed-effects model. Results: Twenty-six subjects were included. There was no significant difference between groups in demographics, clinical role, or US experience. Mean reported CT and US stone sizes were 6.8 ± 4.0 mm and 10.3 ± 4.1 mm, respectively. At baseline, there was no difference in shadow size measurements between groups (p = 0.18), and shadow size was no more accurate than US stone size (p = 0.28 trained; p = 0.81 control), compared to CT. After training, overestimation bias of shadow size in the trained group decreased to 1.6 ± 0.5 mm (p

Heightened systemic inflammation contributes to cardiovascular (CVD) events in people living with HIV (PLWH), although not all PLWH develop CVD, thus suggesting a genetic modifying role. We examined GCH1 polymorphisms, which have been associated with reduced endothelial function in European populations with CVD and increased inflammation, in a racially diverse cohort of US PLWH initiating antiretroviral therapy (ART). GCH1 polymorphisms differed by race and were not associated with flow-mediated dilation or carotid intima-media thickness before or after 48 weeks of ART.

Feasibility of ultrasonic propulsion and burst wave lithotripsy (BWL) to noninvasively reposition distal ureteral stones to facilitate passage and relieve pain was tested. Patients presenting to the clinic or emergency department were recruited. Thirteen subjects underwent ultrasonic propulsion (lower amplitude, longer duration pulses) alone, and 10 subjects also received intermittent BWL (higher amplitude, shorter duration pulses). All participants were awake and underwent a pain assessment pre- and post-procedure. For analysis, subjects were sub-categorized based on whether their stone was acute or chronic (present for ≤10 days or >10 days from their initial ED or symptomatic presentation, respectively). Seventeen subjects were enrolled in the acute study population and 6 subjects were enrolled in the chronic population. Overall, 94% of acute stones passed in an average of 3.4 days post-procedure relative to 54% in 7.5 days in the American Urological Association guidelines. 67% of chronic cases passed stones or fragments, and two surgeries were cancelled. Pain reduction was statistically significant ( p = 0.0215). Adverse events were limited to hematuria on initial urination post-procedure (BWL only, n = 3) and a mild sensation, akin to a pinprick, associated with fewer than 10 of 620 propulsion bursts ( n = 3). [Work supported by NIH-P01-DK04331.]

Burst Wave Lithotripsy (BWL) is a new stone treatment that utilizes ultrasound to fracture renal calculi. However, it is not known if BWL alters renal function, so we tested if a clinical dose of BWL impacts glomerular filtration rate (GFR) or kidney blood flow. Treatment consisted of placing each pig (32–42 kg) on its side, locating the lower pole of the right kidney, and treating that kidney with a BWL dose of 18,000 ultrasound pulses at 10Hz, 20 cycles/pulse and a peak negative pressure of −7 MPa (n = 6). Six additional pigs were used as sham controls. Inulin and para-aminohippuric acid (PAH) were infused into the pigs with blood and urine samples being collected both before and 1-h after BWL treatment. The concentrations of inulin and PAH were determined in the samples and used to calculate GFR and effective renal plasma flow (eRPF). For the BWL treated group, GFR and eRPF did not change after BWL exposure (−6.7 ± 7.2% for GFR, −10.9 ± 5.5% for eRPF), and this response was like the sham control group ( P = 0.23 for GFR, P = 0.08 for eRPF). A typical clinical dose of BWL caused no change in renal function. [Work supported by NIH, Grant P01 DK43881.]

The goal is to test effectiveness and safety of transcutaneous ultrasound pulses for facilitating clearance of residual urinary stone fragments in a randomized control trial (RCT). The study is conducted in a clinic setting with the control and treatment arms undergoing all the same activities with the exception of the ultrasonic propulsion procedure and associated pain questionnaire. Subjects are followed 90 days for assessment of adverse events and for up to 5 years for stone growth and symptomatic stone visits. Twenty-six of 33 subjects have been recruited in each arm The most recent treatment is reported. The subject received shock wave lithotripsy and did not pass any fragments for 17 months. The subject was randomized to the treatment arm. Fragments began moving with the third 3-s propulsion pulse at output 2 of 5 levels. Fifty-two percent of propulsion pulses (41 of 79) resulted in fragment movement. The subject reported no pain at the beginning or end of the procedure and telephoned within 2 h to report passing 9 fragments, no hematuria, and no adverse events. The treatment results of this RCT are compelling as an immediate and casual effect was measured. [Work supported by NIH-P01-DK043881 and VA Puget Sound resources.]

Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25-2.92)], genistein [1.51 (1.02-2.22), daidzein [1.80 (1.18-2.75) and glycitein [1.67 (1.15-2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93-2.25), 1.65 (1.07-2.54), 1.73 (1.13-2.66) and 1.80 (1.18-2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.

Greater visual contrast between calculi and tissue would improve ultrasound (US) imaging of urolithiasis and potentially expand clinical use. The color Doppler twinkling artifact has been suggested to provide enhanced contrast of stones compared with brightness mode (B-mode) imaging, but results are variable. This work provides the first quantitative measure of stone contrast in humans for B-mode and color Doppler mode, forming the basis to improve US for the detection of stones.Using a research ultrasound system, B-mode imaging was tuned for detecting stones by applying a single transmit angle and reduced signal compression. Stone twinkling with color Doppler was tuned by using low-frequency transmit pulses, longer pulse durations, and a high-pulse repetition frequency. Data were captured from 32 subjects, with 297 B-mode and Doppler images analyzed from 21 subjects exhibiting twinkling signals. The signal to clutter ratio (i.e., stone to background tissue) (SCR) was used to compare the contrast of a stone on B-mode with color Doppler, and the contrast between stone twinkling and blood-flow signals within the kidney.The stone was the brightest object in only 54% of B-mode images and 100% of Doppler images containing stone twinkling. On average, stones were isoechoic with the tissue clutter on B-mode (SCR = 0 dB). Stone twinkling averaged 37 times greater contrast than B-mode (16 dB, p 0.0001) and 3.5 times greater contrast than blood-flow signals (5.5 dB, p = 0.088).This study provides the first quantitative measure of US stone to tissue contrast in humans. Stone twinkling contrast is significantly greater than the contrast of a stone on B-mode. There was also a trend of stone twinkling signals having greater contrast than blood-flow signals in the kidney. Dedicated optimization of B-mode and color Doppler stone imaging could improve US detection of stones.

Huge data volumes and redundant information are common problems in the field of hyperspectral target recognition. In this study, we propose a method to ensure the accuracy of target recognition while reducing the amount of data, where the effective bands in the hyperspectral data are selected for which the third-order derivative spectrum approaches zero. Next, a feature optimization method based on a combination of the derivative spectrum is proposed for hyperspectral target recognition, where a combination of the derivative spectrum and original spectrum is used as the basic vector after dimensionality reduction. The analyzed bands are decreased to reduce spectral interference and the data volume. The dimension of the combinatorial derivative spectrum is then increased to obtain more spectral information from the effective bands of the hyperspectral data. Thus, the proposed method can identify the target more accurately with fewer bands. Our experiments showed that the proposed method outperformed principal components analysis, local discriminant analysis, and kernel principal components analysis in low dimensions.

Background Sarcopenia, cachexia and frailty have overlapping features and clinical consequences, but often go unrecognized. The objective was to detect patients described by clinicians as having sarcopenia, cachexia or frailty within electronic health records (EHR) and compare clinical variables between cases and matched controls. Methods We conducted a case-control study using retrospective data from the Indiana Network for Patient Care multi-health system database from 2016 to 2017. The computable phenotype combined ICD codes for sarcopenia, cachexia and frailty, with clinical note text terms for sarcopenia, cachexia and frailty detected using natural language processing. Cases with these codes or text terms were matched to controls without these codes or text terms matched on birth year, sex and race. Two physicians reviewed EHR for all cases and a subset of controls. Comorbidity codes, laboratory values, and other coded clinical variables were compared between groups using Wilcoxon matched-pair sign-rank test for continuous variables and conditional logistic regression for binary variables. Results Cohorts of 9594 cases and 9594 matched controls were generated. Cases were 59% female, 69% white, and a median (1st, 3rd quartiles) age 74.9 (62.2, 84.8) years. Most cases were detected by text terms without ICD codes n = 8285 (86.4%). All cases detected by ICD codes (total n = 1309) also had supportive text terms. Overall 1496 (15.6%) had concurrent terms or codes for two or more of the three conditions (sarcopenia, cachexia or frailty). Of text term occurrence, 97% were used positively for sarcopenia, 90% for cachexia, and 95% for frailty. The remaining occurrences were negative uses of the terms or applied to someone other than the patient. Cases had lower body mass index, albumin and prealbumin, and significantly higher odds ratios for diabetes, hypertension, cardiovascular and peripheral vascular diseases, chronic kidney disease, liver disease, malignancy, osteoporosis and fractures (all p Conclusions Patients detected with a computable phenotype for sarcopenia, cachexia and frailty differed from controls in several important clinical variables. Potential uses include detection among clinical cohorts for targeting recruitment for research and interventions.

