Improving Outcomes in Emergency General Surgery Patients: What Evidence Is Out There?.

No abstract available

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False Low ETCO2 Measurements From Carbon Dioxide Sampling Nasal Cannula and How to Correct the Situation.

No abstract available

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Respiratory System Mechanics During Low Versus High Positive End-Expiratory Pressure in Open Abdominal Surgery: A Substudy of PROVHILO Randomized Controlled Trial.

BACKGROUND: In the 2014 PROtective Ventilation using HIgh versus LOw positive end-expiratory pressure (PROVHILO) trial, intraoperative low tidal volume ventilation with high positive end-expiratory pressure (PEEP = 12 cm H2O) and lung recruitment maneuvers did not decrease postoperative pulmonary complications when compared to low PEEP (0-2 cm H2O) approach without recruitment breaths. However, effects of intraoperative PEEP on lung compliance remain poorly understood. We hypothesized that higher PEEP leads to a dominance of intratidal overdistension, whereas lower PEEP results in intratidal recruitment/derecruitment (R/D). To test our hypothesis, we used the volumedependent elastance index %E2, a respiratory parameter that allows for noninvasive and radiation-free assessment of dominant overdistension and intratidal R/D. We compared the incidence of intratidal R/D, linear expansion, and overdistension by means of %E2 in a subset of the PROVHILO cohort. METHODS: In 36 patients from 2 participating centers of the PROVHILO trial, we calculated respiratory system elastance (E), resistance (R), and %E2, a surrogate parameter for intratidal overdistension (%E2 > 30%) and R/D (%E2

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In Response.

No abstract available

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A Descriptive Survey of Anesthesiology Residency Simulation Programs: How Are Programs Preparing Residents for the New American Board of Anesthesiology APPLIED Certification Examination?.

BACKGROUND: Anesthesiology residency programs may need new simulation-based programs to prepare residents for the new Objective Structured Clinical Examination (OSCE) component of the American Board of Anesthesiology (ABA) Primary Certification process. The design of such programs may require significant resources, including faculty time, expertise, and funding, as are currently needed for structured oral examination (SOE) preparation. This survey analyzed the current state of US-based anesthesiology residency programs regarding simulation-based educational programming for SOE and OSCE preparation. METHODS: An online survey was distributed to every anesthesiology residency program director in the US. The survey included 15 to 46 questions, depending on each respondent's answers. The survey queried current practices and future plans regarding resident preparation specifically for the ABA APPLIED examination, with emphasis on the OSCE. Descriptive statistics were summarized. [chi]2 and Fisher exact tests were used to test the differences in proportions across groups. Spearman rank correlation was used to examine the association between ordinal variables. RESULTS: The responding 66 programs (49%) were a representative sample of all anesthesiology residencies (N = 136) in terms of geographical location ([chi]2 P = .58). There was a low response rate from small programs that have 12 or fewer clinical anesthesia residents. Ninety-one percent (95% confidence interval [95% CI], 84% -95%) of responders agreed that it is the responsibility of the program to specifically prepare residents for primary certification, and most agreed that it is important to practice SOEs (94%; 95% CI, 88%-97%) and OSCEs (89%; 95% CI, 83%-94%). While 100% of respondents reported providing mock SOEs, only 31% (95% CI, 24%-40%) of respondents provided mock OSCE experiences. Of those without an OSCE program, 75% (95% CI, 64%-83%) reported plans to start one. The most common reasons for not having an OSCE program already in place, and the perceived challenges for implementing an OSCE program, were the same: lack of time (faculty and residents), expertise in OSCE development and assessment, and funding. CONCLUSIONS: The results provide data from residency programs for benchmarking their simulation curriculum and ABA APPLIED Examination preparation offerings. Despite agreement that residency programs should prepare residents for the ABA APPLIED Examination, many programs have yet to implement an OSCE preparation program, in part due to lack of financial resources, faculty expertise, and time. Additionally, in contrast to the SOE, the OSCE is a new format for ABA primary certification. As a result, the lack of consensus concerning preparation needs could be related to the amount information that is available regarding the examination content and assessment process. (C) 2017 International Anesthesia Research Society

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Postpartum Tubal Sterilization: Making the Case for Urgency.

The parturient who requests postpartum sterilization has given consideration to and has made decisions regarding this aspect of her medical care long before her delivery. She arrives at parturition expecting the postpartum procedure to be performed as intended. The American Congress of Obstetricians and Gynecologists has reaffirmed its opinion that postpartum sterilization is an urgent procedure, owing to the safety and superior effectiveness of tubal sterilization via minilaparotomy in the immediate postpartum period, and the adverse consequences for mothers, babies, and society when the procedure is not actualized as desired and intended. In contrast, recent practice guidelines for obstetric anesthesia address anesthetic procedural aspects and short-term safety but overlook the long-term complications and considerations associated with failure to perform postpartum sterilization as planned. In practice, procedure completion rates are strikingly low, reportedly ranging from 31% to 52%. Reasons for failure to complete abound and include inadequate resources or inavailability of necessary personnel; obstetrician reluctance due to concerns for patient regret in younger women or medical comorbidities; barriers related to provision of obstetric care in a religiously affiliated hospital, or incomplete, improperly completed, or unavailable original federal consent forms among Medicaid-insured women. The federal requirement to wait 30 days after signing informed consent, and to retain the original signed document to be physically verified at time of the procedure, serves as a significant source of health care disparity for Medicaid-dependent mothers. This article reviews these larger issues of maternal health and comprehensive maternal care to broaden the anesthesiologist's appreciation of major benefits and potential risks of postpartum sterilization, including long-term effects, to promote an evidence-based, informed, and proactive role in delivering equitable, safe, and optimal care for these patients. (C) 2017 International Anesthesia Research Society

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Investigation of Two Prototypes of Novel Noncontact Technologies for Automated Real-Time Capture of Incremental Drug Administration Data From Syringes.

BACKGROUND: An ideal electronic anesthesia recording system would be capable of not only recording physiological data but also injectable drug doses given, including those given incrementally from one syringe, without recourse to manual data entry. We compared 2 prototype devices which wirelessly recognized individual syringes and measured changes in their plunger positions via 2 different optical noncontact means, allowing calculation of incremental drug doses given. METHODS: Both devices incorporated a radio-frequency identification reader, which wirelessly read a unique code from a radio-frequency identification tag within syringe drug labels. A custom-designed cradle oriented any inserted 1-mL to 20-mL syringe in a repeatable position. The "laser" device had a moving laser beam broken by the end of the syringe plunger. The infrared (IR) device measured time of travel of IR light from a sender to a syringe plunger and back to a receiver. Both devices could therefore determine the drug and volume administered since the previous occasion when any syringe had been used. For each syringe size of 1, 2, 5, 10, and 20 mL, 121 plunger-length measurements were made over their full range, with each machine against a reference method of water filling and weighing using a randomized de Bruijn sequence. RESULTS: For every syringe size, the laser device showed greater accuracy and precision, lower bias, and narrower limits of agreement (95% confidence intervals = bias +/- 1.96 SD) than the IR device when compared to the reference method. For all syringe sizes, the range of bias was -0.05 to 0.32 mL for the laser and -2.42 to 1.38 mL for the IR. Lin concordance correlation coefficient values for the IR versus reference methods ranged from 0.6259 to 0.9255, with the lowest coefficients seen in syringes with the shortest distance of plunger travel (2 and 5 mL), while in laser versus reference comparisons, these coefficients were similar (0.9641-0.9981) over all syringe lengths. CONCLUSIONS: Both devices measured syringe volume changes, demonstrating potential for measuring incremental drug doses, recording these, and also the time of each measurement. The IR device had no moving parts, which would be advantageous in a clinical situation. However, the current embodiment was not deemed accurate enough for clinical use, potentially remediable through improvements in hardware and software design. The laser device showed high accuracy and precision over all syringe sizes and contained volumes, and was considered potentially accurate enough for clinical use with suitable development. (C) 2017 International Anesthesia Research Society

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Administration of Tetrahydrobiopterin (BH4) Protects the Renal Microcirculation From Ischemia and Reperfusion Injury.

BACKGROUND: Abdominal aortic aneurysm surgery with suprarenal cross-clamping is often associated with renal injury. Although the mechanism underlying such injury is unclear, tissue ischemia and reperfusion, which induces endothelial dysfunction and decreases the availability of tetrahydrobiopterin (BH4), may play a role. We evaluated whether BH4 administration prevents renal ischemia/reperfusion injury in an animal model of aortic cross-clamping. METHODS: Nineteen anesthetized, mechanically ventilated, and invasively monitored adult sheep were randomized into 3 groups: sham animals (n = 5) that underwent surgical preparation but no aortic clamping; an ischemia/reperfusion group (n = 7), where the aorta was clamped above the renal arteries for 1 hour, and a BH4 group (n = 7), in which animals received 20 mg/kg of BH4 followed by aortic cross-clamp for 1 hour. Animals were followed for a maximum of 6 hours after reperfusion. The renal microcirculation was evaluated at baseline (before clamping), and 1, 4, and 6 hours after reperfusion using side-stream dark field videomicroscopy. The renal lactate-to-pyruvate ratio was evaluated using microdialysis. The primary outcome was the change in proportion of small perfused vessels before and after injury. Secondary outcomes were renal tissue redox state and renal function. RESULTS: Ischemia/reperfusion injury was associated with increases in heart rate and mean arterial pressure, which were blunted by BH4 administration. From the first to the sixth hour after reperfusion, the small vessel density (estimated mean difference [EMD], 1.03; 95% confidence interval [CI], 0.41-1.64; P = .003), perfused small vessel density (EMD, 0.84; 95% CI, 0.29-1.39; P = .005), and proportion of perfused small vessels (EMD, 8.60; 95% CI, 0.85-16.30; P = .031) were altered less in the BH4 than in the ischemia/reperfusion group. The renal lactate-to-pyruvate ratios were lower in the cortex in the BH4 than in the ischemia/reperfusion group from the first to the sixth hour after reperfusion (EMD, -19.16; 95% CI, -11.06 to 33.16; P = .002) and in the medulla from the first to the fourth hour (EMD, -26.62; 95% CI, -18.32 to 38.30; P = .020; and EMD, -8.68; 95% CI, -5.96 to 12.65; P = .019). At the sixth hour, serum creatinine was lower in the BH4 than in the ischemia/reperfusion group (EMD, -3.36; 95% CI, -0.29 to 1.39; P = .026). CONCLUSIONS: In this sheep model of renal ischemia/reperfusion, BH4 pretreatment reduced renal microvascular injury and improved renal metabolism and function. Further work is needed to clarify the potential role of BH4 in ischemia/reperfusion injury. (C) 2017 International Anesthesia Research Society

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Perioperative Surgical Home: Evaluation of a New Protocol Focused on a Multidisciplinary Approach to Manage Children Undergoing Posterior Spinal Fusion Operation.

