Wilcoxon Matched-pairs Signed-rank Test Research Articles

Perfusion CT to Assess Response to Neoadjuvant Chemotherapy and Radiation Therapy in Pancreatic Ductal Adenocarcinoma: Initial Experience.

BackgroundChange in tumor size at CT is insufficient for reliable assessment of treatment response after neoadjuvant chemotherapy and radiation therapy (CRT) and shows poor correlation with histologic grading of response.PurposeTo investigate the use of perfusion CT to predict the response of pancreatic ductal adenocarcinoma (PDA) to CRT.Materials and MethodsBetween June 2016 and May 2018, study participants with biopsy-proven PDA were prospectively recruited to undergo perfusion CT before and after planned CRT. Blood flow (BF), blood volume (BV), and permeability-surface area product (PSP) were quantified from CT images. Participants were categorized into responders and nonresponders according to therapy response. The Mann-Whitney test was used to compare the baseline perfusion values between responders and nonresponders, and the Wilcoxon matched-pairs signed rank test was used to compare perfusion values before and after CRT.ResultsThe final cohort of 21 participants (median age, 68 years; interquartile range [IQR], 65-72 years; eight men) underwent dynamic perfusion (dual-source) CT before neoadjuvant CRT. All participants underwent pancreatectomy. Eighteen participants underwent post-CRT perfusion CT. Baseline BF was higher in responders (n = 10) than in nonresponders (n = 11) (median, 44 [IQR, 39-56] vs 28 [IQR, 16-52] mL/100 g/min; P = .04), while BV and PSP were similar between groups (median BV, 4.3 [IQR, 3.5-6.9] vs 2.0 [IQR, 1.6-6.5] mL/100 g, P = .15; median PSP, 25 [IQR, 21-30] vs 20 [IQR, 10-34] mL/100 g/min, P = .31). Response Evaluation Criteria in Solid Tumors (RECIST) and carbohydrate antigen (CA) 19-9 showed no correlation with perfusion parameters (eg, RECIST and BF: r = 0.05, P = .84, 95% confidence interval [CI]: -0.40, 0.48; CA 19-9 and BF: r = 0.06, P = .78, 95% CI: -0.39, 0.49) or histopathologic response (r = 0.16, P = .47, 95% CI: -0.3, 0.57 and r = 0.09, P = .71, 95% CI: -0.37, 0.51, respectively). For responders, perfusion parameters increased after CRT (eg, median BF, 54 [IQR, 42-73] vs 43 [IQR, 28-53] mL/100 g/min; P = .04). The perfusion change in nonresponders was not significant (median BF, 43 [IQR, 28-53] vs 33 [IQR, 16-52] mL/100 g/min; P = .06).ConclusionPerfusion CT may be useful in helping predict the histopathologic response to therapy in pancreatic ductal adenocarcinoma.© RSNA, 2019See also the editorial by Sinitsyn in this issue.

A retrospective cohort study of plasma exchange in central nervous system demyelinating events in children

BackgroundPlasma exchange (PLEX) may improve recovery of acute central nervous system (CNS) demyelinating events related to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), and MOG-antibody associated demyelination (MOG) if recovery with pulse steroids (PS) is incomplete. Although there is a single randomized controlled trial in adults, there are limited case series in children. We aimed to describe the effectiveness and safety of PLEX in children with acute events of MS, NMOSD, TM, ADEM, and MOG with limited improvement after PS. MethodsThis was a retrospective cohort study of children with acute CNS demyelinating events seen at a single tertiary referral center who received PLEX as a second- or third-line therapy between 2006 and 2018. Through chart review of clinical notes, presence of clinical improvement by physician assessment was recorded pre- and post-PS and pre- and post-PLEX. Expanded Disability Status Scale (EDSS) scores were collected pre- and post-PLEX. We evaluated the number who improved clinically with PLEX and compared pre- and post-PLEX EDSS with Wilcoxon matched pairs signed-rank test. Results26 patients followed at the Pediatric MS Center at the University of California, San Francisco received PLEX for acute events of MS (n = 15), NMOSD (n = 7), MOG (n = 2), TM (n = 1), and ADEM (n = 1). At time of PLEX initiation, median age was 13.5 years (range 3–17) and median time between the acute event onset and PLEX initiation was 22 days (range 3–94). 14 of 24 patients had documented clinical improvement after PS. Of those who improved during PS (n = 14), 13 had additional improvement after PLEX. Of those with no improvement after PS (n = 10), 8 improved after PLEX. 16 of 26 patients had pre- and post-PLEX EDSS scores available. Median pre-PLEX EDSS score was 4.0 (range 3.0–8.0), and median post-PLEX EDSS score was 3.75 (range 0–8.0) (p = 0.062). 5 patients had improved EDSS scores by 1 or more points. Adverse events during PLEX included hypotension (n = 3), nausea (n = 2), headache (n = 2), hypocalcemia (n = 2), hypofibrinogenemia (n = 2), thrombocytopenia (n = 1), spinal cord hemorrhage (n = 1), acute non-occlusive thrombosis of internal jugular vein (n = 1), occlusion of the central line (n = 1), edema of the neck (n = 1), and gastrointestinal discomfort (n = 1). ConclusionsPLEX is an overall well-tolerated second-line treatment option for pediatric patients with severe acute CNS demyelinating events with limited response to PS.

