Live surgery: highly educational or harmful?

PURPOSE: Live surgery (LS) is considered a useful teaching opportunity. The benefits must be balanced with patient safety concerns. To evaluate the rate of complications of a series of urologic LS performed by experts during the Congress Challenge in Laparoscopy and Robotics (CILR). METHODS: We present a large, multi-institution, multi-surgeon database that derives from 12 CILR events, from 2004 to 2015 with a total of 224 cases. Radical prostatectomy (RP) was the most common procedure and a selection of complex cases was noted. The primary measure was postoperative complications and use of a Postoperative Morbidity Index (PMI) to allow quantitative weighing of postoperative complications. RESULTS: From 12 events, the number of cases increased from 11 in 2004 to 27 in 2015 and a total of 27 surgeons. Of 224 cases (164 laparoscopic and 60 robotic), there were 26 (11.6%) complications: 5 grade I, 5 grade II, 3 grade IIIa, 12 grade IIIb and 1 grade V, the latter from laparoscopic cystectomy. Analysis of PMI was 23 times higher from cystectomy compared to RP. CONCLUSIONS: In the setting of live surgery, the overall rate of complications is low considering the complexity of surgeries. The PMI is not higher in more complex procedures, whereas RP seems very safe.

Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects.

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.

Urban Roadway Runoff Is Lethal to Juvenile Coho, Steelhead, and Chinook Salmonids, But Not Congeneric Sockeye.

We compared the sensitivity of closely related Pacific salmon and steelhead (Oncorhynchus spp.) to untreated urban stormwater runoff across three storm events. Juvenile coho, sockeye, steelhead, and Chinook were exposed for 24 h to untreated urban runoff and then transferred to clean water for 48 h. As anticipated from previous studies, coho were highly susceptible to runoff toxicity, with cumulative mortality rates ranging from 92%-100% across the three storms. By contrast, juvenile sockeye were unaffected (100% survival), and cumulative mortality rates were intermediate for steelhead (4%-42%) and Chinook (0%-13%). Furthermore, coho died rapidly following the onset of stormwater exposure (generally <4 h), whereas mortality in Chinook and steelhead was delayed by 1-2 days. Similar to previous findings for coho, steelhead and Chinook did not recover when transferred to clean water. Lastly, significant mortality occurred in coho even when roadway runoff was diluted by 95% in clean water. Our findings extend the urban runoff mortality syndrome in salmonids and point to a near-term need for sublethal studies in steelhead and Chinook to more precisely understand stormwater risks to threatened species recovery efforts in the western United States.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Inflammatory cytokines differentially up-regulate human endometrial haptoglobin production in women with endometriosis.

BACKGROUND: Evidence suggests that eutopic endometrium from women with endometriosis (US-E) has intrinsic functional anomalies compared with women without endometriosis (US-C). We hypothesized that differences in endometrial haptoglobin (eHp) mRNA and protein levels exist between eutopic endometrium from US-E and US-C and that inflammatory mediators may be involved. METHODS: Endometrial stromal cells and tissue explants from US-E (n = 18) and US-C (n = 18) were cultured (24 h/48 h for cells/explants) with interleukin (IL)-1alpha, -1beta, -6, -8 or tumor necrosis factor-alpha (TNF-alpha) at 0-100 ng/ml. eHp protein in media and mRNA levels were quantified by enzyme-linked immunosorbent assay and quantitative PCR. RESULTS: In eutopic endometrial stromal cells from US-E, IL-1beta, IL-6 and TNF-alpha (10 ng/ml) increased eHp mRNA levels (P = 0.002, P < 0.001 and P < 0.001, respectively) and eHp protein (P = 0.023, 0.031 and 0.006, respectively) versus control. In endometrial tissues from US-E, IL-1beta, IL-6 and TNF-alpha increased eHp mRNA (P < 0.001, P = 0.017 and P < 0.001, respectively) and eHp protein (P < 0.001, P = 0.007 and 0.039, respectively) versus control. IL-1alpha and IL-8 had small or no effects on isolated endometrial cells or tissues. In US-C, IL-1beta, IL-8 and TNF-alpha each reduced eHp mRNA in endometrial stromal cells (all P < 0.001) versus control; IL-1alpha and IL-6 had no effect. eHp mRNA increased in endometrial tissues from US-C in response to IL-1beta (P = 0.008), IL-6 (P = 0.015) and TNF-alpha (P = 0.031) versus control; IL-1alpha or IL-8 had no effect. CONCLUSIONS: Endometrium from US-E differentially responds to specific inflammatory cytokines by production of eHp. We propose that up-regulation of endometrial eHp by inflammatory mediators disrupts normal endometrial function and may facilitate the pathogenesis of endometriosis.