BACKGROUND: The concept of Perioperative Surgical Home has been gaining significant attention in surgical centers. This model is delivering and improving coordinated care in a cost-effective manner to patients undergoing surgical procedures. It starts with the decision for surgical intervention, continues to the intraoperative and postoperative periods, and follows into long-term recovery. Constant re-evaluation of outcomes and modifications of delivery provides a feedback loop for improvement. Children's Hospital Los Angeles initiated a new protocol in June 2014 to manage children undergoing Posterior Spinal Fusion (PSF) with the goal to improve patient experience and lower the hospital length of stay and cost. METHODS: A retrospective chart review identified patients who underwent a PSF for idiopathic scoliosis before and after initiation of a new treatment protocol designed by a team of anesthesiologists, surgeons, nurses, and physical therapists. The new protocol included preoperative teaching of parents and patients, intraoperative anesthetic and surgical management, and immediate to long-term postoperative medical management. In addition to demographics, we examined length of stay, cost of hospitalization, pain scores on discharge, length of patient-controlled analgesia use, time to first solid food intake, and time to ambulation. RESULTS: Thirty-six patients were identified preinitiation and postinitiation of the protocol (total n = 72). There was no statistically significant difference in age, sex, use of intrathecal morphine, or estimated blood loss. Patients enrolled in the new protocol had higher American Society of Anesthesiologists classification (P = .003), significantly lower duration of patient-controlled analgesia use, time to first solid food intake, and time to ambulation (P= .001). The pain scores were higher at the time of discharge, although the difference was not statistically significant. Length of stay was significantly shorter in the new protocol group (P = .001), accounting for $292,560 in cost savings for the hospital. CONCLUSIONS: These data show that the cooperation of different teams in designing new management guidelines for patients requiring a PSF can significantly decrease the total length of stay and cost of hospitalization without altering quality of care. (C) 2017 International Anesthesia Research Society

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Pupillary Unrest: Is It a Generalizable Finding?.

No abstract available

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Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6 130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: >=2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) x 109/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 x 109/L, 100 to 150 x 109/L, and 150 x 109/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (>=2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48.5.41; P = .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery. (C) 2017 International Anesthesia Research Society

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In Response.

No abstract available

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Epidemiologic Analysis of Elective Operative Procedures in Infants Less Than 6 Months of Age in the United States.

BACKGROUND: This study uses publicly available data to analyze the total number of elective, potentially deferrable operative procedures involving infants

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A Shared Opportunity for Improving Electronic Medical Record Data.

With the recent rapid adoption of electronic medical records (EMRs), studies reporting results based on EMR data have become increasingly common. While analyzing data extracted from our EMR for a retrospective study, we identified various types of erroneous data entries. This report investigates the root causes of the incompleteness, inconsistency, and inaccuracy of the medical records analyzed in our study. While experienced health information management professionals are well aware of the many shortcomings with EMR data, the aims of this case study are to highlight the significance of the negative impact of erroneous EMR data, to provide fundamental principles for managing EMRs, and to provide recommendations to help facilitate the successful use of electronic health data, whether to inform clinical decisions or for clinical research. (C) 2017 International Anesthesia Research Society

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Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical.

BACKGROUND: Pain intensity ratings and opioid consumption (OC) are ubiquitous indicators of pain in postoperative trials of the efficacy of interventional procedures. Unfortunately, consensus on the appropriate statistical handling of these outcomes has not been reached. The aim of this article was, therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. METHODS: Data from a randomized, double-blind, placebo-controlled study investigating the analgesic efficacy of a regional anesthetic block following a major elective surgical procedure were analyzed. The original data included measurements of pain intensity (visual analog scale [VAS]) at rest and during coughing (VAS0/2/4/6/12/18/24 hrs) and OC0-6/0-24 hrs administered by patient-controlled analgesia. The statistical analyses included comparisons of discrete pain intensity scores (VAS0/2/4/6/12/18/24 hrs), summary measures of pain intensity ratings (area under the curve [AUC]-VAS0-6/0-24 hrs; mean VAS0-6/0-24 hrs), and OC0-6/0-24 hrs. Finally, the analyses also included an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC0-6/0-24 hrs). Also, estimation of effect size, generalized odds ratio of the individual analgesic outcome variables was performed. RESULTS: Sixty-one patients were included in the final data analysis. Discrete pain intensity ratings differed significantly between the treatment groups at specific postoperative time points, but appropriate correction for multiple comparisons eliminated some of these differences. AUC-VAS0-6 hrs differed significantly at rest and during coughing, while no difference was found for AUC-VAS0-24 hrs. In contrast, mean VAS0-6 hrs and VAS0-24 hrs differed significantly between treatment groups at rest and during coughing. OC0-6/0-24 hrs differed significantly between the treatment groups. Finally, also PIOC0-6/0-24 hrs differed significantly at rest and during coughing. CONCLUSIONS: Our analyses demonstrate that the applied statistical method may alter the statistical significance and estimates of effect size of analgesic outcome variables in postoperative pain trials. Our findings underline the importance of defining valid statistical methods for future analgesic drug trials. We propose an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC). The method combines two interdependent analgesic outcomes, lowers the risk of mass significance, and provides more accurate representation of the dynamic nature of postoperative pain and analgesic drug efficacy. (C) 2017 International Anesthesia Research Society

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Hospital-Based Acute Care Within 7 Days of Discharge After Outpatient Arthroscopic Shoulder Surgery.

BACKGROUND: The rate of hospital-based acute care (defined as hospital transfer at discharge, emergency department [ED] visit, or subsequent inpatient hospital [IP] admission) after outpatient procedure is gaining momentum as a quality metric for ambulatory surgery. However, the incidence and reasons for hospital-based acute care after arthroscopic shoulder surgery are poorly understood. METHODS: We studied adult patients who underwent outpatient arthroscopic shoulder procedures in New York State between 2011 and 2013 using the Healthcare Cost and Utilization Project database. ER visits and IP admissions within 7 days of surgery were identified by cross-matching 2 independent Healthcare Cost and Utilization Project databases. RESULTS: The final cohort included 103,476 subjects. We identified 1867 (1.80%, 95% confidence interval [CI], 1.72%-1.89%) events, and the majority of these encounters were ER visits (1643, or 1.59%, 95% CI, 1.51%-1.66%). Direct IP admission after discharged was uncommon (224, or 0.22%, 95% CI, 0.19%-0.24%). The most common reasons for seeking acute care were musculoskeletal pain (23.78% of all events). Nearly half of all events (43.49%) occurred on the day of surgery or on postoperative day 1. Operative time exceeding 2 hours was associated with higher odds of requiring acute care (odds ratio [OR], 1.28; 99% CI, 1.08-1.51). High-volume surgical centers (OR, 0.67; 99% CI, 0.58-0.78) and regional anesthesia (OR, 0.72; 99% CI, 0.56-0.92) were associated with lower odds of requiring acute care. CONCLUSIONS: The rate of hospital-based acute care after outpatient shoulder arthroscopy was low (1.80%). Complications driving acute care visits often occurred within 1 day of surgery. Many of the events were likely related to surgery and anesthesia (eg, inadequate analgesia), suggesting that anesthesiologists may play a central role in preventing acute care visits after surgery. (C) 2017 International Anesthesia Research Society

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Creation and Execution of a Novel Anesthesia Perioperative Care Service at a Veterans Affairs Hospital.

Physician-led perioperative surgical home models are developing as a method for improving the American health care system. These models are novel, team-based approaches that help to provide continuity of care throughout the perioperative period. Another avenue for improving care for surgical patients is the use of enhanced recovery after surgery pathways. These are well-described methods that have shown to improve perioperative outcomes. An established perioperative surgical home model can help implementation, efficiency, and adherence to enhanced recovery after surgery pathways. For these reasons, the Tennessee Valley Healthcare System, Nashville Veterans Affairs Medical Center created an Anesthesiology Perioperative Care Service that provides comprehensive care to surgical patients from their preoperative period through the continuum of their hospital course and postdischarge follow-up. In this brief report, we describe the development, implementation, and preliminary outcomes of the service. (C) 2017 International Anesthesia Research Society

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Stroke Volume Variation-Guided Versus Central Venous Pressure-Guided Low Central Venous Pressure With Milrinone During Living Donor Hepatectomy: A Randomized Double-Blinded Clinical Trial.