Biomarker Guided Diagnosis of Septic Peritonitis in Dogs

Septic peritonitis (SP) is common in dogs and is associated with high mortality. Early recognition is essential to maximizing survival and may be aided by biomarker measurement. The present study aimed to evaluate the ability of biomarkers to discriminate septic peritonitis from non-septic ascites (NSA). Eighteen dogs with SP and 19 age-matched controls with NSA were enrolled. Contemporaneous blood and peritoneal effusion samples were obtained. Concentrations of cell-free DNA (cfDNA), cytokines, glucose, lactate, N-terminal pro-C-type natriuretic peptide (NT-proCNP), nucleosomes, and procalcitonin (PCT) were measured using commercial reagents and assays. Paired biomarker concentrations were compared with the Wilcoxon matched-pairs signed rank test, and biomarker concentrations between groups were compared with the Mann-Whitney U-test. P-values were adjusted for multiple comparisons using the Bonferroni correction. Receiver operating characteristic curves were generated to assess the ability of the above biomarkers to discriminate SP from NSA. Dogs with SP had significantly greater blood CCL2 concentrations than dogs with NSA (P = 0.032). Dogs with SP had significantly greater effusion CCL2, IL-6, IL-10, and lactate concentrations than dogs with NSA (P ≤ 0.0121). Blood-effusion concentration gradients of CCL2, glucose, IL-6, IL-10, and lactate were significantly different in dogs with SP compared to dogs with NSA (P ≤ 0.0165). Effusion lactate concentration had the highest AUROC value (0.866, 95% CI 0.751–0.980, P = 0.0001), although other biomarkers performed similarly. An effusion lactate concentration of 4.2 mmol/L was 72.2% (95% CI 46.5–90.3%) sensitive and 84.2% (95% CI 60.4–96.6%) specific for the diagnosis of SP.

Teaching how to stop the bleed: does it work? A prospective evaluation of tourniquet application in law enforcement officers and private security personnel.

Stop the Bleed (STB) program was launched by the White House, for the use of bleeding control techniques at the scene of traumatic injury. The purpose of this study was to conduct an STB course in private security and law enforcement personnel. Pre- and post-questionnaire using the Likert scale was shared with participants on their knowledge and comfort level with the use of tourniquets. Participants were also observed while placing tourniquets and the time for placement recorded. The didactic portion and practical session of the STB was then taught and participants were again observed placing tourniquets and a questionnaire distributed. Fisher's exact tests or Wilcoxon matched-pairs signed-ranks tests were used to compare pre-post measurements. A total of 151 subjects were enrolled over the course of seven sessions. The tourniquet was applied correctly by 17.2% (26/151) and 92.7% (140/151) at the pre- and post-instruction assessments, respectively (p < 0.001). Mean times to apply the tourniquet were 29.8 ± 18.5 and 18.7 ± 6.7s, respectively (p < 0.001). Subjects reported their level of comfort with the tourniquet to be 5.1 ± 3.3 and 8.8 ± 2.2, respectively (p < 0.001), and their familiarity with anatomy and bleeding control to be 5.2 ± 3.1 and 8.2 ± 2.4, respectively (p < 0.001). At the end of the course, the mean score in response to a question about the extent to which the explanation had helped was 9.0 ± 1.9 (95% CI 8.7-9.4) and to a question about the extent to which teaching would make them feel more secure and safe was 9.2 ± 1.9 (95% CI 8.9-9.5). STB course improved correct tourniquet placement, demonstrated dramatic improvements in application time, and increased levels of comfort. These findings validate the need for ongoing teaching and education.

