Inciting Events Associated With Lumbar Facet Joint Pain.

BACKGROUND: Low back pain is the leading cause of years lost to disability with approximately 15%-25% of the chronic back pain population suffering from lumbar facet arthropathy. No large-scale study has sought to systematically identify inciting events for lumbar facet arthropathy. The aim of this study is to quantify the proportion of individuals with lumbar facetogenic pain who report a specific precipitating event(s) and to determine if there is a correlation between these events and treatment outcome. METHODS: Institutional electronic medical records were searched based on the current procedural terminology (CPT) codes representing lumbar facet joint radiofrequency ablation for procedures performed between January 2007 and December 2015. All patients had obtained >=50% pain relief based on 6-hour pain diaries after 1 or more diagnostic facet blocks. A positive outcome was defined as >=50% pain relief sustained for longer than 3-month after procedure, without additional procedural interventions. RESULTS: One thousand sixty-nine people were included in analysis. In the 52% of individuals who described an inciting event, the most commonly reported causes were falls (11%), motor vehicle collisions (11%), sports-related injuries (11%, of which weightlifting accounted for 62%), nonspine postsurgical injuries (2%), and "other" (17%). Six hundred seventeen (57.7%) individuals experienced >=50% pain relief sustained for >3 months. Patients whose pain was preceded by an inciting event were more likely to have a positive outcome than those who could not recall a specific precipitating factor (odds ratio, 1.5; confidence interval, 1.02-2.1, P = .01). Another factor associated with outcome was shorter duration of pain (8.1 +/- 9.2 vs 9.7 +/- 10.1 years, P = .02), with an observed modifier effect of age on outcomes. For a 1-year increase in age, there was a 10% increase in the odds of a positive response. CONCLUSIONS: Inciting events are common in patients diagnosed with lumbar facetogenic pain and may be associated with a positive outcome. (C) 2017 International Anesthesia Research Society

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The Effect of Glycopyrrolate on the Incidence of Hypotension and Vasopressor Requirement During Spinal Anesthesia for Cesarean Delivery: A Meta-analysis.

BACKGROUND: The objective of this meta-analysis was to determine the efficacy of glycopyrrolate at reducing spinal hypotension during cesarean delivery. METHODS: A literature search was performed to identify randomized controlled trials investigating the effect of glycopyrrolate on spinal-induced hypotension during cesarean delivery. Primary outcomes were intraoperative hypotension and vasopressor requirement (phenylephrine equivalents). Secondary outcomes included heart rate (HR), nausea and vomiting, dry mouth, and Apgar scores. Risk ratios (RRs), and mean differences (MDs) were calculated using random-effects modeling with 95% confidence intervals for primary outcomes and 99% confidence intervals for secondary outcomes. RESULTS: Five randomized controlled trials met our inclusion criteria. A total of 311 patients were included: 153 received glycopyrrolate and 158 placebo. The incidence of spinal-induced hypotension was no different with prophylactic glycopyrrolate compared to control (RR, 0.93 [0.71 1.21]; P = .59), but the total phenylephrine dose required was significantly reduced with glycopyrrolate (MD, -62.64 [micro]g [-107.61 to .17.66 [micro]g]; P = .006). The maximal HR achieved in the glycopyrrolate group was significantly higher compared to controls (MD, 15.85 bpm [5.40- 26.31]; P

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Comparison of Registered and Reported Outcomes in Randomized Clinical Trials Published in Anesthesiology Journals.

BACKGROUND: Randomized clinical trials (RCTs) provide high-quality evidence for clinical decision-making. Trial registration is one of the many tools used to improve the reporting of RCTs by reducing publication bias and selective outcome reporting bias. The purpose of our study is to examine whether RCTs published in the top 6 general anesthesiology journals were adequately registered and whether the reported primary and secondary outcomes corresponded to the originally registered outcomes. METHODS: Following a prespecified protocol, an electronic database was used to systematically screen and extract data from RCTs published in the top 6 general anesthesiology journals by impact factor (Anaesthesia, Anesthesia & Analgesia, Anesthesiology, British Journal of Anaesthesia, Canadian Journal of Anesthesia, and European Journal of Anaesthesiology) during the years 2007, 2010, 2013, and 2015. A manual search of each journal's Table of Contents was performed (in duplicate) to identify eligible RCTs. An adequately registered trial was defined as being registered in a publicly available trials registry before the first patient being enrolled with an unambiguously defined primary outcome. For adequately registered trials, the outcomes registered in the trial registry were compared with the outcomes reported in the article, with outcome discrepancies documented and analyzed by the type of discrepancy. RESULTS: During the 4 years studied, there were 860 RCTs identified, with 102 RCTs determined to be adequately registered (12%). The proportion of adequately registered trials increased over time, with 38% of RCTs being adequately registered in 2015. The most common reason in 2015 for inadequate registration was registering the RCT after the first patient had already been enrolled. Among adequately registered trials, 92% had at least 1 primary or secondary outcome discrepancy. In 2015, 42% of RCTs had at least 1 primary outcome discrepancy, while 90% of RCTs had at least 1 secondary outcome discrepancy. CONCLUSIONS: : Despite trial registration being an accepted best practice, RCTs published in anesthesiology journals have a high rate of inadequate registration. While mandating trial registration has increased the proportion of adequately registered trials over time, there is still an unacceptably high proportion of inadequately registered RCTs. Among adequately registered trials, there are high rates of discrepancies between registered and reported outcomes, suggesting a need to compare a published RCT with its trial registry entry to be able to fully assess the quality of the study. If clinicians base their decisions on evidence distorted by primary outcome switching, patient care could be negatively affected. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. (C) 2017 International Anesthesia Research Society

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Low End-Tidal Carbon Dioxide at the Onset of Emergent Trauma Surgery Is Associated With Nonsurvival: A Case Series.

BACKGROUND: End-tidal carbon dioxide (EtCO2) is a valuable marker of the return of adequate circulation following cardiac arrest due to medical causes. Previously, the prognostic value of capnography in trauma has been studied among limited populations in prehospital and emergency department settings. We aimed to investigate the relationship between early intraoperative EtCO2 and nonsurvival of patients undergoing emergency surgery at a level 1 academic trauma center as a case series. If there is a threshold below which survival was extremely unlikely, it might be useful in guiding decision-making in the early termination of futile resuscitative efforts. METHODS: Following institutional review board approval, a data set was created to investigate the relationship between EtCO2 values at the onset of emergent trauma surgery and nonsurvival. Patients who were admitted and transferred to the operating room (OR) directly from a resuscitation bay were identified using the Ryder Center trauma registry (October 1, 2013, to June 30, 2016). Electronic records from the hospital's anesthesia information management system were queried to identify the matching anesthesia records. The maximum EtCO2 values within 5 and 10 minutes of the onset of mechanical ventilation in the OR were determined for patients undergoing general anesthesia with mechanical ventilation. Patients were divided into 2 groups: those who were discharged from the hospital alive (survivors) and those who died in the hospital prior to discharge (nonsurvivors). The threshold EtCO2 giving a positive predictive value of 100% for in-hospital mortality was determined from a graphical analysis of the data. Association of determined threshold and mortality was analyzed using the 2-tailed Fisher exact test. RESULTS: There were 1135 patients who met the inclusion criteria. Within the first 5 minutes of the onset of mechanical ventilation in the OR, if the maximum EtCO2 value was

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Patient Survey of Referral From One Surgeon to Another to Reduce Maximum Waiting Time for Elective Surgery and Hours of Overutilized Operating Room Time.