BACKGROUND: We previously demonstrated the usefulness of milrinone for living donor hepatectomy. However, a less-invasive alternative to central venous catheterization and perioperative contributors to good surgical outcomes remain undetermined. The current study evaluated whether the stroke volume variation (SVV)-guided method can substitute central venous catheterization during milrinone-induced profound vasodilation. METHODS: We randomly assigned 42 living liver donors to receive either SVV guidance or central venous pressure (CVP) guidance to obtain milrinone-induced low CVP. Target SVV of 9% was used as a substitute for CVP of 5 mm Hg. The surgical field grade evaluated by 2 attending surgeons on a 4-point scale was compared between the CVP- and SVV-guided groups (n = 19, total number of scores = 38 per group) as a primary outcome variable. Multivariable analysis was performed to identify independent factors associated with the best surgical field as a post hoc analysis. RESULTS: Surgical field grades, which were either 1 or 2, were not found to be different between the 2 groups via Mann-Whitney U test (P = .358). There was a very weak correlation between SVV and CVP during profound vasodilation such as CVP

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Improving Outcomes in Emergency General Surgery Patients: What Evidence Is Out There?.

No abstract available

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Cardiac cycle efficiency and dicrotic pressure variations: new parameters for fluid therapy: A pilot observational study.

BACKGROUND: During a fluid challenge, the changes in cardiac performance and peripheral circulatory tone are closely related to the position of the ventricle on the Frank-Starling curve. Some patients have a good haemodynamic response to a fluid challenge, others hardly any response. The early haemodynamic effects of a fluid challenge could predict the final response before the entire fluid volume has been administered. OBJECTIVE: To assess whether a multivariate logistic regression model, including pulse pressure variation (PPV), cardiac cycle efficiency (CCE), arterial elastance and the difference between the dicrotic pressure and both systolic and mean arterial pressure (SAP - Pdic and MAP - Pdic) can predict cardiac responsiveness early during a fluid challenge in comparison with the standard procedure described elsewhere. DESIGN: Observational pilot study. SETTING: Elective surgical patients undergoing laparotomy, enrolled in two Italian University Hospitals. PATIENTS: Fifty adult surgical patients, ventilated with a lung protective strategy, were enrolled and data from 46 were analysed. INTERVENTIONS: A fluid challenge consisting of 500 ml of crystalloid infused over 10 min. MAIN OUTCOME MEASURES AND ANALYSIS: The changes in CCE, arterial elastance, SAP - Pdic and MAP - Pdic were compared using analysis of variance. A multivariate logistic regression analysis utilising baseline values and the first minute measuring a variation statistically significant for the considered variables. RESULTS: At baseline, PPV correctly identified 70% of patients (89% of non-responders; 42% of responders). The model, including baseline PPV, [DELTA]CCE and [DELTA]SAP - Pdic, correctly identified the efficiency of fluid challenge in 87% of patients (84.2% of responders; 92.5 of non-responders) after 5 min from fluid challenge infusion. CONCLUSION: In this pilot study conducted in a population of surgical patients mechanically ventilated with a VT less than 8 ml kg-1, a dynamic model of fluid challenge assessment, including PPV, [DELTA]CCE and [DELTA]SAP - Pdic, enhances the prediction of fluid challenge response after 5 min of a 10-min administration. TRIAL REGISTRATION: ACTRN12616001479493. (C) 2017 European Society of Anaesthesiology

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Pulse photoplethysmographic amplitude and heart rate variability during laparoscopic cholecystectomy: A prospective observational study.

BACKGROUND: Surgical stress affects the autonomic nervous system by increasing sympathetic outflow. One method of monitoring sympathetic activity is pulse photoplethysmographic analysis. From this two indices can be derived - autonomic nervous system state (ANSS) and ANSS index (ANSSi). It has recently been claimed that these indices can be used to measure sympathetic activity in anaesthetised patients, but their validity has not yet been demonstrated. OBJECTIVE: To measure changes in pulse photoplethysmographic indices and determine any agreement with autonomic nervous system modulation of the cardiovascular system in healthy study participants during surgery under general anaesthesia. DESIGN: Prospective observational study. SETTING: Single-centre study based at a tertiary care centre in Milan, Italy. PATIENTS: Healthy patients undergoing general anaesthesia for elective laparoscopic cholecystectomy. INTERVENTIONS: ANSS, ANSSi, and heart rate variability (HRV) were analysed at three main times: baseline, after induction of general anaesthesia, and after pneumoperitoneum insufflation. MAIN OUTCOME MEASURES: The magnitude of changes in photoplethysmographic and HRV indices was measured. The agreement between pulse photoplethysmographic and HRV-derived indices was assessed by Bland-Altman plots. RESULTS: In total, 52 patients were enrolled and their data analysed. Both pulse photoplethysmographic and HRV indices changed during the study phases. An agreement was found between ANSSi and low frequency spectral components of HRV [bias 10.2nu, 95% confidence interval (CI) -13 to 33.4], high frequency spectral components of HRV (bias 6.1 nu, 95% CI -16.3-28.6), and low frequency/high frequency ratio (bias 16.1nu, 95% CI -1.4-33.5). The agreement was weaker between ANSSI and HRV indices. CONCLUSION: The study endorses the use of pulse photoplethysmographic indices ANSS and ANSSi as surrogates to estimate changes of autonomic modulation of the cardiovascular system in healthy adults during surgery under general anaesthesia. Orcid ID: http://ift.tt/2tMAaTr. (C) 2017 European Society of Anaesthesiology

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The relative effects of dexmedetomidine and propofol on cerebral blood flow velocity and regional brain oxygenation: A randomised noninferiority trial.

BACKGROUND: Dexmedetomidine constricts cerebral blood vessels without a concomitant reduction in cerebral metabolic oxygen consumption. Its safety as a sedative in patients with neurological diseases thus remains uncertain. OBJECTIVE: Our primary objective was to test the hypothesis that dexmedetomidine is noninferior to propofol as regards cerebral blood flow (CBF) velocity and brain oxygenation. DESIGN: Unblinded randomised trial. SETTING: Cleveland Clinic Hospital, Cleveland, from November 2010 to July 2013. PATIENTS: Forty-four patients scheduled for insertion of a deep-brain stimulating electrodes. INTERVENTIONS: Patients were randomised to receive either dexmedetomidine or propofol sedation during deep-brain stimulating electrode insertion. MAIN OUTCOME MEASURES: Intraoperative CBF velocity was measured with transcranial Doppler, and brain oxygenation was assessed with near-infrared spectroscopy. Noninferiority of dexmedetomidine to propofol was defined as a less than 20% difference in means. RESULTS: Twenty-three patients were given dexmedetomidine and 21 propofol. Baseline characteristics and operative management were similar in each group. Dexmedetomidine was noninferior to propofol on both CBF and brain oxygenation, confirming our primary hypothesis. For cerebral flood flow, the estimated ratio of means (dexmedetomidine/propofol) was 0.94 [90% CI: 0.84 to 1.05], P = 0.011 for noninferiority. For brain oxygenation, the estimated ratio of means was 0.99 [90% CI: 0.96 to 1.02], P

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Enucleation of solid pseudopapillary tumor with a preoperative nasopancreatic drainage stent in a child

Abstract

Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor with low-grade malignancy in children. A complete surgical resection can achieve a favorable prognosis. Although several reports have indicated that enucleation is considered a safe and effective treatment, the most significant complication is injury to the main pancreatic duct. The usefulness and safety of tumor enucleation after preoperative placement of an endoscopic nasopancreatic drainage stent (NPDS) has recently been reported. We present the case of SPT in a 10-year-old girl. To avoid and detect injury to the main pancreatic duct during operation, an NPDS was endoscopically placed before laparotomy. The patient underwent a complete enucleation of the tumor with the guidance of an NPDS. Our case is the first report of a successful enucleation of an SPT with a preoperative placement of an NPDS. This procedure may lead to safe enucleation of a pancreatic tumor with low malignancy, such as SPT, in children.

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Laparoscopic surgery for sigmoid colon cancer after multiple operations including urinary diversion with Indiana pouch: A case report

Abstract

A 73-year-old man with lower abdominal pain was diagnosed at our hospital with sigmoid colon cancer. He had previously undergone radical cystectomy with Indiana pouch construction and gastrectomy to treat bladder cancer and gastric cancer, respectively. We performed a laparoscopic Hartmann's operation with Japanese D3 lymph node dissection. We observed severe adhesion in the abdominal cavity; adhesions between the urostomy and sigmoid colon were particularly severe. The tumor had invaded to the distal rectum, which had adhered to the pubic bone and the previously reconstructed urinary pouch. By performing careful and persistent laparoscopic dissection, we completed the operation without damaging the urostomy and with no remnant tumor tissue (R0). The postoperative course was uneventful, and the patient was doing well with no evidence of cancer recurrence 1 year after surgery.