Free-breathing fetal cardiac MRI with doppler ultrasound gating, compressed sensing, and motion compensation.

BackgroundFetal cardiovascular MRI complements ultrasound to assess fetal cardiovascular pathophysiology.PurposeTo develop a free‐breathing method for retrospective fetal cine MRI using Doppler ultrasound (DUS) cardiac gating and tiny golden angle radial sampling (tyGRASP) for accelerated acquisition capable of detecting fetal movements for motion compensation.Study TypeFeasibility study.SubjectsNine volunteers (gestational week 34–40). Short‐axis and four‐chamber views were acquired during maternal free‐breathing and breath‐hold.Field Strength/Sequence1.5T cine balanced steady‐state free precession.AssessmentA self‐gated reconstruction method was improved for clinical application by using 1) retrospective DUS gating, and 2) motion detection and rejection/correction algorithms for compensating for fetal motion. The free‐breathing reconstructions were qualitatively and quantitatively assessed, and DUS‐gating was compared with self‐gating in breath‐hold reconstructions. A scoring of 1–4 for overall image quality, cardiac, and extracardiac diagnostic quality was used.Statistical TestsFriedman's test was used to assess differences in qualitative scoring between observers. A Wilcoxon matched‐pairs signed rank test was used to assess differences between breath‐hold and free‐breathing acquisitions and between observers' quantitative measurements.ResultsIn all cases, 111 free‐breathing and 145 breath‐hold acquisitions, the automatically calculated DUS‐based cardiac gating signal provided reconstructions of diagnostic quality (median score 4, range 1–4). Free‐breathing did not affect the DUS‐based cardiac gated retrospective radial reconstruction with respect to image or diagnostic quality (all P > 0.06). Motion detection with rejection/correction in k‐space produced high‐quality free‐breathing DUS‐based reconstructions [median 3, range (2–4)], whereas free‐breathing self‐gated methods failed in 80 out of 88 cases to produce a stable gating signal.Data ConclusionFree‐breathing fetal cine cardiac MRI based on DUS gating and tyGRASP with motion compensation yields diagnostic images. This simplifies acquisition for the pregnant woman and thus could help increase fetal cardiac MRI acceptance in the clinic. Level of Evidence: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:260–272.

CO2 and O2 removal during continuous veno-venous hemofiltration: a pilot study

BackgroundCarbon dioxide (CO2) accumulation is a challenging issue in critically ill patients. CO2 can be eliminated by renal replacement therapy but studies are scarce and clinical relevance is unknown. We prospectively studied CO2 and O2 behavior at different sample points of continuous veno-venous hemofiltration (CVVH) and build a model to calculate CO2 removal bedside.MethodsIn 10 patients receiving standard CVVH under citrate anticoagulation, blood gas analysis was performed at different sample points within the CVVH circuit. Citrate was then replaced by NaCl 0.9% and sampling was repeated. Total CO2 (tCO2), CO2 flow (V̇CO2) and O2 flow (V̇O2) were compared between different sample points. The effect of citrate on transmembrane tCO2 was evaluated. Wilcoxon matched-pairs signed rank test was performed to evaluate significance of difference between 2 data sets. Friedman test was used when more data sets were compared.ResultsV̇CO2 in the effluent (26.0 ml/min) correlated significantly with transmembrane V̇CO2 (24.2 ml/min). This represents 14% of the average expired V̇CO2 in ventilated patients. Only 1.3 ml/min CO2 was removed in the de-aeration chamber, suggesting that CO2 was almost entirely cleared across the membrane filter. tCO2 values in effluent, before, and after the filter were not statistically different. Transmembrane tCO2 under citrate or NaCl 0.9% predilution also did not differ significantly. No changes in V̇O2 were observed throughout the CVVH circuit. Based on recorded data, formulas were constructed that allow bedside evaluation of CVVH-attributable CO2 removal.ConclusionA relevant amount of CO2 is removed by CVVH and can be quantified by one simple blood gas analysis within the circuit. Future studies should assess the clinical impact of this observation.Trial registrationThe trial was registered at https://clinicaltrials.gov with trial registration number NCT03314363 on October 192,017.