In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was

X-linked hypophosphatemia, due to PHEX mutations results in elevated fibroblast growth factor 23, hypophosphatemia and rickets/osteomalacia. Conventional therapy requires high doses of phosphate salts combined with active vitamin D analogues. Known complications of this regimen include nephrocalcinosis and secondary and tertiary hyperparathyroidism. The prevalence of hyperparathyroidism and treatment with parathyroidectomy in XLH is uncertain. The goal of this study was to estimate the prevalence of hyperparathyroidism and parathyroidectomy among XLH patients. We also characterized the outcome of parathyroidectomy for XLH patients. We conducted a retrospective chart review study from 1/1/2010 to 12/31/2017 using data from electronic records and paper charts. All XLH patients attending our center were eligible for analysis if they had at least one concurrent measurement of parathyroid hormone (PTH) and serum calcium. Categorization was based on the highest PTH and calcium values, persistence of hypercalcemia and a history of parathyroidectomy. Of the 104 patients having a diagnosis of XLH, 84 had concurrent measurements available of calcium and PTH. Data were available from 46 patients as adults and 43 as children (5 as both). Of these, 71/84 (84.52%), had evidence of secondary or tertiary hyperparathyroidism at any time point. Secondary hyperparathyroidism (defined as any PTH value ≥65pg/mL and not hypercalcemic) occurred in 35/43 (81.4%) children and 41/46 (89.1%) adults at any time point. Resolution of secondary hyperparathyroidism was observed in all children, except two with parathyroidectomies at ages 15 and 18 for tertiary hyperparathyroidism. Resolution of secondary hyperparathyroidism was observed in 27/41 adults. Tertiary (or hypercalcemic) hyperparathyroidism had an overall prevalence of 14/84 (16.67%) patients or 14/46 (30.4%) of adults (n=10 with PTH ≥65 pg/mL plus Calcium ≥10.5 mg/dl; n=1 with PTH ≥65 pg/mL plus Calcium 10.2-10.4 mg/dl; n=2 with PTH ≥50 pg/mL plus Calcium ≥10.5 mg/dL; n=1 with parathyroidectomy prior to presentation to our center). Parathyroidectomy was documented in 8/84 (9.5%) of the total population, or 8/46 (17.4%) of adults with XLH. After parathyroidectomy, residual or recurrent tertiary hyperparathyroidism was detected in 6/8 patients at a median of 6 years (ranging from 0 to 29 years). One patient had chronic postoperative hypoparathyroidism, and one patient remains normocalcemic 4 years after surgery. The majority of patients with XLH develop hyperparathyroidism during treatment with phosphate and active vitamin D. A significant proportion develop hypercalcemic hyperparathyroidism and most had recurrence of parathyroid autonomy after surgery. Careful monitoring and dose adjustment to minimize elevations of PTH are recommended.