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Knowledge, Awareness, and Prevention of Hepatitis B Virus Infection Among Korean American Parents

Abstract

Hepatitis B (HB) affects 240 million people around the world, and children and young adults make up a large proportion of the infected population. Approximately 1 million people die from HB each year. Despite the seriousness of HB and its complications, many are poorly linked to clinical care. A lack of health literacy may be a critical barrier hindering access to HB care for adults as well as children in these populations. We, therefore, performed a survey to assess the level of knowledge of HB among Korean American parents. The survey was conducted on 521 Korean American adults who attended community-based HB awareness campaigns held at various locations throughout the metropolitan New York area between January 2015 and November 2016. Of these, 296 parents, who had children between ages 1 and 30, were identified. All participants were asked a series of questions regarding various aspects of HB and were evaluated on the basis of their awareness on each subject. A separate questionnaire was also employed to obtain demographic characteristics of the participants. The study revealed a significant deficit of knowledge of HB in most aspects the survey evaluated. Although the majority of the participants knew that HB is a liver disease, and many of them had been screened for HB, they had a poor understanding of vaccination, screening, their own HB status, modes of HBV transmission, and the consequences and treatment of HB. The participants also had a low level of awareness of their own children's HB status. This study demonstrates a low level of knowledge of HB among Korean American parents electing to attend a hepatitis education program. In addition, many parents are not aware of their children's screening and immune (or non-immune) status. The lack of health literacy may contribute to poor health access in HB care, not only in adults but also in children. This suggests an urgent need for education on HB in Korean American parents as well as in young children.

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Stereotactic biopsy in elderly patients: risk assessment and impact on treatment decision

Abstract

To evaluate risk profile, diagnostic yield and impact on treatment decision of stereotactic biopsy (SB) in elderly patients with unclear cerebral lesions. In this single center retrospective analysis we identified all patients aged ≥70 years receiving SB between January 2005 and December 2015. Demographic data, Karnofsky Performance Status (KPS), histology, comorbidity (by CHA2DS2-VASc Score) and use of anticoagulation were retrieved. We scrutinized diagnostic yield, procedural complications (mortality, transient and permanent morbidity), hospitalization time and therapeutic consequence. For correlation analysis Chi-Square, Mann–Whitney rank sum test and binary regression were used. Two hundred and thirty patients were included. In 229 patients SB was technically successful. Median age was 74 (70–87) years, 56.1% of patients were male and median preoperative KPS was 80% (30–100). Median CHA2DS2-VASc Score was 4 (1–9), with 29.6% receiving anticoagulation. Median hospital stay was 8 (2–29) days. Pathological diagnosis was conclusive in 97% revealing neoplastic lesions in 91.7% (high-grade glioma 62.6%, lymphoma 18.3%, metastasis 4.8%, low-grade glioma 3.0% and other tumors 3.0%) and non-neoplastic lesions in 5.3% of cases. Procedure-related mortality was 0.4%, transient and permanent morbidity occurred in 19 patients (8.3%) and eight patients (3.5%). Complication rate was not associated with any of the above-mentioned parameters. Adjuvant therapy was initiated in 171 (74.3%) patients. Decision against disease-specific therapy was only influenced by preoperative KPS (p < 0.001). SB in elderly patients is characterized by a favorable risk profile and high diagnostic yield, allowing tissue based therapeutic consequences even in patients with high comorbidity and anticoagulant medication.

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Isolates of the emerging pathogen Candida auris present in the UK have several geographic origins

Abstract

Candida auris has recently emerged as a serious nosocomial health risk, with widespread outbreaks in numerous hospitals worldwide and the existence of geographic region-specific discrete clonal lineages. Here we have compared the rDNA sequences of 24 isolates of Candida auris from 14 different hospital centers in the United Kingdom with those of strains from different international origins present in the public sequence databases. Here we show that UK isolates of C. auris fall into three well-supported clades corresponding to lineages that have previously been reported from India, Malaysia and Kuwait, Japan and Korea, and South Africa, respectively.

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Assessing the risk of false positive serum galactomannan among patients receiving piperacillin/tazobactam for febrile neutropenia

Abstract

Galactomannan (GM) assay is commonly used as an early diagnostic tool for invasive fungal infection (IFI) in high-risk hematology patients. False positivity is frequently observed in GM with the use of piperacillin/tazobactam. The usage of generic drugs over the original brand has a significant cost advantage. The aim of this study was to assess the performance of GM test among patients receiving original and generic piperacillin/tazobactam formulations. The study included 85 adult patients; 62.4% were male with hematological malignancy currently receiving piperacillin/tazobactam. The study group was divided into two groups: patients receiving original and generic piperacillin/tazobactam. Serum GM index was positive in one of 35 patients receiving original piperacillin/tazobactam, whereas it was positive in 46 out of 50 patients receiving generic piperacillin/tazobactam (P < .001). However, the patients receiving generic piperacillin/tazobactam underwent computed tomography (CT) scans more frequently than those receiving original piperacillin/tazobactam (P = .047). In addition, in vitro analysis of GM was performed in two generics and one original piperacillin/tazobactam vials. One generic piperacillin/tazobactam vial included high GM level. False positivity of serum GM with generic formulations of piperacillin/tazobactam is still an ongoing issue in hematology patients. A high rate of serum GM index false positivity may unexpectedly lead to a higher rate of CT scan. Selected piperacillin/tazobactam vials in each batch should be checked for GM to identify a false positivity of GM before purchase.

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Molecular and antifungal susceptibility study on trichosporonemia and emergence of Trichosporon mycotoxinivorans as a bloodstream pathogen

Abstract

A total of 21 Trichosporon spp. isolates from blood over a period of 5 years (January 2009 to December 2013) were included in the study. The most common underlying diseases found were pancreatitis (33.3%) and cancer (33.3%). Trichosporon asahii (80.9%) was the commonest species followed by Trichosporon mycotoxinivorans (14.2%) and Trichosporon faecale (4.7%). On IGS1 region sequencing the most predominant T. asahii type in our region was genotype 1 (16/17 isolates; 94.1%) and one isolate belonged to genotype 4. Following the interpretative breakpoints for Candida albicans according to CLSI guidelines amphotericin B minimum inhibitory concentrations (MICs) were ≤1 μg/ml for 38% of isolates. Fluconazole MICs were ≤4 μg/ml for 33.3% of the isolates. Itraconazole MICs were ≤0.5 μg/ml for 52.3% of the isolates. However, the MICs to posaconazole and voriconazole were ≤0.5 μg/ml for all the isolates. The MICs to caspofungin and micafungin were ≤0.5 μg/ml for only 0.09% of the isolates. This study reemphasizes that IGS1 sequencing is the most reliable technique for accurate identification of Trichosporon spp. and also to identify the newer species like T. mycotoxinivorans, which still remains rare. Surveillance of antifungal susceptibility patterns can provide the local drug resistance data to the clinicians which can further aid better management of patients.

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A new marker sequence for systematics of medically important fungi based on amino acid sequence of the largest subunit of RNA polymerase I

Abstract

Molecular evolution has dominated taxonomic studies for decades, replacing traditional methods for identification and classification. However, there is a need for better markers to resolve the problems that have limited their usefulness. In this report, we introduce the protein tag (Ptag) sequence, a highly polymorphic amino acid sequence within the C-terminal region of the largest subunit of RNA polymerase I, as a new systematic tag sequence for delineating the evolutionary history of medically important fungi. As Ptag sequences are highly polymorphic between species and low within species, 42 fungal species representing the main taxonomic groups in the phyla Ascomycota and Basidiomycota were tested. The phylogenetic tree inferred from the Ptag sequences showed high consistency with the accepted classification of the Assembling the Fungal Tree of Life (AFTOL) project. Moreover, it could resolve the interspecies phylogenetic relationships of the tested taxa. In contrast, the phylogeny inferred from the nucleotide tag (Ntag) sequence, encoding the Ptag peptide, displayed lesser discriminatory power in resolving the phylogenetic relationships among distantly related taxa. In the case of closely related fungal species, the phylogenetic trees for Ptag and Ntag sequences were consistent with the tree for ITS1 sequences of 11 dermatophytic species. Taken together, the Ptag sequences should contribute to inferring phylogeny among species whereas the Ntag sequences should be useful to analyze variations among closely related species to resolve taxonomic issues in fungi.

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Diffusion of Pneumocystis jirovecii in the surrounding air of patients with Pneumocystis colonization: frequency and putative risk factors

Abstract

In a prospective bicentric study, Pneumocystis jirovecii excretion and diffusion was explored in air samples collected in the rooms occupied by 17 Pneumocystis-colonized patients. P. jirovecii DNA was detected by real-time PCR in the air collected from 3 patients’ rooms (17.6%), with identical genotypes in corresponding clinical and air samples. Pneumocystis DNA was detected for 2/3 patients with autoimmune disease treated with corticosteroids versus 1/6 patients with hematologic disease and 0/5 kidney transplant recipients. These data confirm the possible excretion of the fungus by Pneumocystis-colonized patients and thus bring additional arguments for the prevention of airborne transmission in hospital wards.

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Refractory sporotrichosis due to Sporothrix brasiliensis in humans appears to be unrelated to in vivo resistance

Abstract

Sporotrichosis is a subacute to chronic infection caused by members of the Sporothrix schenckii complex. Itraconazole is the first choice antifungal drug for treating this infection, with terbinafine and potassium iodide as alternatives and amphotericin B used in cases of severe infections. Correlation of antifungal susceptibility data with the clinical outcome of the patients is scarce. The aim of this study was to correlate clinical and mycological data in patients with refractory sporotrichosis. In this work, antifungal susceptibilities, determined according to the reference M38-A2 CLSI protocol, of 25 Sporothrix strains, isolated from seven human cases of sporotrichosis with adversities in the treatment, are presented. Tested drugs included itraconazole, ketoconazole, posaconazole, voriconazole, terbinafine, and amphotericin B. Fungi were identified using the T3B PCR fingerprinting. This method identified all strains as Sporothrix brasiliensis and also demonstrated a high degree of similarity between the strains. In general, voriconazole was ineffective against all strains, and elevated minimal inhibitory concentrations (MICs) were observed for amphotericin B. High itraconazole and terbinafine MICs were not observed in S. brasiliensis isolates from patients of this study. Moreover, a significant increase in itraconazole and terbinafine MIC values from strains isolated from the same patient in different periods was not observed. The results suggest that the antifungal susceptibility to terbinafine and itraconazole determined by the reference method does not play an important role in therapeutic failure of sporotrichosis and that acquisition of resistance during prolonged antifungal treatment is not likely to occur in S. brasiliensis.

