A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better.

BACKGROUND: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. METHODS: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. RESULTS: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. CONCLUSIONS: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03502330.

Trends and patterns of initial percutaneous nephrolithotomy and subsequent procedures among commercially-insured US adults with urinary system stone disease: a 10-year population-based study.

PURPOSE: To describe trends and patterns of initial percutaneous nephrolithotomy (PCNL) and subsequent procedures from 2010 to 2019 among commercially-insured US adults with urinary system stone disease (USSD). METHODS: Retrospective study of administrative data from the IBM® MarketScan® Database. Eligible patients were aged 18-64 years and underwent PCNL between 1/1/2010 and 12/31/2019. Measures of interest for analysis of trends and patterns included the setting of initial PCNL (inpatient vs. outpatient), percutaneous access (1 vs. 2-step), and the incidence, time course, and type of subsequent procedures (extracorporeal shockwave lithotripsy [SWL], ureteroscopy [URS], and/or PCNL) performed up-to 3 years after initial PCNL. RESULTS: A total of 8,348 patients met the study eligibility criteria. During the study period, there was a substantial shift in the setting of initial PCNL, from 59.9% being inpatient in 2010 to 85.3% being outpatient by 2019 (P < 0.001). The proportion of 1 vs. 2-step initial PCNL fluctuated over time, with a low of 15.1% in 2016 and a high of 22.0% in 2019 but showed no consistent yearly trend (P = 0.137). The Kaplan-Meier estimated probability of subsequent procedures following initial PCNL was 20% at 30 days, 28% at 90 days, and 50% at 3 years, with slight fluctuations by initial PCNL year. From 2010 to 2019, the proportion of subsequent procedures accounted for by URS increased substantially (from 30.8 to 51.8%), whereas SWL decreased substantially (from 39.5 to 14.7%) (P < 0.001). CONCLUSIONS: From 2010 to 2019, PCNL procedures largely shifted to the outpatient setting. Subsequent procedures after initial PCNL were common, with most occurring within 90 days. URS has become the most commonly-used subsequent procedure type.

Comparison of Clinical Outcomes of Gripping Surface Technology Staple Reloads versus Standard Staple Reloads Used with Manual Linear Surgical Staplers.

Purpose: Linear surgical staplers reduce rates of surgical adverse events (bleeding, leaks, infections) compared to manual sutures thereby reducing patient risks, surgeon workflow disruption, and healthcare costs. However, further improvements are needed. Ethicon Gripping Surface Technology (GST) reloads, tested and approved by regulatory authorities in combination with powered staplers, may reduce surgical risks through improved tissue grip. While manual staplers are used in some regions due to affordability, clinical data on GST reloads used with manual staplers are unavailable. This study compared surgical adverse event rates of manual staplers with GST vs standard reloads. These data may be used for label changes in China and Latin America. Patients and Methods: Patients undergoing general or thoracic surgery between October 1, 2015 and August 31, 2021 using ECHELON FLEX™ manual staplers with GST or standard reloads were identified from the Premier Healthcare Database. GST reloads were compared to standard reloads for non-inferiority in bleeding and anastomotic leak for general surgery. Secondary outcomes included sepsis for general surgery, and bleeding and prolonged air leak for thoracic surgery. Covariate balancing was performed using stable balancing weights. Results: The general and thoracic surgery cohorts contained 4571 (GST: 2780; standard: 1791) and 814 (GST: 514; standard: 300) patients, respectively. GST reloads were non-inferior to standard reloads for bleeding and anastomotic leak (adjusted cumulative incidence ratio: 1.02 [90% CI: 0.71, 1.45] and 1.03 [90% CI: 0.72, 1.46], respectively) for general surgery. Compared with standard reloads, GST reloads had a similar incidence of sepsis (2.2% vs 2.1%) for general surgery and lower incidences of bleeding (9.5% vs 16.0%) and prolonged air leak (12.6% vs 14.0%,) for thoracic surgery. Conclusion: GST reloads, compared to standard reloads, used with ECHELON FLEX™ manual staplers had comparable perioperative bleeding and anastomotic leak for general surgery, and lower incidences of safety events for thoracic surgery.

Retrospective Comparison of Clinical and Economic Outcomes of Non-Donor Patients Undergoing Radical Nephrectomy Using One of Two Different Linear Stapler Technologies for Transection of the Renal Vessels: Fixed-Height Gripping Surface Reloads vs Variable-Height Reloads.