BACKGROUND: Studies of shared (patient-provider) decision making for elective surgical care have examined both the decision whether to have surgery and patients' understanding of treatment options. We consider shared decision making applied to case scheduling, since implementation would reduce labor costs. METHODS: Study questions were presented in sequence of waiting times, starting with 4 workdays. "Assume the consultant surgeon (ie, the surgeon in charge) you met in clinic did not have time available to do your surgery within the next 4 workdays, but his/her colleague would have had time to do your surgery within the next 4 workdays. Would you have wanted to discuss with a member of the surgical team (eg, the scheduler or the surgeon) the availability of surgery with a different, equally qualified surgeon at Mayo Clinic who had time available within the next 4 workdays, on a date of your choosing?" There were 980 invited patients who underwent lung resection or cholecystectomy between 2011 and 2016; 135 respondents completed the study and 6 respondents dropped out after the study questions were displayed. RESULTS: The percentages of patients whose response to the study questions was "4 days" were 58.8% (40/68) among lung resection patients and 58.2% (39/67) among cholecystectomy patients. The 97.5% 2-sided confidence interval for the median maximum wait was 4 days to 4 days. Patients' choices for the waiting time sufficient to discuss having another surgeon perform the procedure did not differ between procedures (P = .91). Results were insensitive to patients' sex, age, travel time to hospital, or number of office visits before surgery (all P >= .20). CONCLUSIONS: Our results indicate that bringing up the option with the patient of changing surgeons when a colleague is available and has the operating room time to perform the procedure sooner is being respectful of most patients' individual preferences (ie, patient-centered). (C) 2017 International Anesthesia Research Society

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Abnormal Calcium Levels During Trauma Resuscitation Are Associated With Increased Mortality, Increased Blood Product Use, and Greater Hospital Resource Consumption: A Pilot Investigation.

BACKGROUND: Admission hypocalcemia predicts both massive transfusion and mortality in severely injured patients. However, the effect of calcium derangements during resuscitation remains unexplored. We hypothesize that any hypocalcemia or hypercalcemia (either primary or from overcorrection) in the first 24 hours after severe injury is associated with increased mortality. METHODS: All patients at our institution with massive transfusion protocol activation from January 2013 through December 2014 were identified. Patients transferred from another hospital, those not transfused, those with no ionized calcium (Ca2+) measured, and those who expired in the trauma bay were excluded. Hypocalcemia and hypercalcemia were defined as any level outside the normal range of Ca2+ at our institution (1-1.25 mmol/L). Receiver operator curve analysis was also used to further examine significant thresholds for both hypocalcemia and hypercalcemia. Hospital mortality was compared between groups. Secondary outcomes included advanced cardiovascular life support, damage control surgery, ventilator days, and intensive care unit days. RESULTS: The massive transfusion protocol was activated for 77 patients of whom 36 were excluded leaving 41 for analysis. Hypocalcemia occurred in 35 (85%) patients and hypercalcemia occurred in 9 (22%). Mortality was no different in hypocalcemia versus no hypocalcemia (29% vs 0%; P = .13) but was greater in hypercalcemia versus no hypercalcemia (78% vs 9%; P

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Crisis Management in Acute Care Settings: Human Factors and Team Psychology in a High-Stakes Environment, 3rd ed.

No abstract available

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Implementation of a Standardized Transfusion Protocol for Cardiac Patients Treated With Venoarterial Extracorporeal Membrane Oxygenation Is Associated With Decreased Blood Component Utilization and May Improve Clinical Outcome.

BACKGROUND: Extracorporeal membrane oxygenation supplies oxygenated blood to the body supporting the heart and lungs. Survival rates of 20% to 50% are reported among patients receiving ECMO for cardiac arrest, severe cardiogenic shock, or failure to wean from cardiopulmonary bypass following cardiac surgery. Bleeding is one of the most common complications in ECMO patients due to coagulopathy, systemic anticoagulation, and the presence of large bore cannulas at systemic pressure. Absence of a standardized transfusion protocol in this population leads to inconsistent transfusion practices. Here, we assess a newly developed dedicated transfusion protocol in this clinical setting. METHODS: Data were retrospectively reviewed for the first 30 consecutive cardiac ECMO patients prior and post implementation of the ECMO transfusion protocol. Diagnoses, laboratory results, blood component utilization, and outcomes were collected and analyzed. RESULTS: Comorbidities were similar between the 2 eras, as well as the pre-ECMO ejection fraction (P = .568) and duration on ECMO (P = .278). Transfusion utilization data revealed statistically significant decreases in almost all blood components and a savings in blood component acquisition costs of 51% ($175, 970). In addition, an almost 2-fold increase in survival rate was observed in the post-ECMO transfusion protocol era (63% vs 33%; relative risk = 1.82; 95% confidence interval, 1.07-3.10; P = .028). CONCLUSIONS: Our data indicate that implementation of a standardized transfusion protocol, using more restrictive transfusion indications in cardiac ECMO patients, was associated with reduced blood product utilization, decreased complications, and improved survival. This multidepartmental approach facilitates better communication and adherence to consensus clinical decision making between intensive care unit, surgery, and transfusion service and optimizes care of complicated and acutely ill patients. (C) 2017 International Anesthesia Research Society

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Treatment of Hyponatremic Encephalopathy in the Critically Ill.

Objectives: Hyponatremic encephalopathy, symptomatic cerebral edema due to a low osmolar state, is a medical emergency and often encountered in the ICU setting. This article provides a critical appraisal and review of the literature on identification of high-risk patients and the treatment of this life-threatening disorder. Data Sources, Study Selection, and Data Extraction: Online search of the PubMed database and manual review of articles involving risk factors for hyponatremic encephalopathy and treatment of hyponatremic encephalopathy in critical illness. Data Synthesis: Hyponatremic encephalopathy is a frequently encountered problem in the ICU. Prompt recognition of hyponatremic encephalopathy and early treatment with hypertonic saline are critical for successful outcomes. Manifestations are varied, depending on the extent of CNS's adaptation to the hypoosmolar state. The absolute change in serum sodium alone is a poor predictor of clinical symptoms. However, certain patient specific risks factors are predictive of a poor outcome and are important to identify. Gender (premenopausal and postmenopausal females), age (prepubertal children), and the presence of hypoxia are the three main clinical risk factors and are more predictive of poor outcomes than the rate of development of hyponatremia or the absolute decrease in the serum sodium. Conclusions: In patients with hyponatremic encephalopathy exhibiting neurologic manifestations, a bolus of 100 mL of 3% saline, given over 10 minutes, should be promptly administered. The goal of this initial bolus is to quickly treat cerebral edema. If signs persist, the bolus should be repeated in order to achieve clinical remission. However, the total change in serum sodium should not exceed 5 mEq/L in the initial 1-2 hours and 15-20 mEq/L in the first 48 hours of treatment. It has recently been demonstrated in a prospective fashion that 500 mL of 3% saline at an infusion rate of 100 mL per hour can be given safely. It is critical to recognize the early signs of cerebral edema (nausea, vomiting, and headache) and intervene with IV 3% sodium chloride as this is the time to intervene rather than waiting until more severe symptoms develop. Cerebral demyelination is a rare complication of overly rapid correction of hyponatremia. The principal risk factors for cerebral demyelination are correction of the serum sodium more than 25 mEq/L in the first 48 hours of therapy, correction past the point of 140 mEq/L, chronic liver disease, and hypoxic/anoxic episode. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Corynebacterium striatum as an Unusual Case of Endocarditis in an Intravenous Drug User: Case Report and Review of the Literature.

A 59-year-old man, with a history of intravenous drug use, was admitted for 1 week of intermittent fever after a year of recurrent bouts of cellulitis. He quickly defervesced on empiric antibiotic therapy. Admission blood cultures were positive for Corynebacterium striatum as were wound cultures, which also grew methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus. A holosystolic murmur was heard. His transthoracic echocardiogram showed mitral valve prolapse, regurgitation, and a flail leaflet. The transesophageal echocardiogram revealed small perforations and a vegetation of the mitral valve. The endocarditis was successfully treated with surgical repair of the mitral valve and 6 weeks of intravenous vancomycin. Corynebacterium striatum is an unusual cause of endocarditis. It should not be dismissed as a contaminant in patients with risk factors for endocarditis. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Cytomegalovirus Infection in the Era of Preemptive Strategy in Allogeneic Hematopoietic Cell Transplant Recipients: Progression From Viremia to Disease Remains Rare But Unpredictable.