Preliminary Effectiveness of Auricular Point Acupressure on Chemotherapy-Induced Neuropathy: Part 2 Laboratory-Assessed and Objective Outcomes

PurposeTo manage chemotherapy-induced neuropathy (CIN), this paper explores reliable and valid objectives measures to evaluate the treatment effects of auricular point acupressure (APA). Design/MethodThis study was a repeated-measures one-group design. Participants received four weeks of APA to manage their CIN. The laboratory-assessed and objective outcomes included quantitative sensory testing, grip and pinch strength, and inflammatory biomarkers. Wilcoxon matched pairs signed-rank tests were conducted to determine change scores of outcomes at pre- vs. post- and pre- vs. 1-month follow-up. Spearman’s rho correlation coefficient was used to examine the linear association of score changes of all objective study outcomes. ResultsComparing pre-and-post APA, (1) the mean score of the monofilament for all lower extremity sites tested decreased after APA, indicating sensory improvement; (2) the suprathreshold pinprick stimuli mean scores on the upper extremities increased, except the scores from the index finger and thumb; (3) the pain tolerance of thumb and trapezius areas increased; (4) decreasing IL1β (p = .05), IFNγ (p = .02), IL-2 (p = .03), IL-6 (p = .05), IL-10 (p = .05), and IP10/CXCL10 (p = .04) were observed pre-post APA. Conditional pain modulation was significantly (p< .05) associated with pain intensity (r = 0.55), tingling (r = 0.59); and IL1β concentration (r = 0.53) pre-post APA. The sustained effects of 4-week APA were observed at the 1-month follow-up. ConclusionsOur study findings demonstrated the promising effectiveness of APA in the management of CIN, and these treatment effects can be assessed using reliable and valid objective measures. Clinical ImplicationsIf the efficacy of APA to manage CIN is confirmed in a larger sample, APA has the potential to be a scalable treatment for CIN because it is a reproducible, standardized, and easy-to-perform intervention.

Pre-Exercise Blood Glucose Levels Determine the Amount of Orally Administered Carbohydrates during Physical Exercise in Individuals with Type 1 Diabetes-A Randomized Cross-Over Trial.

The aim of the study was to assess the amount of orally administered carbohydrates needed to maintain euglycemia during moderate-intensity exercise in individuals with type 1 diabetes. Nine participants with type 1 diabetes (four women, age 32.1 ± 9.0 years, BMI 25.5 ± 3.9 kg/m2, HbA1c 55 ± 7 mmol/mol (7.2 ± 0.6%)) on insulin Degludec were randomized to cycle for 55 min at moderate intensity (63 ± 7% VO2peak) for five consecutive days on either 75% or 100% of their regular basal insulin dose. The impact of pre-exercise blood glucose concentration on the carbohydrate requirement was analyzed by one-way ANOVA stratified for pre-exercise blood glucose quartiles. The effect of the basal insulin dose on the amount of orally administered carbohydrates was evaluated by Wilcoxon matched-pairs signed-rank test. The amount of orally administered carbohydrates during the continuous exercise sessions was similar for both trial arms (75% or 100% basal insulin) with median [IQR] of 36 g (9–62 g) and 36 g (9–66 g) (p = 0.78). The amount of orally administered carbohydrates was determined by pre-exercise blood glucose concentration for both trial arms (p = 0.03). Our study elucidated the importance of pre-exercise glucose concentration related orally administered carbohydrates to maintain euglycemia during exercise in individuals with type 1 diabetes.

Effect of 50 mg/kg intravenous tranexamic acid on coagulation assessed by rotational thromboelastometry (ROTEM) in healthy Beagle dogs.

In people, the antifibrinolytic drug tranexamic acid reduces bleeding and the need for blood products with both normal and exaggerated fibrinolysis without increasing the number of thromboembolic events. In dogs, in addition to prevention and treatment of bleeding, higher doses of tranexamic acid can be used to induce vomiting. The objective of this study was to evaluate the effect of a high dose of tranexamic acid on the coagulation of healthy Beagle dogs. A prospective trial was conducted in eight healthy Beagles receiving tranexamic acid for a concurrent trial evaluating different antiemetics. Rotational thromboelastometry (ROTEM) analysis (EXTEM, APTEM, FIBTEM, INTEM) was performed before and 30 minutes after intravenous administration of 50 mg/kg tranexamic acid. ROTEM parameters before and after tranexamic acid administration and between EXTEM and APTEM were compared with Wilcoxon matched-pairs signed rank test and data is presented as median (range). After tranexamic acid administration, FIBTEM clotting time became significantly shorter (p=0.03) from 37 s (28-124 s) to 33 s (27-40 s) and INTEM clot formation time significantly decreased (p=0.02) from 82 s (47-132s) to 60 s (43-107 s). After tranexamic acid APTEM MCF was significantly weaker (p=0.01) with 45 mm (30-63 mm) than EXTEM MCF with 55 mm (43-69 mm) and than APTEM MCF before tranexamic acid with 55 mm (43-69 mm) (p=0.02). All other analysed parameters including maximum lysis did not change after administration of tranexamic acid. The administration of 50 mg/kg intravenous tranexamic acid resulted in small changes in ROTEM profiles without inducing a hypercoagulable clot. In conclusion, tranexamic acid can safely be administered to healthy dogs with normal coagulation profiles. As an additional finding, APTEM parameters measured in the current study do not support the use of this test in dogs.