Purpose: Ultrasound is known to overestimate kidney stone size. We explored measuring the acoustic shadow behind kidney stones combined with different ultrasound imaging modalities to improve stone sizing accuracy.Materials and Methods: A total of 45 calcium oxalate monohydrate stones were imaged in vitro at 3 different depths with the 3 different ultrasound imaging modalities of conventional ray line, spatial compound and harmonic imaging. The width of the stone and the width of the acoustic shadow were measured by 4 operators blinded to the true size of the stone.Results: Average error between the measured and true stone width was 1.4 ± 0.8 mm, 1.7 ± 0.9 mm, 0.9 ± 0.8 mm for ray line, spatial compound and harmonic imaging, respectively. Average error between the shadow width and true stone width was 0.2 ± 0.7 mm, 0.4 ± 0.7 mm and 0.0 ± 0.8 mm for ray line, spatial compound and harmonic imaging, respectively. Sizing error based on the stone width worsened with greater depth (p

In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was

BACKGROUND: Human immunodeficiency virus (HIV) may be related to cardiovascular disease through monocyte activation–associated endothelial dysfunction. METHODS: Blood samples from 15 HIV-negative participants (the uninfected group), 8 HIV-positive participants who were not receiving antiretroviral therapy (ART) (the infected, untreated group), and 15 HIV-positive participants who were receiving ART (the infected, treated group) underwent flow cytometry of endothelial colony-forming cells (ECFCs) and monocyte proportions. IncuCyte live cell imaging of 8 capillary proliferative capacity parameters were obtained from cord blood ECFCs treated with participant plasma. RESULTS: The ECFC percentage determined by flow cytometry was not different between the study groups; however, values of the majority of capillary proliferative capacity parameters (ie, cell area, network length, network branch points, number of networks, and average tube width uniformity) were significantly lower in infected, untreated participants as compared to values for uninfected participants or infected, treated participants (P < .00625 for all comparisons). CD14(+)CD16(+) intermediate monocytes and soluble CD163 were significantly and negatively correlated with several plasma-treated, cord blood ECFC proliferative capacity parameters in the combined HIV-positive groups but not in the uninfected group. CONCLUSIONS: Cord blood ECFC proliferative capacity was significantly impaired by plasma from infected, untreated patients, compared with plasma from uninfected participants and from infected, treated participants. Several ECFC functional parameters were adversely associated with monocyte activation in the HIV-positive groups, thereby suggesting a mechanism by which HIV-related inflammation may impair vascular reparative potential and consequently increase the risk of cardiovascular disease during HIV infection.

BACKGROUND: The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low risk IPMN with low/moderate grade dysplasia may be safely watched whereas high risk IPMN with high grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low and high risk IPMN. METHODS: Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology. RESULTS: Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high grade/invasive IPMN (15,803±1686 vs. 10,275±1228 pg/ml; p=0.0086). Leptin levels were positively correlated with BMI (r=0.65, p

Background Vitamin K inhibits prostate cancer cells, and an altered expression of vitamin K-dependent proteins in prostate tumors has been linked to their aggressiveness and progression. However, little is known about the effect of vitamin K intake on prostate cancer in human populations. Objectives We evaluated the associations of dietary intake of phylloquinone (vitamin K-1), menaquinones (vitamin K-2), and total vitamin K with the development of prostate cancer among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Design Dietary intake of vitamin K was assessed with the Dietary Questionnaire (DQX) at baseline and the Dietary History Questionnaire (DHQ) at the third anniversary of randomization by using high-performance liquid chromatography-based food-composition data obtained from the USDA and published studies. During a median follow-up of 11.8 y, 2978 cases of prostate cancer (including 490 advanced cases) were identified from the 28,356 men who completed DQX. Similarly, 2973 cases of prostate cancer (including 647 advanced cases) were documented from the 48,090 men who completed DHQ. Cox proportional hazards regression was used to estimate prostate cancer risk in relation to the dietary intake of vitamin K. Results After adjustment for confounders, dietary intakes of phylloquinone, menaquinones, and total vitamin K, assessed with either the DQX or DHQ, were not significantly associated with the risk of advanced, nonadvanced, and total prostate cancer. These results remained virtually the same when vitamin K intake was modeled as a categorical (divided into quintiles) or continuous (per IQR increase) variable or after outliers of total vitamin K intake (defined as a value that falls above the sum of third quartile and twice the IQR) were excluded. Conclusions The present study does not suggest that vitamin K intake influences the occurrence of total and advanced prostate cancer in the general US population.

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary collecting system to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 15 of 16 kidneys (94%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 8 of 8 stones on post mortem dissection. A 1-week survival study with the BWL exposures and 10 specific-pathogen-free pigs, showed all findings were within normal limits on clinical pathology, hematology, and urinalysis. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective.