Objective: The aim of this study was to describe our experience with, and identify risk factors associated with, breakthrough cytomegalovirus disease (CMVD) in allogeneic hematopoietic stem cell transplant during regular monitoring and preemptive therapy for CMV viremia. Methods: This was a retrospective study comparing allogeneic hematopoietic stem cell transplant recipients who developed CMVD despite a preemptive treatment strategy to patients with CMV viremia without CMVD. Results: Of 104 recipients transplanted at a single institution, who developed CMV viremia and/or disease, we identified 15 cases of biopsy-proven CMVD and 74 recipients with CMV viremia alone; 30 of 74 were included as control subjects after appropriate surveillance. The rate of CMVD was low at 5%. While patients are monitored for CMV viremia, CMVD was the presenting manifestation of CMV infection in the majority of cases (60%), and 40% did not have viremia at the time of diagnosis. No one risk factor predicted CMVD. Patients with CMVD tended to have high-risk CMV serostatus, moderate to severe graft-versus-host disease, and to have higher mortality rate. Conclusions: Preemptive strategy with targeted therapy to patients with CMV viremia is effective with rare and unpredictable events of breakthrough CMVD. Patients with high-risk CMV serostatus and moderate to severe graft-versus-host disease may need more vigilant observation. Cytomegalovirus disease may occur without viremia requiring close monitoring for symptoms suggestive of CMVD. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Diverticulitis in the Neutropenic Patient.

Diverticulitis is a common gastrointestinal disease; however, it is rarely described in patients with immunosuppression. Neutropenic patients who present with fever and gastrointestinal symptoms such as abdominal pain, diarrhea, and rectal bleeding are suspected to have Clostridium difficile colitis or typhlitis. However, a third possibility, diverticulitis, should be considered and can lead to complications of perforation and sepsis. Acute diverticulitis in the setting of neutropenia is rarely reported in the literature. We present 2 cases of diverticulitis in neutropenic patients with acute myeloid leukemia. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Presumptive Treatment of Chlamydia and Gonorrhea Infections in a Canadian Ambulatory Emergency Department Setting: Determination of Overtreatment and Undertreatment Rates.

Objectives: Presumptive antibiotic treatment may be given for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) infections before a laboratory diagnosis is established, but overtreatment can increase resistance rates. We sought to determine the presumptive treatment prevalence in our emergency department (ED) setting, as well as the number of overtreated and undertreated patients. Methods: We performed a retrospective cohort study of all patients tested for CT/GC in an urban academic ED during a 6-month period in 2015. Presumptive treatment prevalence, overtreatment and undertreatment proportions, and CT- and GC-positive test proportions were calculated with 95% Wald confidence interval (CI) and compared across age and sex. Results: Of 209 included cases (male n = 3, female n = 206), 27 (13%; CI, 8%-18%) received presumptive treatment for CT and 19 (9%; CI, 5%-14%) for GC. Seven cases (3%; CI, 1%-6%) were positive for CT and 0 for GC. Of the 7 CT-positive cases, 2 (29%) received presumptive treatment in the ED, and 5 (71%) were treated after the positive test results were obtained. There was no loss to follow-up. Mean delay to treatment was 10 days, including a mean of 3 days for laboratory analysis. Overtreatment and undertreatment proportions were 93% (CI, 83%-100%) and 3% (CI, 0%-5%) for CT and 100% and 0% for GC, respectively. Positive test result, presumptive treatment, overtreatment, and undertreatment were not associated with age or sex. Conclusions: Given the low CT/GC incidence and good follow-up, at our institution, it would be reasonable to wait for a laboratory diagnosis rather than give presumptive treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Tubo-Ovarian Abscess Caused by Pasteurella multocida in a Young, Intrauterine Device-Wearing Woman Without Animal Contact: A Case Report.

Tubo-ovarian abscesses are usually caused by anaerobic bacteria alone or in mixed infection. Here, we report about a successfully treated 29-year-old patient with bilateral tubo-ovarian abscess caused by Pasteurella multocida. She had no exposure to animals. After the removal of a 1-year-old copper-T intrauterine device at the time of hospitalization, total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed by laparotomy because of the level of the inflammatory lesion of both ovaries. After the administration of antibiotic combination, the patient was discharged home on the fifth postoperative day. In the setting of a tubo-ovarian abscess, rare zoonotic pathogens, such as P. multocida, should also be considered as a causative agent of the infectious process even in the absence of direct or indirect contact with animals. It seems that the asymptomatic colonization of the vagina and the intrauterine device with P. multocida may happen also from unknown origin of the environment with the consequences of severe pelvic infection with tubo-ovarian abscess formation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Vancomycin-Induced Nephrotoxicity in Adolescents Receiving Extended Infusion: Case Series.

Because of concerns of red man syndrome, our institution increased standard vancomycin infusion duration to 90 minutes for 1000-mg doses and 120 minutes for 2000-mg doses. However, in children and adolescents, the dosing interval remained every 6 to 8 hours. The purpose of this pilot study was to identify the incidence of supratherapeutic vancomycin serum concentrations (VSCs) and nephrotoxicity with extended-infusion vancomycin (>=90 minutes). Of the 7 adolescents who received extended-infusion vancomycin, 1 (14.2%) experienced supratherapeutic VSC and nephrotoxicity. Extended-infusion vancomycin for red man syndrome should include assessment of the dosing interval and frequent VSC monitoring if a 6-hour interval is indicated. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Primary Neuroleptospirosis: A Case Report and Literature Review.

Leptospirosis is a highly prevalent, globally distributed zoonosis with an incidence 10 times higher in tropical regions, where the proportion of new cases correlates with rainy seasons. Secondary effects to the central nervous system in the immune phase of the illness typically manifest as aseptic meningitis. However, neurologic sequelae can be diverse and, although rare, other central and peripheral neurologic presentations have been described including the Guillain-Barre syndrome. Neuroleptospirosis as a primary disease manifestation is even more unusual. Below, we present the case of a 27-year-old woman with a Guillain-Barre-like syndrome as a primary manifestation of neuroleptospirosis as confirmed by positive IgM serology test result in paired samples and microscopic agglutination test reactive for Leptospira icterohaemorrhagiae in the convalescent phase. The patient had a favorable clinical outcome after treatment with antibiotics, corticosteroids, ventilator support, and physical therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A Comparison of Nephrotoxicity in Non-Intensive Care Unit Medical-Surgical Patients Receiving Vancomycin Alone Versus Vancomycin With Piperacillin-Tazobactam.

Background: Recent studies have identified an increase in nephrotoxicty in patients receiving vancomycin plus piperacillin-tazobactam (PT) when compared with vancomycin monotherapy. To date, studies have evaluated all hospitalized patients or intensive care unit patients only. The purposes of this study were to examine the incidence of acute kidney injury (AKI) in patients who received vancomycin either as monotherapy or with PT in a non-intensive care unit medical-surgical setting and to identify potential risk factors for the development of AKI. Methods: A retrospective chart review was performed to identify patients who received vancomycin either as monotherapy or in combination with PT for at least 48 hours. Patients were evaluated for development of AKI, defined as serum creatinine increase of 50% from baseline. Statistical analysis included demographic, univariate, and multivariable analyses. Results: One hundred eighty-nine patients met inclusion criteria. More patients in the vancomycin + PT group developed AKI than in the vancomycin monotherapy group (18.4% vs 5.6%, P = 0.008). After multivariable logistic regression of patients receiving vancomycin, PT, African American, and perioperative patients remained statistically associated with AKI. These risk factors gave odds ratios of 3.9, 3.8, and 4.0, respectively. Conclusions: Patients receiving PT in addition to vancomycin were more likely to develop AKI compared with those receiving vancomycin monotherapy. African American and perioperative patients may have a higher risk. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Experience of Treating Patients With Multidrug-Resistant Tuberculosis at a Public Health Hospital in Boston.