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Modeling dermatophytosis in reconstructed human epidermis: A new tool to study infection mechanisms and to test antifungal agents

Abstract

Dermatophytosis is a superficial fungal infection of keratinized structures that exhibits an increasing prevalence in humans and is thus requesting novel prophylactic strategies and therapies. However, precise mechanisms used by dermatophytes to adhere at the surface of the human epidermis and invade its stratum corneum are still incompletely identified, as well as the responses provided by the underlying living keratinocytes during the infection. We hereby report development of an in vitro model of human dermatophytosis through infection of reconstructed human epidermis (RHE) by arthroconidia of the anthropophilic Trichophyton rubrum species or of the zoophilic Microsporum canis and Arthroderma benhamiae species. By modulating density of arthroconidia in the inoculum and duration of exposure to such pathogens, fungal infection limited to the stratum corneum was obtained, mimicking severe but typical in vivo situation. Fungal elements in infected RHE were monitored over time by histochemical analysis using periodic-acid Schiff-staining or quantified by qPCR-detection of fungal genes inside RHE lysates. This model brings improvements to available ones, dedicated to better understand how dermatophytes and epidermis interact, as well as to evaluate preventive and therapeutic agents. Indeed, miconazole topically added to RHE was demonstrated to inhibit fungal infection in this model.

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Continuous increase of Trichophyton tonsurans as a cause of tinea capitis in the urban area of Paris, France: a 5-year-long study

Abstract

Tinea capitis (TC) is a highly contagious fungal infection of the scalp due to dermatophytes in children. To obtain information on the epidemiology of TC in the urban area of Paris, we analysed the microbiological results of 3090 patients seen with suspected TC from October 2010 to September 2015 at Saint Louis hospital, Paris, France. A peak of TC was observed in 3–6 year-old children, followed by a progressive decrease until 16 years of age. Of the 1311 positive cultures, 95% (1246) yielded one of the three anthropophilic species [Trichophyton tonsurans (33.5%), Trichophyton soudanense (38.3%), or Microsporum audouinii (28.2%)]. When considering one TC case per family, we observed a significant increase of T. tonsurans (P = .018) during these 5 years. The increase was more pronounced (P = .0047) in patients of West-African descent (n = 666), and was at the expense of M. audouinii and T. soudanense. On the other hand, the Caribbean patients (n = 85) remained predominantly (72.9%) infected by T. tonsurans. Our results show a better virulence of T. tonsurans over other species as already reported. Since T. tonsurans has not been reported in Africa, the infection of patients of West-African descent probably took place in the Paris area by exchanges with Caribbean patients. This increase of TC due to T. tonsurans was observed in the context of griseofulvin being the only licensed paediatric treatment for TC in France, which should deserve reappraisal because terbinafine may be more efficacious.

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Galactomannan testing and Aspergillus PCR in same-day bronchoalveolar lavage and blood samples for diagnosis of invasive aspergillosis

Abstract

In recent years galactomannan antigen testing (GM) and also Aspergillus PCR have become increasingly important for diagnosis of invasive aspergillosis (IA). Whether or not these tests need to be performed with bronchoalveolar lavage fluid (BALF; i.e., primary site of infection), or testing of blood samples is sufficient, remains, however, a matter of debate. We evaluated the diagnostic performance of GM ELISA, and Aspergillus PCR by using BALF samples and blood samples obtained at the same day from a total of 53 immunocompromised patients (16 with probable/proven IA and 37 with no evidence of IA according to the revised EORTC/MSG criteria; 38 patients with hematological malignancies were prospectively enrolled at the Medical University of Graz, Austria, 15 patients with mixed underlying diseases at the Mannheim University Hospital). Patients with possible IA were excluded from this analysis. A total of 34/53 (64%) of all patients and 12/16 (75%) of patients with probable/proven IA received mold-active antifungal prophylaxis/therapy at the time of the BALF procedure. Sensitivities of GM and Aspergillus PCR were 38% and 44% in BALF, and 31% and 0% in blood, respectively. Best sensitivity (75%) for detecting proven/probable IA was achieved when BALF Aspergillus PCR, BALF GM (>1.0 ODI), BALF-culture and serum-GM (>0.5 ODI) were combined (specificity 95%). In conclusion, sensitivities of the evaluated diagnostic tests—when interpreted on their own—were low in BALF and even lower in blood, sensitivities increased markedly when diagnostic tests were combined.

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AST to ALT Ratio is elevated in disseminated histoplasmosis as compared to localized pulmonary disease and other endemic mycoses

Abstract

Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, “soft clues” may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes. We identified 90 cases of EFIs during the study period that met all inclusion criteria (Histoplasma 21, Blastomyces 56, Coccidioides 12, Paracoccidioides 1). We also evaluated 10 control patients with bacterial sepsis. The mean ratio of AST to ALT in patients with disseminated histoplasmosis was 2.69 (95% CI:1.22, 4.16) while for other EFIs, the mean ratio ranged from 0.38 to 1.14 with disseminated coccidioidomycosis and blastomycosis respectively (P < 0.0001). The ratio in patients with bacterial sepsis was 0.84. We propose the use of the AST/ALT ratio as a clinical “soft clue” suggestive of disseminated histoplasmosis in the appropriate host, and to possibly distinguish cross reactivity of the Histoplasma antigen assay with other EFIs.

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Genetic diversity of the Hwp1 gene and HIS3, EF3, CDC3 microsatellites and antifungal susceptibility profiles of Candida albicans isolates from Yaoundé HIV-infected patients

Abstract

The molecular epidemiology and the antifungal susceptibility profiles of Candida albicans are scarce in Cameroon. Authors studied the genetic diversity and the antifungal susceptibility of C. albicans isolates from Yaoundé HIV-infected patients. Clinical isolates were obtained by mycological diagnosis of oropharyngeal swabs, stools, urine, and vaginal swabs from patients. C. albicans isolates were confirmed by the Light cycler real-time PCR of the ITS1 region of the 5.8s ribosomal DNA. The ABC genotypes and the Hwp1 gene amplification were carried out with specific primers. Microsatellite length polymorphism of HIS3, CDC3, and EF3 microsatellites was analysed. The antifungal susceptibility testing was carried out by the CLSI broth microdilution M27-A3 and M27-S4 protocols. The minimal inhibitory concentration (MIC) results were interpreted according to updated clinical breakpoints (CBPs) recommended by the CLSI or epidemiological cut-off values (ECVs). One hundred and thirteen (113) isolates were obtained from the analysis of 1218 samples. The ABC genotyping showed 79 (69.91%) genotype A, 24 (21.23%) genotype B, and 10 (8.84%) genotype C. The Hwp1 gene amplification provided a newly observed genetic polymorphism, named H and 5 genotypes described (H1–H5). The microsatellite analysis generated 65 molecular types. All the isolates were susceptible to amphotericin B (MIC ≤ 1 μg/ml); 79.64% of isolates were wild type to itraconazole (MIC ≤ 0.12 μg/ml); and 86.72% of isolates were susceptible to fluconazole (MIC ≤ 2 μg/ml). These results highlight the important genetic diversity of C. albicans isolates among Yaoundé HIV-infected patients and bring clues for the comprehension of the molecular epidemiology of the yeast in Cameroon.

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Enhancement of the antidermatophytic activity of silver nanoparticles by Q-switched Nd:YAG laser and monoclonal antibody conjugation

Abstract

The objective of this research was to investigate the effect of silver nanoparticles (AgNPs), free or conjugated with monoclonal antibody and mediated by Q-switched Nd:YAG laser on five dermatophytes. The laser was applied for 45 s at 532 nm and 0.8 J/cm². The application of AgNPs combined with laser caused an increase in fungal susceptibility compared to application of AgNPs alone. The MIC₅₀ and MIC₁₀₀ recorded 3 and 9 μg/ml in the case of E. floccosum (the most susceptible species), 10 and 19 μg/ml for T. rubrum (the most tolerant species), respectively. A decrease in keratinase activity reaching 76.1, 67.1, and 62.4% was attained in the case of M. gypseum, T. rubrum, and T. mentagrophyte, respectively, on application of 10 μg/ml AgNPs combined with Nd:YAG laser. Under the same conditions of application, a steady increase in leaked materials coupled with reduction in ergosterol synthesis was reached. The structural alterations occurred to the fungus were more observed on the application of AgNPs in combination with laser where the conidia and hyphae lost their cellular integrity, become flaccid, permanently destructed, and completely killed. The monoclonal antibody conjugated AgNPs did not result in significant variation in in vitro experiments compared with that produced by nonconjugated nanoparticles. However, the conjugates achieved significantly more curing of M. canis–inoculated guinea pigs compared with nonconjugated nanoparticles.