Purpose: To compare outcomes of non-donor patients undergoing radical nephrectomy using fixed-height gripping surface (FHGS) vs variable-height Tri-Staple™ (VHTS) reloads for transection of the renal vessels. Patients and Methods: Using the Premier Healthcare Database of US hospital discharge records, we selected non-donor patients undergoing inpatient radical nephrectomy with dates of admission between 1 October 2015, and 31 December 2020 (first=index admission). The primary outcome was in-hospital hemostasis-related complications (hemorrhage, acute posthemorrhagic anemia, and/or procedure to control bleeding) during the index admission. Secondary outcomes included index admission intraoperative injury, blood transfusion, conversion from minimally invasive to open surgery, total hospital costs, length of stay (LOS), discharge status, and mortality as well as 30-day all-cause inpatient readmission. We used stable balancing weights to balance the FHGS and VHTS groups on numerous patient, procedure, and hospital/provider characteristics, allowing a maximum post-weighting standardized mean difference ≤0.01 for all covariates; we also exactly matched the groups on laterality (right vs left kidney) and intended surgical approach (open, laparoscopic, robotic). We used bivariate multilevel mixed-effects generalized linear models accounting for hospital-level clustering to compare the study outcomes between the FHGS and VHTS groups. Results: After weighting, the FHGS and VHTS groups comprised 2952 and 795 patients, respectively. The observed incidence proportion of the primary outcome of hemostasis-related complications during the index admission was similar between the groups (8.6% for FHGS vs 9.0% for VHTS, difference 0.4% [95% CI -3.2% to 2.5%], P=0.808). Differences between the FHGS and VHTS groups were not statistically significant for any of the secondary outcomes. Conclusion: Endoscopic surgical staplers have become common for transection of the renal vessels during radical nephrectomy, with FHGS and VHTS being the predominant reload types. In this retrospective study of 3747 non-donor patients undergoing radical nephrectomy, use of FHGS vs VHTS reloads was associated with similar clinical and economic outcomes.

Family planning, pregnancy and birth in women with lung conditions: a worldwide survey.

Lung diseases can complicate pregnancy, but little is known about the experiences of pregnancy among women living with such diseases. This survey aimed to understand the experiences of women with a lung condition before and during pregnancy, in childbirth and post-partum. The survey was translated into nine languages and hosted online between March and May 2018. This paper reports on 327 women who had asthma, cystic fibrosis (CF), lymphangioleiomyomatosis (LAM) and sarcoidosis as a sole or primary lung condition. Women with CF and LAM were most likely to report that their condition influenced their decision to have children. Those with CF and LAM who did become pregnant reported greater satisfaction with their healthcare during pregnancy and gave more consideration to factors such as location and type of birth; they were also more concerned about the impact of the pregnancy on their health than women with other diseases. Women with sarcoidosis reported receiving conflicting advice as to both the impact of their condition on pregnancy and how becoming pregnant might impact their health. Women with asthma reported not always being able to access the information they needed from healthcare professionals. The results suggest that healthcare providers should be having dialogues with affected women early on, from before conception, throughout the pregnancy and after giving birth, and training should be provided to healthcare staff to equip them with the information they need to do this.

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.

PURPOSE: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. PATIENTS AND METHODS: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. RESULTS: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23-443). Median cycles were 4.5 (range, 2-21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. CONCLUSIONS: This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

A New Method for Improving Extraction Efficiency and Purity of Urine and Plasma Cell-Free DNA.

This study assessed three commercially available cell-free DNA (cfDNA) extraction kits and the impact of a PEG-based DNA cleanup procedure (DNApure) on cfDNA quality and yield. Six normal donor urine and plasma samples and specimens from four pregnant (PG) women carrying male fetuses underwent extractions with the JBS cfDNA extraction kit (kit J), MagMAX Cell-Free DNA Extraction kit (kit M), and QIAamp Circulating Nucleic Acid Kit (kit Q). Recovery of a PCR product spike-in, endogenous TP53, and Y-chromosome DNA was used to assess kit performance. Nucleosomal-sized DNA profiles varied among the kits, with prominent multi-nucleosomal-sized peaks present in urine and plasma DNA isolated by kits J and M only. Kit J recovered significantly more spike-in DNA than did kits M or Q (p < 0.001) from urine, and similar amounts from plasma (p = 0.12). Applying DNApure to kit M- and Q-isolated DNA significantly improved the amplification efficiency of spike-in DNA from urine (p < 0.001) and plasma (p ≤ 0.013). Furthermore, kit J isolated significantly more Y-chromosome DNA from PG urine compared to kit Q (p = 0.05). We demonstrate that DNApure can provide an efficient means of improving the yield and purity of cfDNA and minimize the effects of pre-analytical biospecimen variability on liquid biopsy assay performance.