Background: Management of patients with multidrug-resistant tuberculosis (MDR-TB) is challenging and resource intensive. We describe demographic/clinical characteristics, management, and outcomes of patients with MDR-TB in a designated TB unit in a public health hospital located in Boston, Massachusetts. Methods: Records of 42 patients treated for MDR-TB between 1993 and 2014 were reviewed. Data were extracted from paper/electronic medical records. Results: Forty-two patients were treated for MDR-TB between 1993 and 2014. The mean age was 41.9 years (17-78 years); 35 patients (83%) were foreign born. Thirty-three patients (78%) were diagnosed as having pulmonary TB, 5 (12%) as having extrapulmonary disease, and 4 (10%) as having both pulmonary and extrapulmonary TB. Thirty-six patients (86%) received an injectable agent; half received injectable therapy for 4 months or less. Fourteen (33%) received inhaled aminoglycosides. Mean time to culture conversion was 3.4 months. Thirty-three patients (79%) required admission to the inpatient unit for respiratory isolation, psychosocial reasons, or management of acute toxicities. Duration of treatment ranged from 10 to 29 months. All patients successfully completed therapy. There were no deaths. Conclusions: All patients demonstrated clinical improvement and culture conversion, where appropriate, without relapse. Despite variations in treatment regimens, a significant number of individuals were cured with less than the recommended 6 months of injectable therapy. Given the complexity of second-line drugs and associated toxicities, the treatment of MDR-TB should be reserved for those with experience in this area with the support of a strong public health infrastructure to aid in this endeavor. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Lung Abscess Due to Aspergillus lentulus and Pseudomonas aeruginosa in a Patient With Granulomatosis With Polyangiitis: Case and Review of the Literature.

Aspergillus lentulus has been recognized within Aspergillus section Fumigati as a phenotypically similar but genetically distinct species, displaying reduced susceptibility to antifungal agents. It has been described as a cause of invasive aspergillosis in patients who underwent hematopoietic stem cell transplantation, solid organ transplant recipients, those on prolonged corticosteroid therapy, or in patients with structural lung disease including chronic obstructive pulmonary disease. We report a case of successful treatment of probable invasive pulmonary aspergillosis due to A. lentulus and polymicrobial infection with Pseudomonas aeruginosa in a patient with relapsing granulomatosis with polyangiitis and recent high-dose steroid therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of Antimicrobial Stewardship Consultation Service at an Academic Institution.

Background: Antimicrobial stewardship programs (ASPs) aim to optimize antimicrobial use to decrease resistance and acquisition of hospital-acquired infections, improve patient outcomes, and reduce health care costs. We evaluated interventions and outcomes associated with a dedicated stewardship consult service staffed by physician assistant with supervision from infectious disease physician. Methods: This was a retrospective study of electronic medical records of adult patients evaluated by the ASP team from November 2012 to December 2013 in an 802-bed teaching hospital in Detroit, Mich. Hospice patients were excluded. Patient characteristics, type of infection, microbiological cultures, antimicrobials utilized, interventions performed, and clinical outcomes were assessed. Results: Three hundred thirty-five patients met the inclusion criteria. Median age was 67 years, and 52% were male. The most common infections were lower respiratory (28%) and urinary tract infections (21%). However, 24% were diagnosed as having no infection, and of these, 67% had asymptomatic bacteriuria. Escherichia coli (21%) and methicillin-resistant Staphylococcus aureus (14%) were most frequently isolated pathogens. The ASP team denied 38% of peripherally inserted central catheter requests and recommended intravenous-to-oral conversion in 38% cases, discontinuation of antibiotics in 27%, and de-escalation of therapy in 13%. Vancomycin (18%) and quinolones (16%) were the most commonly prescribed antibiotics. The majority of patients (95%) had clinical success, whereas very few developed Clostridium difficile infection (1.5%) or had infection-related readmission (2%) within 30 days. Conclusions: Our ASP consult service reduced unnecessary peripherally inserted central catheter placement and antimicrobial use with favorable clinical success and patient outcomes. In light of the new regulatory ASP requirements, a midlevel provider may be beneficial to and an integral part of an infectious disease physician-supervised stewardship team. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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An Unusual Cause of a Prostatic Abscess: Tuberculosis.

Prostatic abscesses are most commonly caused by bacterial uropathogens, but may also be due to fungi or mycobacteria. We present a case of disseminated tuberculous infection presenting as a prostatic abscess. Genitourinary tract tuberculous is an uncommon clinical entity, with prostatic involvement being the least common form. Diagnosis is by acid-fast bacilli smear and culture of prostatic fluid/tissue, with polymerase chain reaction as an emerging tool for the early recognition of these infections. Treatment is with prostatic debridement and initiation of standard 4-drug antituberculosis medications. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Successful Primary Therapy With Posaconazole for Fulminant Progressive Disseminated Histoplasmosis in a Renal Transplant Recipient.

For severe cases of progressive disseminated histoplasmosis (PDH), Infectious Diseases Society of America recommends treatment with liposomal amphotericin B for 2 weeks followed by itraconazole. In patients who are at risk for renal failure and for renal transplant patients on multiple nephrotoxic medications, there are no alternatives currently in clinical use. Posaconazole has shown promise in the animal experiments and also as salvage therapy in patients who have failed therapy with polyene and azole antifungal agents. Posaconazole has seldom been used as an initial drug for severe cases of PDH. We report a case of a renal transplant patient with severe PDH, on immunosuppressive therapy, successfully treated with posaconazole. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Evaluation of Clinical Outcomes With Various Meropenem Dosing Regimens in Septic Patients.

Background: Studies have demonstrated equal efficacy between meropenem 500 mg intravenously every 6 hours and 1000 mg intravenously every 8 hours. Few critically ill patients were included in these studies, and theoretical pharmacokinetic and pharmacodynamic concerns exist with the more conservative dosing regimen. We sought to compare the efficacy of these 2 dosing regimens in septic patients at our institution. Methods: A retrospective, single-center, cohort study was performed comparing 2 meropenem dosing regimens in septic patients admitted to 5 intensive care units at the University of North Carolina Medical Center. The primary outcome was rate of clinical success at 7, 10, and 14 days. Secondary outcomes included time to clinical success, rate of microbiologic failure, in-hospital mortality, meropenem-related mortality, and intensive care units and hospital length of stay. Results: One hundred seventeen patients meeting inclusion and exclusion criteria were analyzed. Clinical success at 7 (69% vs 81.8%; P = 0.163), 10 (76.2% vs 84.8%; P = 0.403), and 14 days (84.5% vs 87.9%; P = 0.591) did not differ significantly between the meropenem 500 mg and 1000 mg groups, respectively. There were higher rates of in-hospital (29.6% vs 14.2%, P = 0.290) and meropenem-related mortality (10.7% vs 6.1%; P = 0.792) and microbiological failure (4.2% vs 0%; P = 0.269) in patients in the 500 mg group. Conclusions: There was not a statistically significant difference in rates of clinical success at 7, 10, and 14 days in septic patients in the meropenem 500 mg group compared with the 1000 mg group. Caution should be used when extrapolating the more conservative dosing strategy to critically ill patients. A larger, matched retrospective analysis or prospective study would be beneficial in determining if these dosing regimens can be used interchangeably in this population. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Geographic Variation in Mentally Unhealthy Days: Air Pollution and Altitude Perspectives

High Altitude Medicine & Biology , Vol. 0, No. 0.


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PD-1/PD-L1 as a prognostic factor in leukemia

Abstract

PD-1 receptor is a component of the immune system that is recognized as a negative regulator of immune responses together with its ligand (PD-L1). In this study, we review the role of the immune system in leukemia cells through PD-1 and its ligand. Relevant literature was identified by a Pubmed search (1994–2017) of English-language papers using the terms "PD-1", "PD-L1", "leukemia", and "prognosis". PD-1 is an inhibitory receptor of CD28 family. Although initially introduced as a driving factor of apoptosis in the activated T cells, pre-clinical studies revealed the importance of this molecule as a checkpoint in ambient tolerance of the immune system. The ligand of this molecule is widely expressed on malignant cells in leukemia and inhibits the cytotoxic T cells. Therefore, targeting PD-1/PD-L1 can sensitize the malignant cells to chemotherapy and increase patient's survival as a therapeutic approach. Recently, immunotherapy has shown promising results in pre-clinical studies using antibodies against PD-1/PD-L1 in different cancers, and it is hoped that the application of these antibodies in combination with other treatments (including chemotherapy) could inhibit leukemia cells and improve the patient's conditions.

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Drugs and obstructive sleep apnoea

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PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression

Purpose: To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression.

Experimental Design: Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.

Results: PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo.

Conclusions: Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer. Clin Cancer Res; 23(14); 3711–20. ©2017 AACR.

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Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics

Purpose: The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance.

Experimental Design: RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients (n = 13) and controls (n = 10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines.