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts

OBJECTIVES The HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers. METHODS We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038). RESULTS There were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein, IL-6, soluble vascular cell adhesion molecule-1, HDL-cholesterol, triglycerides or homeostasis model assessment-insulin resistance. However, efavirenz led to significant increases in total cholesterol [19.39 (23.9) versus -5.78 (16.5) mg/dL; P < 0.001], LDL-cholesterol [13.29 (19.5) versus -2.24 (13.4) mg/dL; P = 0.009] and F2-isoprostanes [92.7 (178.6) versus -101.4 (215.7) pg/mL; P = 0.019] compared with rilpivirine. Two participants from each study group discontinued prematurely for adverse events. CONCLUSIONS There were no significant differences in the changes in endothelial function over 1 month between the efavirenz and rilpivirine groups, although efavirenz had worse lipid changes compared with rilpivirine. Longer-term studies are required for confirmation.

Adrenocorticotropic hormone (ACTH) diurnal patterns contain both smooth circadian rhythms and pulsatile activities. How to evaluate and compare them between different groups is a challenging statistical task. In particular, we are interested in testing (1) whether the smooth ACTH circadian rhythms in chronic fatigue syndrome and fibromyalgia patients differ from those in healthy controls and (2) whether the patterns of pulsatile activities are different. In this paper, a hierarchical state space model is proposed to extract these signals from noisy observations. The smooth circadian rhythms shared by a group of subjects are modeled by periodic smoothing splines. The subject level pulsatile activities are modeled by autoregressive processes. A functional random effect is adopted at the pair level to account for the matched pair design. Parameters are estimated by maximizing the marginal likelihood. Signals are extracted as posterior means. Computationally efficient Kalman filter algorithms are adopted for implementation. Application of the proposed model reveals that the smooth circadian rhythms are similar in the two groups but the pulsatile activities in patients are weaker than those in the healthy controls.

Objective: To discuss a method to establish a three-dimensional model of healthy human knee joint, which can be used for further knee joint biomechanics analysis and simulation. Methods: CT scan and medical image three-dimensional reconstruction software (Mimics) were used to obtain the knee joint three-dimensional finite element model (FEM) according to reverse engineering theory. Results: FEM of knee joint with complete bone structure was established by Mimics. Conclusion: Three-dimensional FEM was established according to CT images exports as IGES file. The model can be used for knee joint biomechanics finite element analysis to provide references and proposals for the clinical diagnoses of knee joint illness, and the design of artificial knee joint prosthesis.

PURPOSE: Posterior acoustic shadow width has been proposed as a more accurate measure of kidney stone size compared to direct measurement of stone width on ultrasound (US). Published data in humans to date have been based on a research US system. Herein, we compare these two measurements in clinical US images. METHODS: Thirty patient image sets where computed tomography (CT) and US images were captured less than one day apart were retrospectively reviewed. Five blinded reviewers independently assessed the largest stone in each image set for shadow presence and size. Shadow size was compared to US and CT stone sizes. RESULTS: Eighty percent of included stones demonstrated anacoustic shadow; 83% of stones without a shadow were ≤ 5 mm on CT. Average stone size was 6.5 mm ± 4.0 on CT, 10.3 mm ± 4.1 on US, and 7.5 mm ± 4.2 by shadow width. On average, US overestimated stone size by 3.8 mm ± 2.4 based on stone width (p < 0.001) and 1.0 mm ± 1.4 based on shadow width (p < 0.0098). Shadow measurements decreased misclassification of stones by 25% among three clinically relevant size categories (≤ 5 mm, 5.1 – 10 mm, > 10 mm), and by 50% for stones ≤ 5 mm. CONCLUSIONS: US overestimates stone size compared to CT. Retrospective measurement of the acoustic shadow from the same clinical US images is a more accurate reflection of true stone size than direct stone measurement. Most stones without a posterior shadow are ≤ 5 mm.