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Human primary myeloid dendritic cells interact with the opportunistic fungal pathogen Aspergillus fumigatus via the C-type lectin receptor Dectin-1

Abstract

Aspergillus fumigatus is an opportunistic fungal pathogen causing detrimental infections in immunocompromised individuals. Dendritic cells (DCs) are potent antigen-presenting cells and recognize the A. fumigatus cell wall component β-1,3 glucan via Dectin-1, followed by DC maturation and cytokine release. Here, we demonstrate that human primary myeloid DCs (mDCs) interact with different morphotypes of A. fumigatus. Dectin-1 is expressed on mDCs and is down-regulated after contact with A. fumigatus, indicating that mDCs recognize A. fumigatus via this receptor. Blocking of Dectin-1, followed by stimulation with depleted zymosan diminished the up-regulation of the T-cell co-stimulatory molecules CD40, CD80, HLA-DR and CCR7 on mDCs and led to decreased release of the cytokines TNF-α, IL-8, IL-1β and IL-10.

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Chemical and physical strategies in onychomycosis topical treatment: A review

Abstract

Onychomycosis is a fungal infection of the fingernails or toenails caused by dermatophytes, nondermatophytes, moulds, and yeasts. This condition affects around 10–30% people worldwide, negatively influencing patients’ quality of life, with severe outcomes in some cases. Since the nail unit acts as a barrier to exogenous substances, its physiological features hampers drug penetration, turning the onychomycosis treatment a challenge. Currently, there are several oral and topical therapies available; nevertheless, cure rates are still low and relapse rates achieves 10–53%. Also, serious side effects may be developed due to long-term treatment. In light of these facts, researchers have focused on improving topical treatments, either by modifying the vehicle or by using some physical technique to improve drug delivery trough the nail plate, hence increasing therapy effectiveness. Therefore, the aim of this paper is to explain these novel alternative approaches. First, the challenges for drug ungual penetration are presented. Then, the chemical and physical strategies developed for overcoming the barriers for drug penetration are discussed. We hope that the information gathered may be useful for the development of safer and more effective treatments for onychomycosis.

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Characterization of pharyngeal peristaltic pressure variability during volitional swallowing in healthy individuals

Abstract

Background

Recent technological advances incorporated in high resolution manometry have justifiably heightened interest in manometric evaluation of the pharynx. Despite this interest, from both physiologic and clinical perspective there remain a number of unanswered questions regarding the magnitude of variability of pharyngeal pressure phenomena. Therefore, the aim of the present study was to characterize in healthy individuals the inter-subject and recording-site specific variability of pharyngeal peristaltic pressure phenomena.

Methods

We studied 32 healthy subjects (age: 21-83 years,20 under 35 years) during dry,5 and 10 mL water swallows ×3. Pharyngeal peristaltic pressures were recorded using a high resolution (HR) manometric system and a catheter assembly with 36 circumferential sensors spaced at 1 cm intervals positioned trans-nasally to traverse the pharynx, UES and proximal esophagus.

Key Results

Both site-specific pressure data and the Pharyngeal contractile integral (PhCI) showed wide dispersion ranging between values under 50 mm Hg to over 300 mm Hg and 100-600 mm Hg/cm/s,respectively. There was also wide range of dispersion of data for both the standard deviations and the coefficient of variation for all sites (P=.001). The coefficient of variation for PhCI ranged between 0.02 and 0.25 representing data dispersion of 2-25 percent of the mean among subjects (P=.001). Position, age and volume of swallowed fluid did not influence the magnitude of variability.

Conclusions

Deglutitive Pharyngeal peristalsis generates pressures with significant degree of site-related and inter-subject variability. This variability is not influenced by age, position and volume of swallowed fluid.

This study characterizes in healthy individuals the inter-subject and recording-site specific variability of pharyngeal peristaltic pressure phenomena. We found deglutitive pharyngeal peristalsis generates pressures with significant degree of site-related and inter-subject variability. This variability is not influenced by age, position and volume of swallowed fluid.

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Stereotactic biopsy in elderly patients: risk assessment and impact on treatment decision

Abstract

To evaluate risk profile, diagnostic yield and impact on treatment decision of stereotactic biopsy (SB) in elderly patients with unclear cerebral lesions. In this single center retrospective analysis we identified all patients aged ≥70 years receiving SB between January 2005 and December 2015. Demographic data, Karnofsky Performance Status (KPS), histology, comorbidity (by CHA2DS2-VASc Score) and use of anticoagulation were retrieved. We scrutinized diagnostic yield, procedural complications (mortality, transient and permanent morbidity), hospitalization time and therapeutic consequence. For correlation analysis Chi-Square, Mann–Whitney rank sum test and binary regression were used. Two hundred and thirty patients were included. In 229 patients SB was technically successful. Median age was 74 (70–87) years, 56.1% of patients were male and median preoperative KPS was 80% (30–100). Median CHA2DS2-VASc Score was 4 (1–9), with 29.6% receiving anticoagulation. Median hospital stay was 8 (2–29) days. Pathological diagnosis was conclusive in 97% revealing neoplastic lesions in 91.7% (high-grade glioma 62.6%, lymphoma 18.3%, metastasis 4.8%, low-grade glioma 3.0% and other tumors 3.0%) and non-neoplastic lesions in 5.3% of cases. Procedure-related mortality was 0.4%, transient and permanent morbidity occurred in 19 patients (8.3%) and eight patients (3.5%). Complication rate was not associated with any of the above-mentioned parameters. Adjuvant therapy was initiated in 171 (74.3%) patients. Decision against disease-specific therapy was only influenced by preoperative KPS (p < 0.001). SB in elderly patients is characterized by a favorable risk profile and high diagnostic yield, allowing tissue based therapeutic consequences even in patients with high comorbidity and anticoagulant medication.

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Regular aerobic exercise reduces endothelin-1 mediated vasoconstrictor tone in overweight and obese adults

Abstract

Endothelin (ET)-1-mediated vasoconstrictor tone is elevated in overweight and obese adults, contributing to vasomotor dysfunction and increased cardiovascular disease risk. While the effects of habitual aerobic exercise on endothelium-dependent vasodilation in overweight/obese adults has been studied, little is known regarding ET-1 vasoconstriction. Accordingly, the aims of the present study were to determine: (1) if regular aerobic exercise training reduces ET-1-mediated vasoconstrictor tone in overweight and obese adults; and, if so (2) whether the reduction in ET-1 vasoconstriction contributes to exercise-induced improvement in endothelium-dependent vasodilation in this population. Forearm blood flow (FBF) to intra-arterial infusion of selective ET_A receptor blockade (BQ-123, 100 nmol min⁻¹ for 60 min), acetylcholine (4.0, 8.0 and 16.0 μg/100 ml tissue min⁻¹) in the absence and presence of ET_A receptor blockade and sodium nitroprusside (1.0, 2.0 and 4.0 μg/100 ml tissue min⁻¹) were determined before and after a 3-month aerobic exercise training intervention in 25 (16M/9F) overweight/obese (BMI: 30.1 ± 0.5 kg m⁻²) adults. The vasodilator response to BQ-123 was significantly lower (∼25%) and the FBF responses to acetylcholine were ∼35% higher after exercise training. Before the exercise intervention the co-infusion of acetylcholine+BQ-123 resulted in a greater vasodilator response than acetylcholine alone; however, after the exercise intervention the FBF response to acetylcholine was not significantly increased by ET_A receptor blockade. These results demonstrate that regular aerobic exercise reduces ET-1-mediated vasoconstrictor tone in previously sedentary overweight and obese adults. Moreover, decreased ET-1 vasoconstriction is an important mechanism underlying the aerobic exercise-induced improvement in endothelium-dependent vasodilator function in overweight/obese adults.

This article is protected by copyright. All rights reserved

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Frontal dysfunction in patients with restless legs syndrome performing a visual oddball task: an event-related potential source imaging study

Publication date: August 2017
Source:Sleep Medicine, Volume 36
Author(s): Kwang Su Cha, Jeong Woo Choi, Ki-Young Jung, Kyung Hwan Kim
Restless legs syndrome (RLS) is a sensorimotor neurological disorder that is accompanied by the compelling urge to move one's legs, and unpleasant, disturbing sensations in the legs. Several neuropsychological studies have shown that RLS is associated with deficits in cognitive functions, such as attention, working memory, and frontal executive function, presumably due to abnormal frontal activities. However, the mechanism underlying the cognitive deficits in RLS patients is mostly unknown. To investigate the cortical origin of cognitive dysfunction in RLS, we analyzed the P2 and P3 event-related potential (ERP) components evoked by a visual oddball task using distributed cortical source localization via low-resolution brain electromagnetic tomography (LORETA) algorithm. A total of 17 female drug-naive RLS patients and 13 healthy volunteers were enrolled. Multichannel ERPs were recorded while performing a visual oddball task. We identified that the P2 and P3 ERP components were significantly reduced in RLS patients. These patients showed a reduction of the cortical current source densities in temporal periods corresponding to P2 and P3, compared to normal controls. Significant differences between RLS patients and normal controls were mainly found in the frontal region; that is, in the medial prefrontal cortex at the P2 epoch and the anterior cingulate cortex at the P3 epoch. Our neurophysiological results imply that the abnormal activities in the frontal region results in a cognitive deficit in RLS patients, which should be compared with neuropsychological evaluations in a further study.