Results: A total of 418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (P_BC) based on expression of three markers (ROBO1, WNT5A, and CDC42BPB). Setting P_BC = 0.45 as the cutoff for a positive test, urine testing using the three-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the three-marker panel in the independent validation cohort yielded an AUC of 0.87 and overall 83% sensitivity and 89% specificity.

Conclusions: Urine-based molecular diagnostics using this three-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis. Clin Cancer Res; 23(14); 3700–10. ©2017 AACR.

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DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma

Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.

Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.

Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes.

Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. Clin Cancer Res; 23(14); 3610–8. ©2017 AACR.

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Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies

Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose–response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489–98. ©2017 AACR.

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CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.

Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.

Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3–6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.

Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684–91. ©2017 AACR.

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Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells

Purpose: The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used for in vivo stimulation.

Experimental Design: We generated GMP-compliant, GD2.CAR-modified VZVSTs from healthy donors and cancer patients by stimulation of peripheral blood mononuclear cells with overlapping peptide libraries spanning selected VZV antigens, then tested their ability to recognize and kill GD2- and VZV antigen–expressing target cells.

Results: Our choice of VZV antigens was validated by the observation that T cells specific for these antigens expanded in vivo after VZV vaccination. VZVSTs secreted cytokines in response to VZV antigens, killed VZV-infected target cells and limited infectious virus spread in autologous fibroblasts. However, while GD2.CAR–modified VZVSTs killed neuroblastoma cell lines on their first encounter, they failed to control tumor cells in subsequent cocultures. Despite this CAR-specific dysfunction, CAR-VZVSTs retained functional specificity for VZV antigens via their TCRs and GD2.CAR function was partially rescued by stimulation through the TCR or exposure to dendritic cell supernatants.

Conclusions: Vaccination via the TCR may provide a means to reactivate CAR-T cells rendered dysfunctional by the tumor microenvironment (NCT01953900). Clin Cancer Res; 23(14); 3499–509. ©2017 AACR.

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Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Purpose: The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML.

Experimental Design: We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531.

Results: There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measured by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT, FLT3/ITD, or FLT3/ALM (P = 0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (P < 0.001), KMT2A rearrangements (P = 0.009), and inversely associated with inv(16)/t(16;16) (P < 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression.

Conclusions: FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 cell surface expression in pediatric AML. Clin Cancer Res; 23(14); 3649–56. ©2017 AACR.

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Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial

Purpose: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFN production, and iNKT IFN production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB–IV melanoma.

Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 10⁹ cells.

Results: Expanded iNKT cells produced IFN, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1–2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFN responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters.

Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510–9. ©2017 AACR.

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Exposure-Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients

Purpose: To elucidate any differences in the exposure–response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.

Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure–response relationships using unbound flavopiridol AUC were explored using recursive partitioning.

Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).

Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m²/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m²/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592–600. ©2017 AACR.

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Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.

Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.

Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.

Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520–8. ©2016 AACR.

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Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.

Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.

Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).

Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628–37. ©2017 AACR.

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Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC)

Purpose: ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase I study determined the MTD, pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2-positive advanced solid tumors, with an expansion cohort of patients with HER2⁺ MBC.

Experimental Design: ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).

Results: Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2⁺ MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2⁺ MBC (n = 22) treated at doses ≥ MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease ≥ 24 weeks) was 27%.

Conclusions: ONT-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR inhibitors and showed notable antitumor activity in heavily pretreated HER2⁺ MBC patients, supporting its continued development. Clin Cancer Res; 23(14); 3529–36. ©2017 AACR.

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Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer

Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions.

Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE).

Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOE_MTR (NOE_MTR,necrosis = 8.9 ± 0.9%, NOE_{MTR,progression} = 12.6 ± 1.6%, P < 0.0001) and Amide_MTR (Amide_MTR,necrosis = 8.2 ± 1.0%, Amide_{MTR,progression} = 12.0 ± 1.9%, P < 0.0001). MT (MT_necrosis = 4.7 ± 1.0%, MT_progression = 6.7 ± 1.7%, P = 0.009) and NOE_AUC (NOE_AUC,necrosis = 4.3 ± 2.0% Hz, NOE_{AUC,progression} = 7.2 ± 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values.

Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOE_MTR and Amide_MTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667–75. ©2017 AACR.

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Body Composition as a Predictor of Toxicity in Patients Receiving Anthracycline and Taxane-Based Chemotherapy for Early-Stage Breast Cancer

Purpose: Poor body composition metrics (BCM) are associated with inferior cancer outcomes; however, in early breast cancer (EBC), there is a paucity of evidence regarding the impact of BCM on toxicities. This study investigates associations between BCM and treatment-related toxicity in patients with EBC receiving anthracyclines and taxane–based chemotherapy.

Experimental Design: Pretreatment computerized tomographic (CT) images were evaluated for skeletal muscle area (SMA), skeletal muscle density (SMD), and fat tissue at the third lumbar vertebrae. Skeletal muscle index (SMI = SMA/height²) and skeletal muscle gauge (SMG = SMI x SMD) were also calculated. Relative risks (RR) are reported for associations between body composition measures and toxicity outcomes, after adjustment for age and body surface area (BSA).

Results: BCM were calculated for 151 patients with EBC (median age, 49 years; range, 23–75 years). Fifty patients (33%) developed grade 3/4 toxicity, which was significantly higher in those with low SMI (RR, 1.29; P = 0.002), low SMG (RR, 1.09; P = 0.01), and low lean body mass (RR, 1.48; P = 0.002). Receiver operating characteristic analysis showed the SMG measure to be the best predictor of grade 3/4 toxicity. Dividing SMG into tertiles showed toxicity rates of 46% and 22% for lowest versus highest tertile, respectively (P = 0.005). After adjusting for age and BSA, low SMG (<1,475 units) was significantly associated with hematologic (RR, 2.12; P = 0.02), gastrointestinal grade 3/4 toxicities (RR, 6.49; P = 0.02), and hospitalizations (RR, 1.91; P = 0.05).

Conclusions: Poor BCMs are significantly associated with increased treatment-related toxicities. Further studies are needed to investigate how these metrics can be used to more precisely dose chemotherapy to reduce treatment-related toxicity while maintaining efficacy. Clin Cancer Res; 23(14); 3537–43. ©2017 AACR.

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Correction: UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

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Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).

Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.

Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.

Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

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Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.

Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.

Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%–17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.

Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601–9. ©2017 AACR.

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Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma

Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).

Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of pralatrexate plus oral bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m² given weekly 3 weeks out of 4 weeks with daily oral bexarotene (150 or 300 mg/m²), levothyroxine, atorvastatin, folate, and with B12 every 2 months.

Results: At the MTD of 15 mg/m² bexarotene and 15 mg/m² pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5–29.9). Mucositis was the most common adverse event.

Conclusions: The combination of pralatrexate (15 mg/m²) and oral bexarotene (150 mg/m²) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552–6. ©2017 AACR.

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Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sezary Syndrome

Purpose: KIR3DL2 is a recently discovered marker of the malignant clonal cell population in Sézary syndrome. We intended to evaluate the expression of KIR3DL2 on blood T cells as a diagnostic, prognostic, and follow-up marker of Sézary syndrome.

Experimental Design: Sixty-four patients diagnosed with Sézary syndrome were included in this monocentric study. We collected the percentage of KIR3DL2⁺ cells among CD3⁺ T cells, obtained by flow cytometry, and other classical diagnostic criteria for Sézary syndrome at diagnosis and during the follow-up.

Results: Compared with the classical diagnostic factors, KIR3DL2 was the most sensitive diagnostic factor for Sézary syndrome. Univariate and multivariate analyses established that an eosinophil cell count >700/mm³ and a percentage of KIR3DL2⁺ cells within the CD3⁺ T cells >85% at diagnosis were associated with a significantly reduced disease-specific survival. Moreover, KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, the detection of the residual disease following treatment, and the occurrence of relapse, even though patients clinically experienced complete remission and/or undetectable circulating Sézary cells by cytomorphologic analysis.