Real-World Outcomes of Patients Undergoing Open Colorectal Surgery with Wound Closure Incorporating Triclosan-Coated Barbed Sutures: A Multi-Institution, Retrospective Database Study.

PURPOSE: Open colorectal surgery is associated with a high rate of postoperative wound complications. This is a single-arm study of real-world outcomes of triclosan-coated barbed suture (Ethicon's STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Device [SSPP]) used in open colorectal surgery. METHODS: Retrospective cohort study using the Premier Healthcare Database. The study included patients who underwent an inpatient open colorectal surgery with wound closure using SSPP (size 0 or 1 to increase the likelihood the suture was used in fascia) between October 2015-September 2019 (N=593). Wound complications, hospital length of stay, total hospital costs (2019 US$), and all-cause readmissions post-discharge were measured. Post-hoc multivariable analyses compared wound complications between non-elective admissions and elective. RESULTS: The overall incidence of wound complications within 30-days post-procedure was 7.1%, with the majority of those being surgical site infections (SSI) (6.0%). Mean operation time was 190 (standard deviation [SD]=64.4) mins, postoperative length of stay was 8.1 (SD=11.9) days, 30-day readmission rate was 11.8%, and total hospital costs were $31,693 (SD=$40,076). As compared with published literature on the rate of SSI in colorectal surgery, the 30-day rate of SSI in the present study (6.0%) fell within the range of 5.4% to 18.2% for open colorectal surgery and from 4.3% to 21.5% for combined open and minimally invasive procedures. Multivariable-adjusted incidence proportions of wound complications were slightly lower for non-elective admissions and did not differ significantly from those of elective admissions. CONCLUSION: The rate of wound complications observed in the present study falls within the range of rates previously reported in the literature, suggesting a safe and effective role for SSPP in open colorectal surgery. In post hoc analyses, the adjusted rate of wound complications was similar between non-elective and elective admissions. Head-to-head studies are required to determine comparative advantages or disadvantages for SSPP versus other sutures.

Improving spirometry testing by understanding patient preferences.

The American Thoracic Society and European Respiratory Society commissioned a task force to update the technical standards for spirometry testing with the aim of increasing the accuracy, precision and quality of spirometry measurements and improving the patient experience. To inform the task force with patient experiences, the European Lung Foundation, in collaboration with the task force, conducted an online survey in 10 languages between August and September 2018. There were 1760 respondents from 52 countries. The majority were adults (97.1%); the most common reasons for spirometry referral were diagnosis (35.0%) and management of an ongoing condition (60.1%). 53.2% reported regularly using inhalers. Respondents were very experienced with spirometry: 89.9% completed more than one test; 48% completed 10 or more tests. However, most reported not knowing what forced expiratory volume in 1 s (FEV1) means (59.4%) and only 39.6% knew their most recent FEV1; the exception was respondents with cystic fibrosis who reported much greater knowledge. Respondents rated as moderately or seriously problematic: being told to keep blowing when they felt nothing is coming out (31.4%), coughing (30.4%), tiredness (26.3%) and concern about shortness of breath (20.1%). Overall, respondents found spirometry to be acceptable; however, an important minority (17%) found it difficult. Patients want clear information before, during and after the test, including information on stopping medications. Operators have an important role in increasing the ease of patients and changes to the testing environment can increase patient comfort. Patients want access to their results and want to understand how they relate to their individual health.

Healthcare Resource Utilization and Costs in Celiac Disease: A US Claims Analysis.

INTRODUCTION: Celiac disease (CeD) is a lifelong immune-mediated enteropathy in which dietary gluten triggers an inflammatory reaction in the small intestine. This retrospective cohort study examines healthcare resource utilization (HRU) and costs between patients with CeD and matched controls. METHODS: Patients with CeD (cases) with an endoscopic biopsy and ≥2 medical encounters with a CeD diagnosis between January 1, 2010, and October 1, 2015, were identified in the MarketScan databases. The date of the first claim with a CeD diagnosis on or after the endoscopic biopsy was the index date. Cases were matched 1:1 to patients without CeD (controls) on demographic characteristics and Deyo-Charlson Comorbidity Index score. Clinical characteristics, all-cause, and CeD-related HRU and costs (adjusted to 2017 US dollars) were compared between cases and controls during the 12 months before (baseline) and 24 months after (follow-up) the index date. RESULTS: A total of 11,008 cases (mean age 40.6 years, 71.3% women) were matched to 11,008 controls. During the follow-up, a higher proportion of cases had all-cause and CeD-related HRU including inpatient admissions, emergency department visits, gastroenterologist visits, dietician visits, endoscopic biopsies, and gastroenterology imaging (all P ≤ 0.002). Incremental all-cause and CeD-related costs were in the first ($7,921 and $2,894) and second ($3,777 and $935) year of follow-up, driven by outpatient services costs. DISCUSSION: In this US national claims database analysis, there was evidence of an increase in both all-cause and CeD-related HRU and related costs in patients with CeD compared with matched patients without CeD, suggesting a significant economic burden associated with CeD.