Efficacy of electromotive drug administration in delivering botulinum toxin a in children with neuropathic detrusor overactivity—outcomes of a pilot study

Intravesical botulinum toxin A (BtA) injection is well established in managing paediatric neuropathic detrusor overactivity (NDO). Electromotive drug administration (EMDA) is a less invasive method, which can be performed in the clinic, using pulsed electrical current for drug delivery via a urethral catheter. Few small studies report good outcomes following BtA via EMDA (BtA/EMDA) into bladders of children with NDO. The objective of this study is to assess the efficacy of BtA/EMDA in children with NDO, reduced bladder capacity and compliance. Twelve children with NDO on baseline urodynamic study were prospectively included. Pre-BtA/EMDA and post-BtA/EMDA results compared the following four parameters: maximal cystometric capacity, bladder compliance, maximal detrusor pressure (pDetmax) during detrusor overactivity and pDetmax at capacity. The Wilcoxon matched-pairs signed-rank test using Graphpad Prism 8 was used for analysis. Secondary outcomes include adverse effects and symptomatic improvement. Fourteen episodes of BtA/EMDA were performed. Five patients received 3.3 IU/kg of Botox®, and five received 10 IU/kg (maximum 300 IU). Four patients received 10 IU/kg of Dysport®. Two patients in the Dysport®/EMDA group also received Botox®/EMDA more than six months previously. Thirteen of 14 post-EMDA results were completed and included in the paired analysis. No statistically significant improvements in any cystometric parameters were demonstrated. Eight patients subsequently had intravesical BtA injections with significant improvements in both cystometric parameters and symptoms. Two patients subsequently transitioned to adult services; one was commenced on mirabegron, and one has undergone ileocystoplasty with Mitrofanoff appendicovesicostomy. Despite some evidence to support BtA/EMDA in children with NDO, the authors were unable to replicate previously published positive cystometric and symptomatic outcomes. In addition, BtA/EMDA performed poorly when compared with conventional intravesical BtA injections. This implies failure of EMDA to deliver BtA correctly to the target tissue. The large size of the BtA moleculeor the abnormal bladder wall in NDO could account for the negative results. Thorough preparation and consultation was undertaken before this study with BtA/EMDA, and it is discouraging that the authors were unable to reproduce the positive results of other groups. Although safe and acceptable to most patients, the authors cannot recommend the use of BtA/EMDA for NDO in children at present.

Priorities of human papillomavirus-associated oropharyngeal cancer patients at diagnosis and after treatment

IntroductionLittle is known regarding how human papillomavirus-positive oropharyngeal cancer (HPV-OPC) patient goals change with treatment. This study evaluates whether patient ranking of non-oncologic priorities relative to cure and survival shift after treatment as compared to priorities at diagnosis. Materials and MethodsThis is a prospective study of HPV-OPC patient survey responses at diagnosis and after treatment. The relative importance of 12 treatment-related priorities was ranked on an ordinal scale (1 as highest). Median rank (MR) was compared using Wilcoxon matched-pairs signed-rank tests. Prevalence of high concern for 11 treatment-related issues was compared using paired t-test. The effect of patient characteristics on change in priority rank and concern was evaluated using linear regression. ResultsAmong 37 patients, patient priorities were generally unchanged after treatment compared with at diagnosis, with cure and survival persistently ranked top priority. Having a moist mouth uniquely rose in importance after treatment. Patient characteristics largely did not affect change in priority rank. Concerns decreased after treatment, except concern regarding recurrence. DiscussionTreatment-related priorities are largely similar at diagnosis and after treatment regardless of patient characteristics. The treatment experience does not result in a shift of priorities from cure and survival to non-oncologic domains over cure and survival. The rise in importance of moist mouth implies that xerostomia may have been underappreciated as a sequelae of treatment. A decrease in most treatment-related concerns is encouraging, whereas the persistence of specific areas of concern may inform patient counseling.