Conclusions: We show that KIR3DL2 expression is the most sensitive diagnostic criterion of Sézary syndrome when compared with all other available biological criteria. It also represents the best independent prognostic factor for Sézary syndrome–specific death and the most relevant feature for the follow-up of Sézary syndrome, showing the invasion of the functional lymphocytes pool by Sézary cells. KIR3DL2 therefore represents a valuable tool for routine use as a clinical parameter at diagnosis, for prognosis and during patient follow-up. Clin Cancer Res; 23(14); 3619–27. ©2017 AACR.

http://ift.tt/2tSwlNM

Quaternary 2D Transition Metal Dichalcogenides (TMDs) with Tunable Bandgap

Alloying/doping in 2D material is important due to wide range bandgap tunability. Increasing the number of components would increase the degree of freedom which can provide more flexibility in tuning the bandgap and also reduces the growth temperature. Here, synthesis of quaternary alloys Mo_xW_1−xS_2ySe_2(1−y) is reported using chemical vapor deposition. The composition of alloys is tuned by changing the growth temperatures. As a result, the bandgap can be tuned which varies from 1.61 to 1.85 eV. The detailed theoretical calculation supports the experimental observation and shows a possibility of wide tunability of bandgap.

Increasing the number of components in transition metal dichalcogenides can result in broad range of bandgap tuning. The authors have synthesized four (quaternary) (MoWSSe) component alloys of different compositions by changing the precursors and the temperature used in chemical vapor deposition. The bandgap is tuned from 1.61 to 1.85 eV.

http://ift.tt/2tSIT7R

Bulk Bismuth as a High-Capacity and Ultralong Cycle-Life Anode for Sodium-Ion Batteries by Coupling with Glyme-Based Electrolytes

Sodium-ion batteries (SIBs) have attracted great interest for large-scale electric energy storage in recent years. However, anodes with long cycle life and large reversible capacities are still lacking and therefore limiting the development of SIBs. Here, a bulk Bi anode with surprisingly high Na storage performance in combination with glyme-based electrolytes is reported. This study shows that the bulk Bi electrode is gradually developed into a porous integrity during initial cycling, which is totally different from that in carbonate-based electrolytes and ensures facile Na⁺ transport and structural stability. The achievable capacity of bulk Bi in the NaPF₆-diglyme electrolyte is high up to 400 mAh g⁻¹, and the capacity retention is 94.4% after 2000 cycles, corresponding to a capacity loss of 0.0028% per cycle. It exhibits two flat discharge/charge plateaus at 0.67/0.77 and 0.46/0.64 V, ascribed to the typical two-phase reactions of Bi NaBi and NaBi Na₃Bi, respectively. The excellent performance is attributed to the unique porous integrity, stable solid electrolyte interface, and good electrode wettability of glymes. This interplay between electrolyte and electrode to boost Na storage performance will pave a new pathway for high-performance SIBs.

The bulk Bi anode coupled with glyme-based electrolytes presents a high reversible capacity of 400 mAh g⁻¹ and capacity retention of 94.4% after 2000 cycles, corresponding to a capacity loss of 0.0028% per cycle. This is attributed to the unique porous integrity evolved during initial cycles, stable solid electrolyte interface, and good electrode wettability of glymes.

http://ift.tt/2tRYpAV

Conjugated Polymer for Voltage-Controlled Release of Molecules

Conjugated polymers are attractive in numerous biological applications because they are flexible, biocompatible, cost-effective, solution-processable, and electronic/ionic conductive. One interesting application is for controllable drug release, and this has been realized previously using organic electronic ion pumps. However, organic electronic ion pumps show high operating voltages and limited transportation efficiency. Here, the first report of low-voltage-controlled molecular release with a novel organic device based on a conjugated polymer poly(3-hexylthiophene) is presented. The releasing rate of molecules can be accurately controlled by the duration of the voltage applied on the device. The use of a handy mobile phone to remotely control the releasing process and its application in delivering an anticancer drug to treat cancer cells are also successfully demonstrated. The working mechanism of the device is attributed to the unique switchable permeability of poly(3-hexylthiophene) in aqueous solutions under a bias voltage that can tune the wettability of poly(3-hexylthiophene) via oxidation or reduction processes. The organic devices are expected to find many promising applications for controllable drug delivery in biological systems.

The first report of low-voltage-controlled molecular release in solutions with a novel organic device based on poly(3-hexylthiophene) is presented. The releasing rate can be accurately controlled by the duration of the voltage applied on the device. The use of a mobile phone to remotely control the releasing process of an anticancer drug to treat cancer cells is also successfully demonstrated.

http://ift.tt/2tSka3F

Low-Temperature Soft-Cover Deposition of Uniform Large-Scale Perovskite Films for High-Performance Solar Cells

Large-scale high-quality perovskite thin films are crucial to produce high-performance perovskite solar cells. However, for perovskite films fabricated by solvent-rich processes, film uniformity can be prevented by convection during thermal evaporation of the solvent. Here, a scalable low-temperature soft-cover deposition (LT-SCD) method is presented, where the thermal convection-induced defects in perovskite films are eliminated through a strategy of surface tension relaxation. Compact, homogeneous, and convection-induced-defects-free perovskite films are obtained on an area of 12 cm², which enables a power conversion efficiency (PCE) of 15.5% on a solar cell with an area of 5 cm². This is the highest efficiency at this large cell area. A PCE of 15.3% is also obtained on a flexible perovskite solar cell deposited on the polyethylene terephthalate substrate owing to the advantage of presented low-temperature processing. Hence, the present LT-SCD technology provides a new non-spin-coating route to the deposition of large-area uniform perovskite films for both rigid and flexible perovskite devices.

For solvent-rich scalable processes, solvents in liquid films are thermally evaporated to form solid films. Due to the temperature difference during heating, the surface tension difference in perovskite precursor is established and drives the convection to form film defects in cellular patterns. The cellular defects can be eliminated via soft-cover deposition through a strategy of surface tension relaxation.

http://ift.tt/2tSfTgq

A rule-based electronic phenotyping algorithm for detecting clinically relevant cardiovascular disease cases

The implementation of electronic medical records (EMR) is becoming increasingly common. Error and data loss reduction, patient-care efficiency increase, decision-making assistance and facilitation of event sur...

http://ift.tt/2uY4GLH

Effects of additional team-based learning on students’ clinical reasoning skills: a pilot study

In the field of Neurology good clinical reasoning skills are essential for successful diagnosing and treatment. Team-based learning (TBL), an active learning and small group instructional strategy, is a promis...

http://ift.tt/2upar7S

NAP: The Network Analysis Profiler, a web tool for easier topological analysis and comparison of medium-scale biological networks

Nowadays, due to the technological advances of high-throughput techniques, Systems Biology has seen a tremendous growth of data generation. With network analysis, looking at biological systems at a higher leve...

http://ift.tt/2uY4DPM

Time to immunologic recovery and determinant factors among adults who initiated ART in Felege Hiwot Referral Hospital, northwest Ethiopia

CD4 cells are the major targets for human immunodeficiency virus (HIV) and treatment with Antiretroviral Therapy (ART) influences the CD4 cell count of HIV patients. In addition to ART, the time required to re...

http://ift.tt/2up9jkJ

Burden and associated factors of anemia among pregnant women attending antenatal care in southern Ethiopia: cross sectional study

Anemia is a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiologic needs, which varies by age, sex, altitude, smoking, and pregnancy status. The ...

http://ift.tt/2uY71WP

High Conductivity and Electron-Transfer Validation in an n-Type Fluoride-Anion-Doped Polymer for Thermoelectrics in Air

Air-stable and soluble tetrabutylammonium fluoride (TBAF) is demonstrated as an efficient n-type dopant for the conjugated polymer ClBDPPV. Electron transfer from F⁻ anions to the π-electron-deficient ClBDPPV through anion–π electronic interactions is strongly corroborated by the combined results of electron spin resonance, UV–vis–NIR, and ultraviolet photoelectron spectroscopy. Doping of ClBDPPV with 25 mol% TBAF boosts electrical conductivity to up to 0.62 S cm⁻¹, among the highest conductivities that have been reported for solution-processed n-type conjugated polymers, with a thermoelectric power factor of 0.63 µW m⁻¹ K⁻² in air. Importantly, the Seebeck coefficient agrees with recently published correlations to conductivity. Moreover, the F⁻-doped ClBDPPV shows significant air stability, maintaining the conductivity of over 0.1 S cm⁻¹ in a thick film after exposure to air for one week, to the best of our knowledge the first report of an air-stable solution-processable n-doped conductive polymer with this level of conductivity. The result shows that using solution-processable small-anion salts such as TBAF as an n-dopant of organic conjugated polymers possessing lower LUMO (lowest unoccupied molecular orbital), less than −4.2 eV) can open new opportunities toward high-performance air-stable solution-processable n-type thermoelectric (TE) conjugated polymers.