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Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: results from the Danish Blood Donor Study

Publication date: August 2017
Source:Sleep Medicine, Volume 36
Author(s): Maria Didriksen, Andreas S. Rigas, Richard P. Allen, Brendan J. Burchell, Emanuele Di Angelantonio, Maria H. Nielsen, Poul Jennum, Thomas Werge, Christian Erikstrup, Ole B. Pedersen, Mie T. Bruun, Kristoffer S. Burgdorf, Erik Sørensen, Henrik Ullum
ObjectiveRestless legs syndrome (RLS) is a neurological sensorimotor disorder characterized by uncomfortable sensations in the legs. RLS often occurs as a comorbid condition. Besides an increased risk of iron deficiency, blood donors are considered to be generally healthy. Blood donors are therefore an ideal population for studying factors associated with RLS occurrence, herein the role of iron. It is suggested that RLS is linked to sex, age, low socioeconomic status, unhealthy lifestyle, and iron deficiency. The objective of this study is therefore to estimate the RLS prevalence and identify associated biological, sociodemographic, economic, and lifestyle factors in a population of blood donors.MethodsA total of 13,448 blood donors enrolled in the Danish Blood Donor Study from May 2015 to May 2016. RLS cases were identified using the validated Cambridge–Hopkins RLS-questionnaire. Logistic regression models were applied to assess the relationship between RLS and data on socially related factors collected using questionnaires and population registers.ResultsIn this study, 7.2% women and 4.5% men were classified with RLS. RLS was associated with: female sex, high age, smoking, frequent alcohol consumption, and low education. RLS-related symptoms were associated with obesity, parity and donation intensity three years prior to inclusion among women. RLS was not related to: reduced plasma ferritin, employment status, and income.ConclusionsRLS is a frequent disorder in otherwise healthy individuals. The associations discovered in this study can be utilized in preventing or reducing RLS symptoms.



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Obstructive sleep apnea: effect of comorbidities and positive airway pressure on all-cause mortality

Publication date: August 2017
Source:Sleep Medicine, Volume 36
Author(s): Poul Jennum, Philip Tønnesen, Rikke Ibsen, Jakob Kjellberg
ObjectiveMost studies have used cardiovascular and cerebrovascular disease (CVD) end-points to measure the effect of continuous positive airway pressure (CPAP), but pre-diagnostic morbidities involve a range of comorbidities that may influence the consequences of obstructive sleep apnea (OSA). We therefore aimed to evaluate all-cause total mortality after a diagnosis of OSA, the effect of CPAP in women and men, and the potential effect of major comorbidities.MethodsWe used national registry data as a historical cohort and included 22,135 OSA patients aged 20 years or more with comorbidity data three years before diagnosis and follow-up morbidity and mortality over a period of 17 years.ResultsA total of 8129 (37%) accepted CPAP for more than six months; 14,006 (63%) were CPAP non-user/non-compliant. Those treated with CPAP tended to have higher mortality rates. Patients treated with CPAP were more likely to be male, elderly, suffer from diabetes, and present with more cardiovascular diseases than those not treated with CPAP. After a diagnosis of OSA, more patients in the CPAP-treated group developed cardiovascular complications. Female gender was associated with lower mortality, whereas age, diabetes type 2, and hypertension prior to OSA diagnosis were associated with negative effects on outcome. After an OSA diagnosis, male gender, age, diabetes (types 1 and 2), hypertension, and heart failure were all associated with greater mortality. CPAP treatment had a positive effect in middle-aged and elderly people, whereas CPAP in females had no effect on all-cause mortality.ConclusionsCPAP-treated patients present more comorbidities before and after diagnosis compared with non-treated/non-compliant patients, which explains the higher mortality in this group. CPAP treatment is associated with lower mortality rates in middle-aged and elderly (aged 60+ years) males, but only after adjustment for multiple comorbidities. No effect of CPAP treatment on all-cause mortality in female OSA patients was found. Males with OSA, older than 40 years, with comorbidities and a low educational level presented a particularly high mortality risk.



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Experience and psychological impact of anal cancer screening in gay, bisexual and other men who have sex with men: a qualitative study

Abstract

Objective

Human papillomavirus (HPV)-related anal cancer rates are increasing and are particularly high in gay, bisexual and other men who have sex with men (GBM/MSM), especially HIV-positive individuals. Although screening programs for high-risk populations have been advocated, concerns about possible adverse psychological consequences exist. This study aimed to investigate GBM/MSM's experience, understanding and emotional response to screening techniques for anal cancer, to determine how best to minimise psychological distress in future programs.

Methods

In-depth qualitative face-to-face interviews were carried out with 21 GBM/MSM participating in the ‘Study of the Prevention of Anal Cancer' in Sydney, Australia between June 2013-June 2014. Non-random, purposive sampling was used to ensure heterogeneity with respect to HIV-status and screening test results. Framework Analysis method was used to organise the data and identify emerging themes.

Results

Knowledge about anal cancer, HPV and the link between them was limited. Abnormal screening results impacted participants' sense of wellbeing and were associated with anxiety and concern about developing anal cancer. HIV-negative men receiving abnormal results showed higher levels of distress compared to their HIV-positive counterparts. Consultations with general practitioners about abnormal results had an important role in increasing participants' understanding and in moderating their anxiety.

Conclusion

Anal cancer screening should be accompanied by health education around anal cancer, its aetiology and the meaning of associated test results. Simple and effective communication strategies should be encouraged. Collaboration with general practitioners could assist the process of education and reporting test results.

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Primary tumor sites in relation to ultraviolet radiation exposure and skin visibility correlate with survival in cutaneous melanoma

Abstract

The prognostic value of detailed anatomic site and ultraviolet radiation (UVR) exposure patterns has not been fully determined in cutaneous melanoma. Thus, we reviewed medical records for detailed site in a population-based retrospective Swedish patient cohort diagnosed with primary invasive melanoma 1976 − 2003 (n=5,973). We followed the patients from date of diagnosis until death, emigration or December 31^st 2013, and evaluated melanoma-specific survival by subsite in a multivariable regression model adjusting for established prognostic factors. We found that melanoma on chronic UVR exposure sites (face, dorsum of hands; adjusted HR 0.6; CI 0.4 − 0.7) and moderately intermittent UVR sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6 − 0.8) were associated with a favorable prognosis compared with highly intermittent sites (chest, back, neck, shoulders, thighs). Further, melanoma on poorly visible skin sites upon self-examination (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area; HR 1.3; CI 1.1 − 1.5) had a worse prognosis than those on easily visible sites (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). In conclusion, highly intermittent UVR exposure sites and poor skin visibility presumably correlate with reduced melanoma survival, independent of established tumor characteristics. A limitation of the study was the lack of information on actual individual UVR exposure. This article is protected by copyright. All rights reserved.

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Radiotherapy-assisted tumor selective metronomic oral chemotherapy

Abstract

Chemotherapy have commonly been used in maximum tolerated dose (MTD) to completely eradicate the cancer. However, such treatments often failed due to the complex and dynamic nature of cancer. Therefore, it has been suggested that cancer should be treated as a chronic disease, controlling its growth by providing continuous therapeutic pressure for long-term. Such an approach, however, requires a therapy that is non-toxic and orally available with sufficient potency. Herein, we propose a radiotherapy-assisted orally available metronomic apoptosis-targeted chemotherapy, which delivers doxorubicin continuously to the irradiated tumor with high selectivity while causing minimal toxicities to the normal tissues. DEVD-S-DOX/DCK complex is the anticancer prodrug for our strategy that could selectively release doxorubicin in the irradiated tumor tissue with sufficient oral bioavailability. The prodrug was completely inactive by itself, but displayed potent anticancer activity when coupled with radiotherapy. Consequently, the daily oral administration of DEVD-S-DOX/DCK in combination with the low-dose radiotherapy effectively suppressed the growth of tumor in vivo with no significant systemic toxicities despite that the accumulated dose of doxorubicin exceeded 150 mg/kg. Therefore, the our novel therapy using DEVD-S-DOX/DCK complex is considered as an outstanding treatment option for treating cancer for long-term attributed to its oral availability and low-toxicity profile as well as the potent anticancer effect. This article is protected by copyright. All rights reserved.

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Laparoscopic Versus Open Approach for Intersphincteric Resection—Results from a Tertiary Cancer Center in India

Abstract

The study aims to compare open intersphincteric resection (OISR) with laparoscopic intersphincteric resection (LISR) in terms of short-term oncological and clinical outcomes. This is a retrospective review of a prospectively maintained database including all the patients of rectal cancer who underwent intersphincteric resection (ISR) at Tata Memorial Centre between 1st July 2013 and 30th November 2015. Short-term oncological parameters evaluated included circumferential resection margin involvement (CRM), distal resection margin involvement, and number of nodes harvested. Perioperative outcomes included blood loss, length of hospital stay and 30-day postoperative morbidity and mortality. Chi-square test was used to compare the results between the two groups. Thirty nine cases of OISR and 34 cases of LISR were included in the study. Median BMI was higher in LISR group; otherwise, the two groups were comparable in all aspects. There were no conversions in LISR group. CRM involvement was seen in four patients (10%) in the conventional group compared to none in the LISR group. Median hospital stay was comparable between the two groups. Laparoscopic ISR is safe and can be performed with low conversion rate in selected group of patients.