Impact of Plan-Level Access Restrictions on Effectiveness of Biologics Among Patients with Rheumatoid or Psoriatic Arthritis.

BACKGROUND: Novel disease-modifying antirheumatic drugs (DMARDs) can slow disease progression among patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA); however, some health plans require prior authorization (PA) or step therapy for access to treatments. OBJECTIVES: This retrospective study compared treatment effectiveness among RA and PsA patients with and without plan-level access restrictions to biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs). Medication adherence, a component of effectiveness, was also examined as a secondary outcome. METHODS: RA and PsA patients aged 18-64 years with one or more claims for subcutaneous bDMARDs between January 1, 2014 and December 31, 2015, with plan-level access data available, were identified within the IBM MarketScan claims database. The primary outcome was treatment effectiveness assessed during the 12 months following the first qualifying DMARD claim. Multivariate modeling examined the correlation between access restrictions and treatment effectiveness. Medication adherence during the 12-month follow-up period was also compared between patients with and without access restrictions. RESULTS: Among 3993 RA and 1713 PsA patients, 34.2 and 35.1%, respectively, had access restrictions, of whom 70.5 and 78.9%, respectively, had plans with step therapy. Compared with patients whose plans did not require step therapy, odds of treatment effectiveness were 19% lower (odds ratio [OR] 0.81, 95% CI: 0.67-0.98; p  = 0.033) for RA patients and 27% lower (OR 0.73, 95% CI: 0.55-0.98; p = 0.037) for PsA patients in plans with step therapy. Differences in effectiveness were driven by differences in medication adherence, the odds of which were 19% lower (OR 0.81, 95% CI 0.68-0.96; p = 0.014) among RA patients and 29% lower (OR 0.71, 95% CI: 0.54-0.94; p = 0.017) among PsA patients in plans with versus without step therapy. CONCLUSIONS: Compared with patients in plans without access restrictions or with PA only, RA and PsA patients in insurance plans with step therapy had lower odds of treatment effectiveness, mainly due to lower odds of adhering to treatment, during the 12 months following subcutaneous bDMARD initiation.

ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases.

This European Respiratory Society/Thoracic Society of Australia and New Zealand statement outlines a review of the literature and expert opinion concerning the management of reproduction and pregnancy in women with airways diseases: asthma, cystic fibrosis (CF) and non-CF bronchiectasis. Many women with these diseases are now living into reproductive age, with some developing moderate-to-severe impairment of lung function in early adulthood. The statement covers aspects of fertility, management during pregnancy, effects of drugs, issues during delivery and the post-partum period, and patients' views about family planning, pregnancy and parenthood. The statement summarises current knowledge and proposes topics for future research, but does not make specific clinical recommendations.

Clinical Outcomes and Healthcare Resource Utilization for Gastrointestinal Acute Graft-versus-Host Disease after Allogeneic Transplantation for Hematologic Malignancy: A Retrospective US Administrative Claims Database Analysis.

Graft-versus-host disease (GVHD) is the leading cause of nonrelapse mortality among patients who receive allogeneic hematopoietic cell transplantation (allo-HCT). In its acute form (aGVHD), GVHD involves the skin, liver, and gastrointestinal (GI) tract, with GI involvement most strongly associated with poor prognosis. This retrospective cohort study used US healthcare claims data for 2008 to 2015 to identify patients who developed GI aGVHD after allo-HCT performed as curative treatment for hematologic malignancy and compared them with patients who did not develop aGVHD in terms of outcomes related to survival, infections, healthcare resource utilization (HRU), and costs. Whereas the patients without aGVHD saw a 66% improvement in 1-year survival between 2009 and 2015, this effect was not observed in patients with GI aGVHD. Compared with patients without evidence of aGVHD, patients with GI aGVHD were 3.9-fold more likely to develop an infection in the year after allo-HCT. Similarly, patients who developed GI aGVHD were 4.3-fold more likely to have an inpatient admission after allo-HCT discharge, and such an admission cost on average 47% more than an admission for patients without aGVHD. Our findings confirm that GI involvement in aGVHD is associated with higher mortality, risk of infection, HRU, and cost compared with absence of aGVHD.