Bone demineralization, dehydration and stasis put astronauts at increased risk of forming kidney stones in space. The color-Doppler ultrasound “twinkling artifact,” which highlights kidney stones with color, can make stones readily detectable with ultrasound; however, our previous results suggest twinkling is caused by microbubbles on the stone surface which could be affected by the elevated levels of carbon dioxide found on space vehicles. Four pigs were implanted with kidney stones and imaged with ultrasound while the anesthetic carrier gas oscillated between oxygen and air containing 0.8% carbon dioxide. On exposure of the pigs to 0.8% carbon dioxide, twinkling was significantly reduced after 9–25 min and recovered when the carrier gas returned to oxygen. These trends repeated when pigs were again exposed to 0.8% carbon dioxide followed by oxygen. The reduction of twinkling caused by exposure to elevated carbon dioxide may make kidney stone detection with twinkling difficult in current space vehicles.

Due to frequent handovers in broadband wireless communications for the high-speed railway system, communication interruption caused by handover failures could seriously degrade the users' experience. Aiming at reducing the handover failure probability, this paper proposes an effective handover scheme based on the distributed antenna system (DAS) and mobile-relay-aided two-link architecture, i.e., ground-relay link and relay-onboard link, where the mobile relay is mounted on top of the moving train. In addition, an antenna selection scheme with optimal power allocation is proposed to improve handover performance. Our simulation and analysis results show that the DAS structure with macrodiversity can reduce the unnecessary handovers, as well as reduce the handover failure and link outage probabilities compared with the traditional cell without DAS. In addition, the proposed DAS with an antenna selection scheme performs better in terms of handover failure and link outage probabilities than that of DAS with a equal power allocation (EPA) scheme.

Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non–muscle-invasive urothelial carcinoma of the bladder (NMIUC) population. Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate. Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut−, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3–4 event. Six-month CR rate was 8% (0% in IHC+ Mut−; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94–5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment. Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003–11. ©2016 AACR.

Randomized Phase III clinical trials serve as the gold-standard for the evaluation of the efficacy of a medical intervention. Although research and development in earlier stages together with rigorous statistical examination assure a small probability of false positive for a given trial, it is unclear how many false positives were generated from the large number of randomized Phase III trials from the biopharmaceutical industry in the United States. The proportion of comparisons in Phase III trials where the medical intervention has null or negative efficacy, or proportion of null or negative (PNN), is at the central position for the estimation and control of the number of false positives. We seek to estimate PNN using a new Bayesian deconvolution method. Using data from clinicaltrials.gov and other data sources, we identified 1393 trials completed in 2008-2012 that meet our study entry criteria, which are dominated by trials on drugs for treatment purpose. Among the 1221 trials with results available on the selected comparisons, 789 (64.6%) show statistically significant superiority of the intervention, with 561 (45.9%) having a two-sided p-value less than 0.001. The PNN is estimated to be no more than 7-9%. Based on the PNN, we estimated that 18-22% of the trials have at least one comparison with null or negative efficacy, leading to an expectation of no more than 6-8 trials with at least one false positive comparison over a 5-year period.

The purpose of this study was to measure the accuracy of stone-specific algorithms (S-mode) and the posterior acoustic shadow for determining kidney stone size with ultrasound (US) in vivo.Thirty-four subjects with 115 renal stones were prospectively recruited and scanned with S-mode on a research US system. S-mode is gray-scale US adjusted to enhanced stone contrast and resolution by minimizing compression and averaging, and increasing line density and frequency. Stone and shadow width were compared with a recent CT scan and, in 5 subjects with 18 stones, S-mode was compared with a clinical US system.Overall, 84% of stones identified on CT were detected on S-mode and 66% of these shadowed. Seventy-three percent of the stone measurements and 85% of the shadow measurements were within 2 mm of the size on CT. A posterior acoustic shadow was present in 89% of stones over 5 mm versus 53% of stones under 5 mm. S-mode visualized 78% of stones, versus 61% for the clinical system. S-mode stone and shadow measurements differed from CT by 1.6 ± 1.0 mm and 0.8 ± 0.6 mm, respectively, compared with 2.0 ± 1.5 mm and 1.6 ± 1.0 mm for the clinical system.S-mode offers improved visualization and sizing of renal stones. With S-mode, sizing of the stone itself and the posterior acoustic shadow were similarly accurate. Stones that do not shadow are most likely5 mm and small enough to pass spontaneously.