Differential DNA methylation patterns of small B-cell lymphoma subclasses with different clinical behavior.

Non-Hodgkin's lymphoma (NHL) is a group of malignancies of the immune system with variable clinical behaviors and diverse molecular features. Despite the progress made in classification of NHLs based on classical methods, molecular classifications are a work in progress. Toward this goal, we used an array-based technique called differential methylation hybridization (DMH) to study small B-cell lymphoma (SBCL) subtypes. A total of 43 genomic DMH experiments were performed. From these results, several statistical methods were used to generate a set of differentially methylated genes for further validation. Methylation of LHX2, POU3F3, HOXC10, NRP2, PRKCE, RAMP, MLLT2, NKX6.1, LRP1B and ARF4 was validated in cell lines and patient samples and demonstrated subtype-related preferential methylation patterns. For LHX2 and LRP1B, bisulfite sequencing, real-time reverse transcriptase-polymerase chain reaction and induction of gene expression following treatment with the demethylating agent, 5'-aza-2'-deoxycytidine, were confirmed. This new epigenetic information is helping to define molecular portraits of distinct subtypes of SBCL that are not recognized by current classification systems and provides valuable potential insights into the biology of these tumors.

Seasonal Population Dynamics of Megacopta cribraria (Hemiptera: Plataspidae) in Kudzu and Soybean, and Implication for Insecticidal Management in Soybean.

Megacopta cribraria (F.), an invasive species introduced from Asia in 2009, is now prolific in the southeastern United States. Megacopta cribraria develops primarily on kudzu and soybean completing two generations. It is not well understood how this economic pest is affected by changes in geographic distribution in the United States or how population levels have changed since its establishment. The effect of insecticide application timing on field populations of M. cribraria is not well documented. These studies seek to understand how population dynamics of M. cribraria vary with geographic regions in Georgia. Effect of application timing on populations throughout the growing season was also examined. Weekly from 2012 to 2013, all life stages were enumerated from kudzu and soybean environments at several locations throughout Georgia from sweeps samples and flight intercept captures. Coordinates were recorded for locations, and classified as belonging to the Piedmont or Coastal Plain region of the state. Single spray trials were conducted from 2011-2014, and applications were made to soybean at intervals throughout the season. From 2012 to 2015, two kudzu patches near Griffin, GA, were monitored to detect population changes. Differences in population dynamics from locations around the state were found, but no clear effect of latitude, longitude, or region was observed. Insecticide applications applied in July suppressed nymph populations significantly better than treatments made earlier or later. Megacopta cribraria populations declined in 2014 and 2015 compared with 2012 and 2013. These studies provide the critical information for M. cribraria management in soybean in the southeastern United States.

Second cancers in patients with chronic lymphocytic leukemia.

Among 419 persons diagnosed as having chronic lymphocytic leukemia (CLL) in western Washington State between 1974 and 1983 and followed through January 1985, 9 subsequently developed other lymphoid cancers and 48 developed nonlymphoid cancers. Only 2 lymphoid and 21 nonlymphoid cancers were expected based on the rates of the western Washington population as a whole. Lung cancer accounted for about one-third of the excess rate observed. Three of the nonlymphoid tumors that occurred in the patients with CLL were classified as malignant fibrous histiocytomas, which represents an exceptionally high relative incidence for this histologic type. The excess risk of nonlymphoid cancers was present in both sexes, across all age categories, and in every length-of-follow-up interval. These results, taken together with those obtained from earlier investigations, suggest that persons with CLL are at increased risk of developing a second tumor, particularly in the lung. The reasons for this increased risk remain to be elucidated.

Prevention of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the MCF-10A cell line: correlation with increased transforming growth factor alpha production.