Simple, air-stable, solution-processable tetrabutylammonium fluoride (TBAF) doping of an electron-deficient polymer can boost the electrical conductivity to 0.62 S cm⁻¹ and maintain it at >0.1 S cm⁻¹ in a thick film after exposure to air for one week, the first report of an air-stable solution-processable n-doped conductive polymer with this conductivity level. Electron transfer is verified using multiple techniques.

http://ift.tt/2uldgWP

Does recruitment source moderate treatment effectiveness? A subgroup analysis from the EVIDENT study, a randomised controlled trial of an internet intervention for depressive symptoms

Objective

This study aims to examine whether the effects of internet interventions for depression generalise to participants recruited in clinical settings.

Design

This study uses subgroup analysis of the results of a randomised, controlled, single-blind trial.

Setting

The study takes place in five diagnostic centres in Germany.

Participants

A total of 1013 people with mild to moderate depressive symptoms were recruited from clinical sources as well as internet forums, statutory insurance companies and other sources.

Interventions

This study uses either care-as-usual alone (control) or a 12-week internet intervention (Deprexis) plus usual care (intervention).

Main outcome measures

The primary outcome measure was self-rated depression severity (Patient Health Questionnaire-9) at 3 months and 6 months. Further measures ranged from demographic and clinical parameters to a measure of attitudes towards internet interventions (Attitudes towards Psychological Online Interventions Questionnaire).

Results

The recruitment source was only associated with very few of the examined demographic and clinical characteristics. Compared with participants recruited from clinical sources, participants recruited through insurance companies were more likely to be employed. Clinically recruited participants were as severely affected as those from other recruitment sources but more sceptical of internet interventions. The effectiveness of the intervention was not differentially associated with recruitment source (treatment by recruitment source interaction=0.28, p=0.84).

Conclusion

Our results support the hypothesis that the intervention we studied is effective across different recruitment sources including clinical settings.

Trial registration number

ClinicalTrials.gov NCT01636752.

http://ift.tt/2upjG8m

Lag time for retinoblastoma in the UK revisited: a retrospective analysis

Objectives

To explore current delays in diagnosis of retinoblastoma (Rb) and effect on outcome with comparison to a study from the 1990s.

Setting

Primary, secondary, tertiary care: majority from South of England.

Participants

A retrospective analysis of 93 new referrals of sporadic (non-familial) Rb to a specialist Rb unit in London, UK from January 2006 to February 2014.

Primary and secondary outcomes

International Intraocular Retinoblastoma Classification, lag times including parental delay and healthcare professional delay, patients requiring enucleation and requirement of adjuvant chemotherapy postenucleation (high-risk Rb).

Results

During the study period, 29% presented via accident and emergency (A&E). The median referral time from symptom onset to visiting primary care (PC) was 28 days and PC to ophthalmologist 3 days (range 0–181 days). The median time from local ophthalmologist to the Rb Unit was 6 days (0–33). No significant correlation was found between delay and International Classification of Retinoblastoma grade (p>0.05) or between postenucleation adjuvant chemotherapy and enucleation groups (p>0.05). Less enucleations (60%) are being performed compared with the previous study (81%) (p=0.0015).

Conclusions

Parents are attending A&E more compared with the 1990s and this may reflect the effect of public awareness campaigns. More eyes are being salvaged despite a similar number of children requiring adjuvant chemotherapy. High-risk Rb and Group E eyes do not correlate with increased lag time in the UK. Other determinants such as tumour biology may be more relevant.

http://ift.tt/2uY8lJk

Comorbidities, complications and mortality in people of South Asian ethnicity with type 1 diabetes compared with other ethnic groups: a systematic review

Objective

The aim of this systematic review is to explore the association of South Asian (SA) ethnicity on comorbidities, microvascular and macrovascular complications and mortality compared with other ethnic groups in people with type 1 diabetes mellitus (T1DM).

Design

Systematic review.

Method

A systematic literature search strategy was designed and carried out using Medline and Embase for full-text and abstract studies published in English from 1946 to February 2016. The initial search identified 4722 papers. We assessed 305 full-text articles in detail for potential inclusion. Ten papers met the inclusion criteria for review and an additional one paper was included from our secondary search strategy using the bibliography of included studies. In total, 11 studies were included.

Eligibility criteria for selecting studies

Studies were included if they were published in English, involved SA participants with T1DM and compared them with non-SA participants and assessed one of the outcomes of comorbidities, microvascular complications, macrovascular complications and mortality.

Results

SA with T1DM have higher mortality compared with white Europeans (WE), mainly contributed to by excess cardiovascular disease. SA have significantly higher glycated haemoglobin (HbA1c), lower high-density lipoprotein (HDL) and lower rates of neuropathy compared with WE. There were no differences in rates of retinopathy and nephropathy. Compared with Africans, SA had lower levels of microalbuminuria, HbA1c and systolic blood pressure and higher HDL levels. There were no significant differences in the remaining outcomes: cardiovascular disease, retinopathy, neuropathy and body mass index. Furthermore, SA have higher HbA1c levels than Malay and Chinese and higher waistâ"hip ratio and lower HDL levels compared with Chinese only.

Conclusion

Our analysis highlights ethnic disparity in macrovascular outcomes that is so evident for type 2 diabetes mellitus may also be present for SA patients with T1DM. We highlight the need for a large, prospective, cohort study exploring the effect of ethnicity in a uniform healthcare setting.

http://ift.tt/2upjPsc

Trends and factors in human immunodeficiency virus and/or hepatitis C virus testing and infection among injection drug users newly entering methadone maintenance treatment in Guangdong Province, China 2006-2013: a consecutive cross sectional study

Objectives

To assess trends and related factors in HIV and/or hepatitis C virus (HCV) antibody testing and infection among injection drug users (IDUs) newly entering methadone maintenance treatment (MMT) in Guangdong Province, China.

Method

Consecutive cross sectional surveys were conducted in 14 MMT clinics from July 2006 to December 2013 in Guangdong Province, China. IDUs were excluded if they were re-enrolled or referred from other MMT clinics. Trend tests were used to examine HIV and/or HCV testing and infection, sociodemographic characteristics, drug use related behaviours and the past 3 month sexual behaviours on enrolment. Multivariate logistic regression was used to identify correlates of HIV and/or HCV testing and infection.

Results

7539 IDUs with an average age of 35.6±6.2 years were newly enrolled with a history of injection for an average of 11.8±4.9 years. The average frequency of injection before enrolment had been increasing. HIV, HCV and HIV/HCV dual testing increased from 2006 to 2013 (p_trend<0.001). However, all three types of infections remained stable (p_trend>0.05) until reaching a peak in 2011, excluding the first year. Associating with fellow drug users 1–4 times during the past month, injecting for 15+ years and having multiple sexual partners during the past 3 months predicted higher percentages for HIV and/or HCV testing (p<0.05), while those injecting 4+ times per day in the past month and those who had ever shared needles were less likely to take both tests (p<0.05). Having multiple sexual partners, a longer duration of injection drug use and sharing needles or sharing more frequently were major risk factors for HIV, HCV and HIV/HCV co-infection (p<0.05).

Conclusions

The prevalence of HIV and HCV were high and quite stable among new IDU entrants in MMT. Publicising MMT, routine screening, and behavioural and structural interventions is needed.

http://ift.tt/2uXZffv

Primary care workforce and continuous medical education in China: lessons to learn from a nationwide cross-sectional survey

Objectives

This study aimed to examine the education and training background of Chinese community health centres (CHCs) staff, continuous medical education (CME) and factors affecting participation in CME.

Design

Cross-sectional survey.

Setting

Community health centres (CHCs).

Participants

All doctors and nurses working in selected CHCs (excluding those solely practising traditional Chinese Medicine).