Evaluation of three commercially-available chikungunya virus immunoglobulin G immunoassays / Evaluación de tres inmunoensayos comercializados de inmunoglobulina G para el diagnóstico del virus del chikungunya

ABSTRACT The emergence of chikungunya virus in the Americas means the affected population is at risk of developing severe, chronic, rheumatologic disease, even months after acute infection. Accurate diagnostic methods for past infections are essential for differential diagnosis and consequence management. This study evaluated three commercially-available chikungunya Immunoglobulin G immunoassays by comparing them to an in-house Enzyme-Linked ImmunoSorbent Assay conducted by the Centers for Disease Control and Prevention (Atlanta, Georgia, United States). Results showed sensitivity and specificity values ranging from 92.8% - 100% and 81.8% - 90.9%, respectively, with a significant number of false-positives ranging from 12.5% - 22%. These findings demonstrate the importance of evaluating commercial kits, especially regarding emerging infectious diseases whose medium and long-term impact on the population is unclear.(AU)

RESUMEN Como consecuencia de la aparición del virus del chikungunya en las Américas, la población afectada corre el riesgo de padecer reumatismos crónicos graves, aun meses después de la infección aguda. Es fundamental contar con métodos precisos para diagnosticar los antecedentes de la infección a fin de elaborar un diagnóstico diferencial y abordar las manifestaciones de la fase crónica. Se han estudiado tres inmunoensayos comercializados de detección de inmunoglobulinas G para el diagnóstico del chikungunya, comparándolos con el enzimoinmunoanálisis de adsorción (ELISA) propio. Los resultados señalan valores de sensibilidad del 92,8% al 100% y de especificidad del 81,8% al 90,9%, así como un número significativo de falsos positivos, de entre el 12,5% y el 22%.(AU)

Medical costs associated with cardiovascular events among high-risk patients with hyperlipidemia.

OBJECTIVES: This study descriptively examined acute and longer term direct medical costs associated with a major cardiovascular (CV) event among high-risk coronary heart disease risk-equivalent (CHD-RE) patients. It also gives a firsthand look at fatal versus nonfatal CV events. METHODS: The MarketScan(®) Commercial Claims and Encounters Database was used to identify adults with a CV event in 2006-2012 with hyperlipidemia or lipid-lowering therapy use in the 18 months prior to one of the following inpatient CV events: myocardial infarction, ischemic stroke, unstable angina, transient ischemic attack, percutaneous coronary intervention, or coronary artery bypass graft (CABG). Patients were required to have a preindex diagnosis of at least one of the following: peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, or diabetes. A subset analysis was conducted with patients with data linkable to the Social Security Administration Master Death File. Direct medical costs were reported for each quarter following a CV event, for up to 36 months after the first CV event. RESULTS: In total, 38,609 CHD-RE patients were included, mean age 57 years, 31% female. CABG, myocardial infarction, and percutaneous coronary intervention were the most frequent and most expensive first CV events, accounting for >75% of all first CV events with mean first quarter costs ranging from $17,454 (nonfatal transient ischemic attack) to $125,690 (fatal CABG). Overall, 15% of those with a first CV event went on to have a second event during the 36-month study period with mean first quarter nonfatal and fatal costs similar to first event levels. Third CV events were rare, happening in less than 3% of patients. CONCLUSION: CV events among CHD-RE patients were costly regardless of sequence, averaging $47,433 in the first 90 days following an event and remaining high, never returning to preevent levels. When fatal, first CV event costs were 1.2 to 2.9 times higher than when nonfatal.

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205.

KRAS testing of patients with metastatic colorectal cancer in a community-based oncology setting: a retrospective database analysis.