We have recently reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibits epidermal growth factor (EGF) withdrawal-induced apoptosis in the human mammary epithelial cell line MCF-10A. We hypothesized that TCDD-mediated inhibition of apoptosis was due to its ability to stimulate the EGF receptor (EGFR) pathway. Indeed, in the present studies, the EGFR inhibitor AG1478 was able to prevent TCDD-, EGF-, and transforming growth factor alpha (TGF-alpha)-dependent cell recovery and inhibition of apoptosis. These effects were specific for an EGFR-mediated pathway because cotreatment with AG825, an erbB2 inhibitor, had little effect on apoptosis. In addition, TCDD was able to mimic the EGF and TGF-alpha signaling as demonstrated by increasing Akt and extracellular signal-regulated kinase 1,2 phosphorylation. These effects were dependent on EGFR activity because AG1478, but not AG825, was able to prevent EGF-, TGF-alpha, or TCDD-mediated Akt and extracellular signal-regulated kinase 1,2 phosphorylation. The ability of TCDD to stimulate the EGFR pathway and inhibit apoptosis may be due to the ability of TCDD to increase expression of TGF-alpha, a ligand for EGFR. Treatment with 10 nM TCDD increased TGF-alpha mRNA at 2 h and TGF-alpha protein at 6 h. These data suggest a mechanism whereby TCDD is able to inhibit apoptosis in human mammary epithelial cells by stimulating TGF-alpha production, resulting in an autocrine effect.

Quantitation of serum prostate-specific membrane antigen by a novel protein biochip immunoassay discriminates benign from malignant prostate disease.

The lack of a sensitive immunoassay for quantitating serum prostate-specific membrane antigen (PSMA) hinders its clinical utility as a diagnostic/prognostic biomarker. An innovative protein biochip immunoassay was used to quantitate and compare serum PSMA levels in healthy men and patients with either benign or malignant prostate disease. PSMA was captured from serum by anti-PSMA antibody bound to ProteinChip arrays, the captured PSMA detected by surface-enhanced laser desorption/ionization mass spectrometry, and quantitated by comparing the mass signal integrals to a standard curve established using purified recombinant PSMA. The average serum PSMA value for prostate cancer (623.1 ng/ml) was significantly different (P < 0.001) from that for benign prostate hyperplasia (117.1 ng/ml) and the normal groups (age <50, 272.9 ng/ml; age >50, 359.4 ng/ml). These initial results suggest that serum PSMA may be a more effective biomarker than prostate-specific antigen for differentiating benign from malignant prostate disease and warrants additional evaluation of the surface-enhanced laser desorption/ionization PSMA immunoassay to determine its diagnostic utility.

Mechanical correlates of the third heart sound.

In seven chronically instrumented conscious dogs, micromanometers measured left ventricular pressure, and ultrasonic dimension transducers measured left ventricular minor-axis diameter; the latter recording was filtered to examine data between 20 and 100 Hz. Acceptable external heart sounds were recorded with a phonocardiographic microphone in four of the seven dogs. With each dog sedated, intubated and mechanically ventilated, data were obtained during hemodynamic alterations produced by volume loading, phenylephrine, calcium infusion and vena caval occlusion. Damped oscillations were noted consistently in the left ventricular diameter waveform toward the end of rapid ventricular filling. These wall vibrations, assessed by the filtered diameter, correlated well with the third heart sound (S3) on the phonocardiogram. The peak frequency of the wall vibrations increased with increased diastolic pressure (p = 0.004), probably reflecting an increase in myocardial wall stiffness. In contrast, the amplitude of the vibrations varied directly with left ventricular filling rate (p = 0.0001). Thus, S3 seemed to be related specifically to ventricular wall vibrations during rapid filling, and the spectra of the amplitude-frequency relation shifted toward the audible range with increases in diastolic pressure, wall stiffness or filling rate. Spectral analysis of S3 may be useful in assessing pathologic changes in myocardial wall properties.

Comparison of preload recruitable stroke work, end-systolic pressure-volume and dP/dtmax-end-diastolic volume relations as indexes of left ventricular contractile performance in patients undergoing routine cardiac catheterization.

The end-systolic pressure-volume relation, the relation between stroke work and end-diastolic volume, termed the preload recruitable stroke work relation, and the relation between the peak of the first derivative of left ventricular pressure (dP/dtmax) and end-diastolic volume have been employed as linear indexes of left ventricular contractile performance in laboratory animals. The purpose of this study was to examine the relative utility of these indexes during routine cardiac catheterization in seven human subjects (mean age 48 +/- 18 [SD] years) with a normal left ventriculogram and coronary angiogram. Left ventricular pressure was recorded continuously with a micromanometer catheter, and left ventricular volume was derived from digital subtraction contrast ventriculograms obtained at 30-ms intervals. Transient occlusion of the inferior vena cava with a balloon-tipped catheter was employed to obtain beat to beat reductions in left ventricular pressure and volume over 8.7 +/- 1.7 cardiac cycles. Stroke work declined by 49 +/- 13% during vena caval occlusion, but end-systolic pressure fell by only 26 +/- 11%, and changes in dP/dtmax were small and inconsistent (12 +/- 22%). Consequently, the range of data available for determination of the preload recruitable stroke work relation greatly exceeded that for the end-systolic pressure-volume relation and the dP/dtmax-end-diastolic volume relation, and much less linear extrapolation from the measured data was required to determine the volume-axis intercept. Preload recruitable stroke work relations were highly linear (r = 0.95 +/- 0.07), and much more so than end-systolic pressure-volume relations (r = 0.79 +/- 0.23).(ABSTRACT TRUNCATED AT 250 WORDS)