66-LB: Greater Time Spent in Hypoglycemia during Night Compared with Day during Intensified Training in Professional Cyclists with Type 1 Diabetes—A Prospective Observational Study

Aim: To compare time spent in pre-specified glycemic ranges in day and night-time during intensive training in professional cyclists with type 1 diabetes (T1D). Methods: Fifteen male professional cyclists with T1D on multiple daily injections (age 27±4 years, duration T1D 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 7.2±0.7%, O2max 73±4 ml·kg·min-1) performed road cycle sessions (50-90% of the anaerobic threshold, duration 1-6 hours) over 9 consecutive days. Time spent in pre-specified glycemic ranges was compared between day and night time using paired t-test and Wilcoxon matched-pairs signed rank test, P≤0.05. Results: Overall glycemia is shown in Figure 1. More time was spent in level 1 (54-70 mg·dl-1) (6±5% vs. 4±3%, P=0.05) and level 2 hypoglycemia (&amp;lt;54 mg·dL-1) (3±5% vs. 1±4%, P=0.002) during night vs. day periods. During daytime, more time was spent in level 2 hyperglycemia (&amp;gt;299 mg dL-1) (night 0.2±0.4% vs. day 1.4±2.3%, P=0.02). Conclusion: Professional cyclists with T1D spent more time in hypoglycemia during the night compared to day-time during intensified training. Long-lasting insulin-sensitizing effects of endurance exercise may suggest a greater need for additional pre-bed carbohydrates and/or insulin dose reductions. Disclosure O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. F.Y. Fontana: None. K. Skroce: None. L. Festa: None. P.H. Lagrou: None. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research &amp; Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. C. Stettler: None. S.N. Scott: None. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. R.M. Bracken: None. Funding Novo Nordisk A/S

Six Month Polypill Therapy Improves Lipid Profile in Patients with Previous Acute Myocardial Infarction: The Heart-Mex Study

Acute myocardial infarction (AMI) is a leading cause of death in Mexico. Atherogenic lipid profile is a key component in AMI. Thus, it is imperative to find drug therapies able to reduce atherogenic lipids in AMI patients and prevent subsequent myocardial infarctions. To investigate the effect of polypill (Sincronium®) alone or combined with beta blockers (BB) and/or thiazide diuretics (TD) on total cholesterol, triglycerides, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and cardiovascular risk markers in a Mexican population with AMI. Secondary AMI-prevention patients (n=256) were included in the study and categorized into three groups depending on the drug scheme, as follows: polypill (n=150), polypill+BB (n=91), and polypill+ BB+ TD (n=15). Lipid profile and cardiovascular risk markers were evaluated in each patient before and 6months after drug therapy. The Wilcoxon-matched pairs signed rank test showed significant ∼25-30% reductions in total cholesterol, triglycerides, and LDL in the polypill group as compared to polypill+ BB and polypill+ BB+ TD groups. On the contrary, HDL was significantly increased in polypill and polypill+ BB groups. Polypill therapy showed more marked reductions in blood pressure, atherogenic index, Framingham risk score, and vascular age with respect to polypill+ BB and polypill+ BB+ TD groups. This study demonstrates for the first time that polypill therapy without being combined with BB and TD is effective to improve the atherogenic lipid profile and cardiovascular risk markers in AMI patients. Further studies are needed to examine the efficacy of polypill in reducing the occurrence of a second AMI in the Mexican population.

All-ceramic single crowns supported by zirconia implants: 5-year results of a prospective multicenter study.