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Light absorption and the photoformation of hydroxyl radical and singlet oxygen in fog waters

Publication date: September 2017
Source:Atmospheric Environment, Volume 164
Author(s): R. Kaur, C. Anastasio
The atmospheric aqueous-phase is a rich medium for chemical transformations of organic compounds, in part via photooxidants generated within the drops. Here we measure light absorption, photoformation rates and steady-state concentrations of two photooxidants – hydroxyl radical (^•OH) and singlet molecular oxygen (¹O2*) – in 8 illuminated fog waters from Davis, California and Baton Rouge, Louisiana. Mass absorption coefficients for dissolved organic compounds (MACDOC) in the samples are large, with typical values of 10,000–15,000 cm² g-C⁻¹ at 300 nm, and absorption extends to wavelengths as long as 450–600 nm. While nitrite and nitrate together account for an average of only 1% of light absorption, they account for an average of 70% of ^•OH photoproduction. Mean ^•OH photoproduction rates in fogs at the two locations are very similar, with an overall mean of 1.2 (±0.7) μM h⁻¹ under Davis winter sunlight. The mean (±1σ) lifetime of ^•OH is 1.6 (±0.6) μs, likely controlled by dissolved organic compounds. Including calculated gas-to-drop partitioning of ^•OH, the average aqueous concentration of ^•OH is approximately 2 × 10⁻¹⁵ M (midday during Davis winter), with aqueous reactions providing approximately one-third of the hydroxyl radical source. At this concentration, calculated lifetimes of aqueous organics are on the order of 10 h for compounds with ^•OH rate constants of 1 × 10¹⁰ M⁻¹ s⁻¹ or higher (e.g., substituted phenols such as syringol (6.4 h) and guaiacol (8.4 h)), and on the order of 100 h for compounds with rate constants near 1 × 10⁹ M⁻¹ s⁻¹ (e.g., isoprene oxidation products such as glyoxal (152 h), glyoxylic acid (58 h), and pyruvic acid (239 h)). Steady-state concentrations of ¹O2* are approximately 100 times higher than those of ^•OH, in the range of (0.1–3.0) × 10⁻¹³ M. Since ¹O2* is a more selective oxidant than ^•OH, it will only react appreciably with electron-rich species such as dimethyl furan (lifetime of 2.0 h) and substituted polycyclic aromatic hydrocarbons (e.g., 9,10-dimethylbenz[a]anthracene with a lifetime of 0.7 h). Comparing our current Davis samples with Davis fogs collected in the late 1990s shows a decrease in dissolved organic carbon content, similar mass absorption coefficients, lower ^•OH concentrations, but very similar ¹O2* concentrations.



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Source apportionment of PM2.5 across China using LOTOS-EUROS

Publication date: September 2017
Source:Atmospheric Environment, Volume 164
Author(s): R. Timmermans, R. Kranenburg, A. Manders, C. Hendriks, A. Segers, E. Dammers, Q. Zhang, L. Wang, Z. Liu, L. Zeng, H. Denier van der Gon, M. Schaap
China's population is exposed to high levels of particulate matter (PM) due to its strong economic growth and associated urbanization and industrialization. To support policy makers to develop cost effective mitigation strategies it is of crucial importance to understand the emission sources as well as formation routes responsible for high pollution levels. In this study we applied the LOTOS-EUROS model with its module to track the contributions of predefined source sectors to China for the year 2013 using the MEIC emission inventory. It is the first application of the model system to a region outside Europe. The source attribution was aimed to provide insight in the sector and area of origin of PM2.5 for the cities of Beijing and Shanghai. The source attribution shows that on average about half of the PM2.5 pollution in both cities originates from the municipality itself. About a quarter of the PM2.5 comes from the neighbouring provinces, whereas the remaining quarter is attributed to long range transport from anthropogenic and natural components. Residential combustion, transport, and industry are identified as the main sources with comparable contributions allocated to these sectors. The importance of the sectors varies throughout the year and differs slightly between the cities. During winter, urban contributions from residential combustion are dominant, whereas industrial and traffic contributions with a larger share of regional transport are more important during summer. The evaluation of the model results against satellite and in-situ observations shows the ability of the LOTOS-EUROS model to capture many features of the variability in particulate matter and its precursors in China. The model shows a systematic underestimation of particulate matter concentrations, especially in winter. This illustrates that modelling particulate matter remains challenging as it comes to components like secondary organic aerosol and suspended dust as well as emissions and formation of PM during winter time haze situations. All in all, the LOTOS-EUROS system proves to be a powerful tool for policy support applications outside Europe as the intermediate complexity of the model allows the assessment of the area and sector of origin over decadal time periods.



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Allocating emissions to 4 km and 1 km horizontal spatial resolutions and its impact on simulated NOx and O3 in Houston, TX

Publication date: September 2017
Source:Atmospheric Environment, Volume 164
Author(s): Shuai Pan, Yunsoo Choi, Anirban Roy, Wonbae Jeon
A WRF-SMOKE-CMAQ air quality modeling system was used to investigate the impact of horizontal spatial resolution on simulated nitrogen oxides (NOx) and ozone (O3) in the Greater Houston area (a non-attainment area for O3). We employed an approach recommended by the United States Environmental Protection Agency to allocate county-based emissions to model grid cells in 1 km and 4 km horizontal grid resolutions. The CMAQ Integrated Process Rate analyses showed a substantial difference in emissions contributions between 1 and 4 km grids but similar NOx and O3 concentrations over urban and industrial locations. For example, the peak NOx emissions at an industrial and urban site differed by a factor of 20 for the 1 km and 8 for the 4 km grid, but simulated NOx concentrations changed only by a factor of 1.2 in both cases. Hence, due to the interplay of the atmospheric processes, we cannot expect a similar level of reduction of the gas-phase air pollutants as the reduction of emissions. Both simulations reproduced the variability of NASA P-3B aircraft measurements of NOy and O3 in the lower atmosphere (from 90 m to 4.5 km). Both simulations provided similar reasonable predictions at surface, while 1 km case depicted more detailed features of emissions and concentrations in heavily polluted areas, such as highways, airports, and industrial regions, which are useful in understanding the major causes of O3 pollution in such regions, and to quantify transport of O3 to populated communities in urban areas. The Integrated Reaction Rate analyses indicated a distinctive difference of chemistry processes between the model surface layer and upper layers, implying that correcting the meteorological conditions at the surface may not help to enhance the O3 predictions. The model-observation O3 bias in our studies (e.g., large over-prediction during the nighttime or along Gulf of Mexico coastline), were due to uncertainties in meteorology, chemistry or other processes. Horizontal grid resolution is unlikely the major contributor to these biases.



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Genomic alterations in fatal forms of non-anaplastic thyroid cancer: Identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence

Purpose. Patients with anaplastic thyroid cancer have a very high death rate. In contrast, deaths from non-anaplastic thyroid cancer are much less common. The genetic alterations in fatal non-anaplastic thyroid cancers have not been reported. <p>Experimental Design. We performed next-generation sequencing of 410 cancer genes from 57 fatal non-anaplastic thyroid primary cancers. Results were compared to The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC) and to the genomic changes reported in anaplastic thyroid cancer (ATC).</p> <p>Results. There was a very high prevalence of TERT promoter mutations, comparable to that of anaplastic thyroid cancer, and these co-occurred with BRAF and RAS mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes DLG5-RET and OSBPL1A-BRAF were identified. There was a high frequency of mutations in MED12 and these were mutually exclusive to TERT promoter mutations and also to BRAF and RAS mutations. In addition, a high frequency of mutations in RBM10 were identified and these co-occurred with RAS mutations and PIK3CA mutations. Compared to the PTCs in TCGA, there were higher frequencies of mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases.</p> <p>Conclusions. These data support a model whereby fatal non-anaplastic thyroid cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of TERT promoter mutations, MED12 mutations, RBM10 mutations and chromosome 1q gain highlight their likely association with tumor virulence.

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Co-administration of RANKL and CTLA4 antibodies enhances lymphocyte-mediated anti-tumor immunity in mice.

Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in anti-tumor immunity has been suggested by recent case reports in melanoma. Here we provide a rationale for this combination in mouse models of cancer. <br />Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor infiltrating lymphocyte analysis, tumor growth and metastasis using a variety of neutralizing antibodies and gene-targeted mice. <br />Results: RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T cell (Treg) depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity. The optimal combination depended on the presence of activating Fc receptors and lymphocytes (NK cells for metastatic disease and predominantly CD8⁺ T cells for subcutaneous tumor control), while anti-RANKL alone did not require FcR. The significantly higher T-cell infiltration into solid tumors post anti-RANKL and anti-CTLA-4 was accompanied by increased T-cell effector function (cytokine polyfunctionality), and anti-RANKL activity occurred independently of Treg depletion. The majority of RANKL expression in tumors was on T cells whereas RANK-expressing cells were mostly tumor-associated macrophages (TAMs), with some expression also observed on dendritic cells (DC) and myeloid derived suppressor cells (MDSCs). <br />Conclusions: These results provide a rationale for the further investigation of RANKL-RANK interactions in tumor immunity and a basis for development of translational markers of interest in human clinical trials.

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Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Purpose:  This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. <p>Experimental Design:  Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event-continual reassessment method.</p> <p>Results:  Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1-2, without any treatment-related discontinuations. Six (26.1%) patients had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8⁺ T-cells was observed in responders versus non-responders.</p> <p>Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.

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Influence of surgical wrist denervation on proprioceptive changes: A systematic review

Abstract

The denervation of the wrist is a known method to treat the painful wrist. Pain relief and therefore functional improvement is the main goal to be achieved, but very little is known about other effects such the influence on proprioception. There are references that indicate an effect on reflex arcs after a certain stimulus on the wrist, and thus, changes in proprioception may come along with a surgical denervation. This systematic review was conducted to investigate if there is evidence that assesses the influence of surgical wrist denervation on proprioceptive changes and the methods that were used. Very few articles describe an effect of denervation on the proprioception of the wrist. Reliable tests to measure proprioception are rare. Such tests exist but still they comprise bias and lack of minimation of other influences such as optic input. Subject of further investigation should be proprioception itself and methods to test this quality objectively.

Level II, risk/prognostic study.

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