Osteoporosis Current practice and future perspectives.

Initiation of estrogens or other drugs as preventive measures for osteoporosis should be based upon objective estimates of actual, future fracture risk. Bone mass measurements, when considered in the context of age, life expectancy, expected bone loss, and other risk factors, enable improved patient risk stratification, and more rational treatment choices.

The transformation of hexabromocyclododecane in aerobic and anaerobic soils and aquatic sediments.

The biological transformation of hexabromocyclododecane (HBCD), a brominated fire retardant commonly used in a variety of consumer goods, was investigated in aerobic and anaerobic soils and freshwater sediments. Soil, river water, and aquatic sediments were collected from several locations in the United States and transformation of HBCD was evaluated in the correspondingly composed microcosms based on the Organisation for Economic Co-Operation and Development (OECD) Test Guidelines 307 (Aerobic and Anaerobic Transformation in Soil) or 308 (Aerobic and Anaerobic Transformation in Aquatic Sediment Systems). Soil and sediment reaction mixtures, prepared under either aerobic or anoxic conditions, were dosed with HBCD at a concentration ranging from approximately 10 to 80 ng/g dry weight. The soils and sediments were then placed at 20 degrees C for approximately 4 months and the concentration of HBCD in the microcosms was determined at selected time intervals utilizing high-performance liquid chromatography-mass spectrometry (LC-MS). HBCD loss was observed in both the aerobic and anaerobic soils and sediments although the rates were appreciable faster under anoxic conditions. Biologically mediated transformation processes (i.e., biotransformation) accelerated the rate of loss of HBCD when compared to the biologically inhibited (i.e., autoclaved) soils and sediments. Biotransformation half-lives for HBCD were determined to be 63 and 6.9 days in the aerobic and anaerobic soils, respectively, while biotransformation half-lives for HBCD in the two river systems ranged from 11 to 32 days and 1.1 to 1.5 days under aerobic and anaerobic conditions, respectively. Brominated degradation products were not detected in any of the soils or sediments during the course of the study.

Prevention of cigarette smoking-induced platelet aggregate formation by aspirin.

The purpose of this study was to determine whether aspirin could prevent a decrease in the platelet aggregate ratio that we previously found after cigarette smoking. Twenty healthy nonsmokers, who had not taken aspirin in the preceding seven days, smoked two tobacco cigarettes without filters during a 20-minute period. The mean platelet aggregate ratios before and after smoking were 0.91 and 0.80, respectively. When the experiments were repeated 48 hours later and seven to 18 hours after the ingestion of one tablet of aspirin (0.32 g), there was no decrease in the platelet aggregate ratio after smoking. The mean post-smoking platelet aggregate ration after aspirin (0.93) was significantly higher than before aspirin. We conclude that aspirin prevented cigarette smoking-induced platelet aggregate formation.

Passive smoking affects endothelium and platelets.

Blood was obtained before and after ten healthy male nonsmokers sat for 20 minutes in open hospital corridors beside men who were already there smoking by their own initiative. Mean values before and after passive smoking were 0.87 and 0.78 for the platelet aggregate ratio, 2.8 and 3.7 per counting chamber for the endothelial cell count, 0 and 2.8 ng/mL for the plasma nicotine concentration, and 0.9% and 1.3% for the carboxyhemoglobin level. No variable changed significantly during control periods in which the subjects sat in a room where smoking was prohibited. Passive exposure to tobacco smoke affected the endothelial cell count and platelet aggregate ratio in a manner similar to that previously observed with active smoking.

Effect of comprehensive intervention program on survival of patients with human immunodeficiency virus infection.