To assess survival/success rates and patient-reported outcome of zirconia-based posterior single crowns (SCs) supported by zirconia implants in a prospective two-center study after five years of observation. Forty-five patients were restored with 45 zirconia implant-supported posterior SCs composed of zirconia frameworks hand-layered with a leucite-reinforced feldspathic ceramic. Survival rates of SCs were assessed and technical success was evaluated according to modified United States Public Health Care (USPHS) criteria. Furthermore, patient-reported outcome measures (PROMs) were assessed by applying visual analog scales (VAS). Wilcoxon matched-pairs signed-rank test, mixed-effects ordered logistic regression, and linear mixed models were used to evaluate time effects on response variables. Forty patients were available after a mean observation period of 61.0±1.4months. One SC had to be replaced, resulting in a Kaplan-Meier (KM) survival estimate for the SCs of 97.5±2.47%. Since nine reconstructions showed at least in one category a major deviation from the ideal (five major chippings, four with increased occlusal roughness, one significant crevice, and one pronounced over-contouring), the KM success estimate was 79.3±5.8%. Incidence of chipping (n=19) and occlusal roughness (n=35) was frequent (p<0.001). All PROMs at prosthetic delivery except for speech (p=0.139) showed significantly improved VAS scores (81%-94%; p<0.001) compared to pre-treatment evaluations. Thereafter, no decrease in satisfaction could be observed until the 5-year follow-up (93%-97%). Veneered zirconia-based SCs supported by zirconia implants showed high survival rates and highly satisfied patients' needs. However, significant incidence of technical complications is compromising the clinical long-term outcome for this indication.

Quantitation of progenitor cell populations and growth factors after bone marrow aspirate concentration

BackgroundThe number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration.Methods120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance.ResultsCell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins.ConclusionThis data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.

Comparison of anterior capsulotomy techniques: continuous curvilinear capsulorhexis, femtosecond laser-assisted capsulotomy and selective laser capsulotomy

PurposeTo compare the anterior capsulotomy edge tear strength created by manual continuous curvilinear capsulorhexis (CCC), femtosecond laser-assisted capsulotomy (FLACS), and selective laser capsulotomy (SLC).SettingSingapore National Eye Centre, Singapore and Excel-Lens,...

The effect of sounds on nonlinear measures of heart rate variability

Purpose and methodThis purpose of the study is to determine changes in nonlinear heart rate variability (HRV) measures during the passive listening of sounds. Twenty subjects (all women) participated in the study. Subjects listened to four sounds: (1) white noise, (2) the road traffic noise, (3) excitatory music (Diamanda Galas' Women with Steak Knives, (4) lullaby (Ba Mo Leanabh (O My Baby), Arr. William Jackson and Mackenzie, Fiona McKenzie). Emotional responses were assessed with The Affect Grid. The experiment consisted of 5 min sessions (rest and listening). RR intervals were recorded during both sessions. Fractal scaling exponents of HRV were quantified by means of the detrended fluctuation analysis (DFA). Three indices of Poincaré plots were calculated: the width of the cloud (SD1), the length of the cloud (SD2) and the ratio SD2/SD1. The complexity of attractor was assessed by calculation of correlation dimension (D2) and entropy measures (ApEn, SampEn). The following measures were derived from recurrence plot (RP): mean line length (Lmean), maximum line length (Lmax), recurrence rate (REC), determinism (DET), and Shannon entropy of line length distribution (ShanEn). We chose a tolerance level to achieve the REC =5% in accordance with a suggestion of Webber (2007). Freidman ANOVA and Wilcoxon matched‐pairs signed‐ranks tests were used to determine the significance of differences between measurements. Data are mean ± SE.ResultsExcitatory music was interpreted as unpleasant and arousing (valence: −3.07 ± 0.23; arousal: 2.00 ± 0.30). Lullaby was associated with positive emotion with negative arousal (valence: 2.19 ± 0.21; arousal: −1.53 ± 0.28). White noise induced negative valence (−2.53 ± 0.2) and positive arousal (0.95 ± 0.25), road traffic noise induced negative valence (−1.19 ± 0.24) and very low arousal (0.48 ± 0.22). The levels of valence were significantly different across the 4 stimuli (Friedman ANOVA: χ2 = 131.92, p &lt; 0.001). This difference was present in pairs of sounds (Wilcoxon: p &lt; 0.05). The results were the same for arousal (Friedman ANOVA: χ2 = 73.14, p &lt; 0.001). Results of calculation of complexity measures (ApEn, SampEn, D2) exhibit non‐significant differences between rest and sound listening (p &gt; 0.05). Sound listening produces non‐significant response changes in short‐range fractal scaling exponent of DFA (p &gt; 0.05). There was a significant increase in long‐range fractal scaling exponent during excitatory music listening (from 0.40 ± 0.06 to 0.52 ± 0.07). During excitatory music, exposure was found significantly higher values of Lmean, Lmax, and ShanEn (p &lt; 0.05). The RP indexes when listening to the white noise, traffic noise and lullaby showed no significant changes (Wilcoxon: p &gt; 0.05). Poincare plot analysis of RR sequences reveals a significant decrease of the standard deviation of the instantaneous beat‐to‐beat variability data (SD1) during excitatory music listening (p &lt; 0.01). The changes in the length of the cloud (SD2) and SD2/SD1 ratio were nonsignificant (p &gt; 0.05).Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Deep Learning for Automated Contouring of Primary Tumor Volumes by MRI for Nasopharyngeal Carcinoma.

Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.

Cancer-Related Internet Use and Its Association With Patient Decision Making and Trust in Physicians Among Patients in an Early Drug Development Clinic: A Questionnaire-Based Cross-Sectional Observational Study.

BackgroundThe role of cancer-related internet use on the patient-physician relationship has not been adequately explored among patients who are cancer-related internet users (CIUs) in early-phase clinical trial clinics.ObjectiveWe examined the association between cancer-related internet use and the patient-physician relationship and decision making among CIUs in an early drug development clinic.MethodsOf 291 Phase I clinic patients who completed a questionnaire on internet use, 179 were CIUs. Generations were defined by the year of patient’s birth: “millennials” (after 1990) and “Generation X/Y” (1965-1990) grouped as “Millennials or Generation X/Y”; “Baby Boomers” (1946-1964); and “Greatest or Silent Generation” (1945 and earlier). Statistical analyses included the Wilcoxon matched-pairs signed-rank test and the Mann-Whitney U test.ResultsCIUs were 52% (94/179) female, 44% (78/179) were older than 60 years, and 60% (108/179) had household incomes exceeding US $60,000. The sources of information on cancer and clinical trials included physicians (171/179, 96%), the internet (159/179, 89%), and other clinical trial personnel (121/179, 68%). For the overall sample and each generation, the median values for trust in referring and Phase I clinical trial physicians among early drug development clinic CIUs were 5 on a 0-5 scale, with 5 indicating “complete trust.” CIUs’ trust in their referring (5) and phase 1 (5) physicians was higher than CIUs’ trust in Web-based cancer-related information (3; P<.001 for both). CIUs who reported visiting the National Cancer Institute (NCI) website, NCI.org, to learn about cancer reported higher levels of trust in Web-based cancer-related information than CIUs who did not use the NCI website (P=.02). Approximately half of CIUs discussed internet information with their doctor. Only 14% (23/165) of CIUs had asked their physician to recommend cancer-related websites, and 24% (35/144) of CIUs reported at least occasional conflict between their physician’s advice and Web-based information.ConclusionsDespite the plethora of websites related to cancer and cancer clinical trials, patients in early-phase clinical trial settings trust their physicians more than Web-based information. Cancer-related organizations should provide regularly updated links to trustworthy websites with cancer and clinical trial information for patients and providers and educate providers on reliable cancer websites so that they can better direct their patients to appropriate internet content.

Preconceptional factors associated with haemoglobin concentration in early pregnancy: a community-based cohort study in rural northeastern Tanzania.

Maternal anaemia in early pregnancy is associated with poor pregnancy outcomes. Furthermore, preconceptional health can influence the health during pregnancy. The aim of this study was to investigate which preconceptional factors were associated with haemoglobin (Hb) concentration in early pregnancy. In Tanzania, 226 women were followed at preconception and during early pregnancy. Red blood cell (RBC) morphology, serum micronutrient concentration, demographic characteristics and health status were assessed in preconception and in early pregnancy. The association between preconceptional factors and Hb concentration in early pregnancy was investigated using simple and multiple linear regression analyses stratified by preconceptional anaemia status. Mean Hb was 123 and 119g/l before conception and during early pregnancy (median gestational age 53days) respectively. Preconceptional mid-upper arm circumference (MUAC) (adjusted coefficient (AC) 0.35 95% CI 0.9-0.61) and preconceptional Hb concentration (AC 0.45 95% CI 0.36-0.54) were positively associated with early pregnancy Hb concentration, whereas preconceptional microcytic hypochromic RBC morphology (AC -6.00 95% CI -9.56 to -2.44) was negatively associated with early pregnancy Hb concentration. In addition, treatment of preconceptional malaria was positively associated with early pregnancy Hb concentration (AC 6.45 95% CI 0.74-12.2) among women with preconceptional anaemia. In contrast, among preconceptional non-anaemic women, only preconceptional Hb concentration and medium socio-economic status was positively associated with early pregnancy Hb concentration. Mid-upper arm circumference (MUAC) and Hb measurements in preconception can help to detect women at increased risk of low Hb concentration in early pregnancy.