BACKGROUND: In 2009, treatment guidelines were updated to recommend KRAS testing at diagnosis for patients with metastatic colorectal cancer (mCRC). We investigated KRAS testing rates over time and compared characteristics of KRAS-tested and not-tested patients in a community-based oncology setting. METHODS: Adult patients with a diagnosis of mCRC from 2008-2011 were selected from the ACORN Data Warehouse (ACORN Research LLC, Memphis, TN). Text mining of physician progress notes and full chart reviews identified KRAS-tested patients, test dates, and test results (KRAS status). The overall proportion of eligible patients KRAS-tested in each calendar year was calculated. Among KRAS-tested patients, the proportion tested at diagnosis (within 60 days) was calculated by year. Univariate and multivariate analyses were used to compare patient characteristics at diagnosis between tested and not-tested cohorts, and to identify factors associated with KRAS testing. RESULTS: Among 1,363 mCRC patients seen from 2008-2011, 648 (47.5%) were KRAS-tested. Among newly diagnosed mCRC patients, the rate of KRAS testing increased from 5.9% prior to 2008, to 13.9% in 2008, and then jumped dramatically to 32.3% in 2009, after which a modest yearly increase continued. The proportions of KRAS-tested patients who had been diagnosed in previous years but not tested previously increased from 17.7% in 2008 to 27.0% in 2009, then decreased to 19.0% in 2010 and 17.6% in 2011. Among patients who were KRAS-tested, the proportions tested at the time of diagnosis increased annually (to 78.4% in 2011). Patients more likely to have been tested included those with lung metastases, poor performance status, more comorbidities, and mCRC diagnosis in 2009 or later. CONCLUSIONS: The frequency of KRAS testing increased over time, corresponding to changes in treatment guidelines and epidermal growth factor receptor inhibitor product labels; however, approximately 50% of eligible patients were untested during the study period.

Influence of menstrual cycle phase on neural and craving responses to appetitive smoking cues in naturally cycling females.

INTRODUCTION: Functional magnetic resonance imaging (fMRI) has been used extensively in an attempt to understand brain vulnerabilities that mediate maladaptive responses to drug cues. Using perfusion fMRI, we have consistently shown reward-related activation (medial orbitofrontal cortex/ventral striatum) to smoking cues (SCs). Because preclinical and clinical studies generally show that progesterone may reduce reward and craving, we hypothesized that females in the follicular phase of the cycle (FPs; when progesterone levels are low) would have greater reward-related neural responses to SCs compared with females in the luteal phase (LPs). METHODS: Sated cigarette-dependent premenopausal naturally cycling females underwent pseudo-continuous arterial spin-labeled perfusion fMRI during exposure to 10-min audio visual clips of appetitive SCs and non-SCs. Brain responses to SCs relative to non-SCs were examined among females grouped according to menstrual cycle (MC) phase at the time of scanning (22 FPs, 15 LPs). Craving scores were acquired pre- and post-SC exposure. RESULTS: FPs showed increased neural responses to SCs compared with non-SCs in the medial orbitofrontal cortex (p ≤ .05 corrected), whereas LPs did not. FPs reported SC-elicited craving (p ≤ .005), whereas LPs did not. Within FPs, SC-induced craving correlated with increased neural responses in the anterior insula (r = 0.73, p < .0001). CONCLUSIONS: FPs may be more vulnerable to relapse during appetitive SC exposure than LPs. Because the influence of MC phase on drug cue neural activity has not been examined, these results contribute to our knowledge of the neurobiological underpinnings of responses to drug cues, and they highlight the importance of monitoring menstrual cycle phase in all areas of addiction research.

Activity and participation in children with neurofibromatosis type 1.

We describe activity and participation in children and youth with neurofibromatosis type 1 (NF1), and compared an intervention and control group after a strengthening program using the Pediatric Outcomes Data Collection Instrument (PODCI) and the Children's Assessment of Participation and Enjoyment (CAPE). Questionnaires were filled out by parents at baseline, 12-weeks, and 1-year. The intervention group performed a strengthening program twice a week for ten weeks, followed by a 9-month independent program. Thirty-six participants (18 control, 18 intervention) between the ages of 5- and 18-years (mean 10.6 years, SD 4.6 years) were enrolled, and 34 completed the 1-year assessment. There were significant differences between formal and informal participation (p<0.0001) in baseline CAPE scores for the entire cohort. At 12 weeks, PODCI upper extremity function improved in intervention and decreased in controls (p=0.040), while happiness declined in intervention and increased in control (p=0.003). There were no significant differences between control and intervention groups in any of the CAPE or PODCI change scores from baseline to 1-year. Upper extremity function, sport and physical function, comfort/pain and happiness PODCI scores were lower than normative values. The NF1 cohort had low participation in formal active physical and skill-based activities. The companionship and location dimensions suggest participation occurs with family and other relatives in the home or a relative's home and reflects a pattern of social isolation from peers.