BACKGROUND: In October 1989, an early intervention program (EIP) for human immunodeficiency virus (HIV) infection was initiated in New Jersey to provide medical care and social services to the enrollees. OBJECTIVE: To assess the overall effect of the EIP on the survival of HIV-infected patients. METHODS: Patient information collected through June 30, 1993, was analyzed from the Jersey City Medical Center EIP clinic. Survival from enrollment to death was calculated for patients who received follow-up at the clinic (active) and for those who only had the enrollment visit (inactive). The data were matched with the New Jersey death certificate registry. RESULTS: Of 938 patients enrolled from October 1989 to December 1991, 767 had T-cell subsets determined within 3 months of enrollment: 641 patients were active and 126 were inactive. At entry, inactive patients had a lower median CD4+ T-cell count and were more likely to be symptomatic than active patients. Among the 640 active and 125 inactive patients analyzed for survival (survivors > or = 2 months), there were 144 (22.5%) and 48 (38.4%) deaths, respectively. Kaplan-Meier analysis indicated longer survival for active patients than for inactive patients (P < .001, Wilcoxon's test for homogeneity of strata); eg, survival probability at 2 years was 86% for active patients and 64% for inactive patients. Active patients also had longer survival than inactive patients when stratified by CD4+ T-cell levels or by clinical status. Only active and inactive patients with both CD4+ T-cell levels lower than 0.20 x 10(9)/L (< 200/microL) and symptoms of HIV or acquired immunodeficiency syndrome had similar survival rates. Survival was not influenced by sex, race, or HIV transmission category. CONCLUSION: Participation in the EIP was associated with longer survival of HIV-infected patients.

Postdischarge geriatric assessment of hospitalized frail elderly patients.

BACKGROUND: The diffusion of comprehensive geriatric assessment services has been rather limited in North America partly because of reimbursement and organizational constraints. OBJECTIVE: To evaluate the impact of a comprehensive geriatric assessment intervention for frail older patients that is started before hospital discharge and is continued at home. METHODS: Patients older than 65 years were selected who had either unstable medical problems, recent functional limitations, or potentially reversible geriatric clinical problems. Patients (n = 354) were randomly assigned to either the intervention group or a control group. Information on survival, readmissions, nursing home placement, medication use, and health status was collected at 30 and 60 days after hospital discharge. RESULTS: No differences were observed between the two treatment groups in survival, hospital readmission, or nursing home placement by 60 days. After adjustment for baseline characteristics, no significant differences were observed between the two groups on measures of physical functioning, social functioning, role limitations, health perceptions, pain, mental health, energy and/or fatigue, health change, or overall well-being. CONCLUSIONS: Although efficacy has been demonstrated for some forms of comprehensive geriatric assessment, the types of services that are easier to establish (inpatient consultation services and ambulatory assessment) have not been shown to improve outcomes. Our results indicate that outcomes are unaffected by a limited form of comprehensive geriatric assessment begun in the hospital and completed at home. Further efforts are needed to develop and to evaluate realistic approaches to comprehensive geriatric assessment.

Soil bioretention protects juvenile salmon and their prey from the toxic impacts of urban stormwater runoff.

Green stormwater infrastructure (GSI), or low impact development, encompasses a diverse and expanding portfolio of strategies to reduce the impacts of stormwater runoff on natural systems. Benchmarks for GSI success are usually framed in terms of hydrology and water chemistry, with reduced flow and loadings of toxic chemical contaminants as primary metrics. Despite the central goal of protecting aquatic species abundance and diversity, the effectiveness of GSI treatments in maintaining diverse assemblages of sensitive aquatic taxa has not been widely evaluated. In the present study we characterized the baseline toxicity of untreated urban runoff from a highway in Seattle, WA, across six storm events. For all storms, first flush runoff was toxic to the daphniid Ceriodaphnia dubia, causing up to 100% mortality or impairing reproduction among survivors. We then evaluated whether soil media used in bioretention, a conventional GSI method, could reduce or eliminate toxicity to juvenile coho salmon (Oncorhynchus kisutch) as well as their macroinvertebrate prey, including cultured C. dubia and wild-collected mayfly nymphs (Baetis spp.). Untreated highway runoff was generally lethal to salmon and invertebrates, and this acute mortality was eliminated when the runoff was filtered through soil media in bioretention columns. Soil treatment also protected against sublethal reproductive toxicity in C. dubia. Thus, a relatively inexpensive GSI technology can be highly effective at reversing the acutely lethal and sublethal effects of urban runoff on multiple aquatic species.