Main outcome measures

CME recorded by CHCs and self-reported CME participation.

Methods

A stratified random sample of CHCs based on geographical distribution and 2:1 urban–suburban ratio was selected covering three major regions of China. Two questionnaires, one for lead clinicians and another for frontline health professionals, were administered between September–December 2015, covering the demographics of clinic staff, staff training and CME activities.

Results

149 lead clinicians (response rate 79%) and 1734 doctors and 1846 nurses completed the survey (response rate 86%). Of the doctors, 54.5% had a bachelor degree and only 47% were registered as general practitioners (GPs). Among the doctors, 10.5% carried senior titles. Few nurses (4.6%) had training in primary care. Those who have reported participating in CME were 91.6% doctors and 89.2% nurses. CME participation in doctors was more commonly reported by older doctors, females, those who were registered as a GP and those with intermediate or senior job titles. CME participation in nurses was more common among those with a bachelor degree or intermediate/senior job titles or those with longer working experience in the CHC.

Conclusion

Only half of doctors have bachelor degrees or are registered as GPs as their prime registration in the primary care workforce in China. The vast majority of CHC staff participated in CME but there is room for improvement in how CME is organised.

http://ift.tt/2upuaEG

Assessing the medium-term impact of a home-visiting programme on child maltreatment in England: protocol for a routine data linkage study

Introduction

Child maltreatment involves acts of omission (neglect) or commission (abuse) often by caregivers that results in potential or actual harm to a child. The Building Blocks trial (ISRCTN23019866) assessed the short-term impact of an intensive programme of antenatal and postnatal visiting by specially trained nurses to support young pregnant women in England. The Building Blocks: 2–6 Study will assess the medium-term impacts of the programme for mothers and children (n=1562), through the linkage of routinely collected data to the trial data, with a particular emphasis on the programme's impact on preventing child maltreatment.

Methods and analysis

We have developed a bespoke model of data linkage whereby outcome data for the trial cohort will be retrieved by linked anonymous data abstraction from NHS Digital, Office for National Statistics and the Department for Education's National Pupil Database. Participants will be given reasonable opportunity to opt out of this study prior to data transfer. The information centres will match participants to the information held in their databases using standard identifiers and send extracts to a third-party safe haven. The study will have 80% power to detect a 4% difference (4%vs8%) for the binary primary outcome of child in need status (from birth to key stage 1) at a two-sided 5% alpha level by following up 602 children in each trial arm. Analysis will be by intention to treat using logistic multilevel modelling. A cost-and-consequences analysis will extend the time frame of the economic analysis from the original trial.

Ethics and dissemination

The study protocol has been approved by the National Health Service Wales Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group. Methods of innovative study design and findings will be disseminated through peer-reviewed journals and conferences; results will be of interest to clinical and policy stakeholders in the UK.

Trial registration number

ISRCTN23019866.

http://ift.tt/2uY0iw8

Does a one-day workshop improve clinical facultys comfort and behaviour in practising and teaching evidence-based medicine? A Canadian mixed methods study

Objective

The purpose of this study was to determine the impact of a 1-day evidence-based medicine (EBM) workshop on physician attitudes and behaviours around teaching and practicing EBM.

Design

A mixed methods study using a before/after cohort.

Setting

A medical school delivering continuing professional development to 1250 clinical faculty over a large geographic area in Canada.

Participants

105 physician clinical faculty members.

Intervention

A 1-day workshop presented at 11 different sites over an 18-month period focusing on EBM skills for teaching and clinical practice.

Outcome measures

(1) A quantitative survey administered immediately before and after the workshop, and 3–6 months later, to assess the hypothesis that comfort with teaching and practising EBM can be improved.

(2) A qualitative survey of the expectations for, and impact of the workshop on, participant behaviours and attitudes using a combination of pre, post and 3 to 6-month follow-up questionnaires, and telephone interviews completed 10–14 months after the workshop.

Results

Physician comfort with their EBM clinical skills improved on average by 0.93 points on a 5-point Likert scale, and comfort with EBM teaching skills by 0.97 points (p values 0.001). Most of this improvement was sustained 3–6 months later. Three to fourteen months after the workshop, half of responding participants reported that they were using the Population Intervention Comparator Outcome (PICO) methodology of question framing for teaching, clinical practice or both.

Conclusions

Comfort in teaching and practicing EBM can be improved by a 1-day workshop, with most of this improvement sustained 3–6 months later. PICO question framing can be learnt at a 1-day workshop, and is associated with a self-reported change in clinical and teaching practice 3–14 months later. This represents both level 2 (attitudes) and level 3 (behaviours) change using the Kirkpatrick model of evaluation.

http://ift.tt/2upfNA6

Feeding styles, parenting styles and snacking behaviour in children attending primary schools in multiethnic neighbourhoods: a cross-sectional study

Objective

The aim of the present study was to investigate whether feeding styles and parenting styles are associated with children's unhealthy snacking behaviour and whether the associations differ according to children's ethnic background.

Method

Cross-sectional data from the population-based 'Water Campaign' study were used. Parents (n=644) of primary school children (6–13 years) completed a questionnaire covering sociodemographic characteristics, feeding style dimensions ('control over eating', 'emotional feeding', 'encouragement to eat' and 'instrumental feeding'), parenting style dimensions ('involvement' and 'strictness') and children's unhealthy snacking behaviour. Logistic regression analyses were performed to determine whether feeding styles and parenting styles were associated with children's unhealthy snacking behaviour.

Result

Overall, children whose parents had a higher extent of 'control over eating' had a lower odds of eating unhealthy snacks more than once per day (OR, 0.57; 95% CI 0.42 to 0.76). Further stratified analysis showed that 'control over eating' was associated with less unhealthy snacking behaviour only in children with a Dutch (OR, 0.37; 95% CI 0.20 to 0.68) or a Moroccan/Turkish (OR, 0.44; 95% CI 0.25 to 0.77) ethnic background. 'Encouragement to eat' was associated with a lower odds of eating unhealthy snacks every day in children with a Dutch ethnic background only (OR, 0.48; 95% CI 0.25 to 0.90). 'Instrumental feeding' was associated with a higher odds of eating unhealthy snacks more than once a day in children with a Moroccan/Turkish ethnic background only (OR, 1.43; 95% CI 1.01 to 2.04).

Conclusion

Our results suggest that 'control over eating' may be associated with less unhealthy snack consumption in children. The associations of feeding styles and parenting styles with children's unhealthy snacking behaviour differed between children with different ethnic backgrounds.

http://ift.tt/2uXV2sc

Being normal, not vulnerable: case study of a 2-day residential programme for young adults with cancer

Objectives

To identify and describe the outcomes and facilitating processes of participation at 'Find Your Sense of Tumour' (FYSOT), a 2-day residential programme/conference for young people with cancer, from the perspective of professionals attending and patient representatives.

Design

Case study.

Setting

Observation of the 'Find Your Sense of Tumour' over 18s residential programme and face-to-face interviews in hospital and phone interviews.

Participants

Twenty-six participants — 19 professionals from hospitals across the UK who accompanied young people to FYSOT; 3 programme organisers; and 4 young people from the programme steering committee.

Methods

Participant observation and semistructured interviews.

Results

This process evaluation of an educational, social and peer-to-peer support residential weekend for young people with cancer identified key outcomes for young people — positive attitudes (increased sociability, confidence), belonging (feeling accepted, understood), recreation (trying new activities, having fun) and increased knowledge (balance between educational talks and interactions with other young people); and three overarching facilitating processes — being with other young people, the professionals accompanying young people to the event for support and guidance, and the conference/intentional programming. Being in a safe, relaxed and fun environment with other young people facilitates the development of peer support networks and increases young people's confidence and knowledge. Although the focus of the residential programme is on young people, interviewees acknowledge the impact of attending on professionals' motivation, learning and changes in practice.

Conclusions

This study has extended our understanding of the role of residential programmes by identifying outcomes and facilitating mechanisms. We have shown that residential programmes have an important role in providing participants with social, emotional and informational support, as well as play an important role in redefining normality. Longitudinal quantitative and qualitative research is needed to optimise outcomes and design and implement quality programmes that support young people's development.

http://ift.tt/2upu2Vs