CD3+/CD16+CD56+ cell numbers in peripheral blood are correlated with higher tumor burden in patients with diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma is the commonest histological type of malignant lymphoma, and remains incurable in many cases. Developing more efficient immunotherapy strategies will require better understanding of the disorders of immune responses in cancer patients. NKT (natural killer-like T) cells were originally described as a unique population of T cells with the co-expression of NK cell markers. Apart from their role in protecting against microbial pathogens and controlling autoimmune diseases, NKT cells have been recently revealed as one of the key players in the immune responses against tumors. The objective of this study was to evaluate the frequency of CD3(+)/CD16(+)CD56(+) cells in the peripheral blood of 28 diffuse large B-cell lymphoma (DLBCL) patients in correlation with clinical and laboratory parameters. Median percentages of CD3(+)/CD16(+)CD56(+) were significantly lower in patients with DLBCL compared to healthy donors (7.37% vs. 9.01%, p = 0.01; 4.60% vs. 5.81%, p = 0.03), although there were no differences in absolute counts. The frequency and the absolute numbers of CD3(+)/CD16(+)CD56(+) cells were lower in advanced clinical stages than in earlier ones. The median percentage of CD3(+)/CD16(+)CD56(+) cells in patients in Ann Arbor stages 1-2 was 5.55% vs. 3.15% in stages 3-4 (p = 0.02), with median absolute counts respectively 0.26 G/L vs. 0.41 G/L (p = = 0.02). The percentage and absolute numbers of CD3(+)/CD16(+)CD56(+) cells were significantly higher in DL -BCL patients without B-symptoms compared to the patients with B-symptoms, (5.51% vs. 2.46%, p = 0.04; 0.21 G/L vs. 0.44 G/L, p = 0.04). The percentage of CD3(+)/CD16(+)CD56(+) cells correlated adversely with serum lactate dehydrogenase (R= -445; p 〈 0.05) which might influence NKT count. These figures suggest a relationship between higher tumor burden and more aggressive disease and decreased NKT numbers. But it remains to be explained whether low NKT cell counts in the peripheral blood of patients with DLBCL are the result of their suppression by the tumor cells, or their migration to affected lymph nodes or organs.


Comparison between in-phase and opposed-phase T1-weighted breath-hold FLASH sequences for hepatic imaging.
Our goal was to compare in-phase (IP) and opposed-phase (OP) sequences for GRE breath-hold hepatic imaging. Non-contrast-enhanced IP and OP GRE breath-hold images were obtained in 104 consecutive patients referred for abdominal MRI at 1.0 T. For both sequences, the TR, FA, matrix, FOV, slice thickness, interslice gap, and measurements were kept constant. Images were compared quantitatively [liver/spleen and liver/lesion signal difference/noise ratio, (SD/N)] and qualitatively (artifacts, lesion detection and conspicuity, and intrahepatic anatomy). There was no statistically significant difference when comparing IP and OP sequences for liver/spleen and liver/lesion SD/N or for the qualitative parameters. In patients with fatty infiltration, the OP sequences yielded substantially lower values for liver/spleen and liver/lesion SD/N (0.9 and -1.2, respectively) than the IP sequences (20 and 17, respectively). Furthermore, in several cases with fatty infiltration, many more lesions were identified using IP images. The use of IP and OP GRE sequences provides complementary diagnostic information. Focal liver lesions may be obscured in the setting of fatty infiltration if only OP sequences are employed. A complete assessment of the liver with MR should include both IP and OP imaging.


Modelling aerobic stabilization of domestic and industrial sludge using a multi-component biomass model.
The objective of the study was to investigate the achievable limits of aerobic sludge stabilization applied on waste-activated sludge generated in domestic, tannery, and pharmaceutical wastewater treatment plants. Stabilization study involved monitoring of conventional parameters and model evaluation of oxygen uptake rate and particulate components of waste sludge. Multi-component biomass approach was adopted based on death-regeneration mechanism. The results showed that sludge stabilization efficiency ranged between 25% and 30%, which was closely related to the fate of different particulate fractions of biomass, that is, viable biomass, hydrolysable particulates, and microbial metabolic products. Model calibration exercises yield in rate coefficient ranges of 0.18-0.32/day for biomass decay and 0.60-0.65/day for hydrolysis of non-biomass components. Degradation rates of particulate metabolic products were estimated as 0.035, 0.04, and 0.01/day for domestic, tannery, and pharmaceutical sludge, respectively. Relatively low degradation rates compared to conventional biological treatment processes confirmed reduced microbial activity in the course of aerobic stabilization.


Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
An imbalance between maternal angiogenic/anti-angiogenic factors concentrations has been observed in preeclampsia (PE) and other obstetrical syndromes. However, the frequency of pathologic findings in the placenta and the changes in maternal plasma angiogenic/anti-angiogenic factor concentrations differ between late- and early-onset PE. The aim of this study was to determine if the maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 and 2 (sVEGFR-1 and sVEGFR-2) are different in late-onset PE with and without placental pathologic findings consistent with maternal underperfusion. A cross-sectional study was conducted including 64 uncomplicated women and 66 women with late-onset PE (>34 weeks) who had blood samples and placenta available for pathologic examination. Patients with late-onset PE were divided into those with and without placental histologic findings consistent with maternal underperfusion as proposed by the Society for Pediatric Pathology. Maternal plasma concentrations of PlGF, sEng, sVEGFR-1 and sVEGRF-2 were determined by ELISA. Non-parametric statistics were used for analysis. 1) the prevalence of placental histological findings consistent with maternal underperfusion among women with late-onset PE was higher than that of those with an uncomplicated pregnancy (47% (31/66) vs. 7.8% (5/64), respectively; p < 0.01); 2) patients with late-onset PE and histological findings consistent with maternal underperfusion had a significantly lower median plasma concentration of PlGF, plasma PlGF/sVEGFR-1 ratio and plasma PlGF/sEng ratio than those with late-onset PE without placental underperfusion lesions (each p < 0.05); 3) the most common pathological findings in the placenta of patient with PE were lesions consistent with villous changes (77%, 24/31); and 4) isolated vascular lesions in the placenta were found only in 2 cases (6.5%), and the rest had a combination of villous and vascular lesions. Nearly half of the patients with late-onset PE have placental lesions consistent with maternal underperfusion. These lesions are associated with an imbalance in the maternal concentration of angiogenic/anti-angiogenic factors. We propose that there is a link between maternal underperfusion and an anti-angiogenic state characterized by the changes in the concentrations of angiogenic and anti-angiogenic factors in women with late onset PE.


Persistence with biologic therapies in the Medicare coverage gap.
To describe persistence with teriparatide and other biologic therapies in Medicare Part D plans with and without a coverage gap. Retrospective (2006) cohort study of Medicare Part D prescription drug plan beneficiaries from a large benefits company. Two plans with a coverage gap (defined as "basic") were combined and compared with a single plan with coverage for generic and branded medications (defined as "complete"). Patients taking alendronate (nonbiologic comparator), teriparatide, etanercept, adalimumab, interferon β-1a, or glatiramer acetate were selected for the study. For patients with complete coverage, equivalent financial thresholds were used to define the "gap."The definition of discontinuation was failure to fill the index prescription after reaching the gap. For alendronate, 27% of 133,260 patients had enrolled in the complete plan. Patients taking biologic therapies had more commonly enrolled in complete plans: teriparatide (66% of 6221), etanercept (58% of 1469), adalimumab (52% of 824), interferon β-1a (60% of 438), and glatiramer acetate (53% of 393). For patients taking either alendronate or teriparatide, discontinuation rates were higher in the basic, versus complete, plan (adjusted odds ratios, 2.02 and 3.56, respectively). Discontinuation did not significantly vary by plan type for etanercept, adalimumab, interferon β-1a, or glatiramer acetate. For patients who reached the coverage gap, discontinuation was more likely for patients taking osteoporosis (OP) medication. Not having a coverage gap was associated with improved persistence with OP treatment.


A 2D-ELDOR study of the liquid ordered phase in multilamellar vesicle membranes.
2D-ELDOR spectroscopy has been employed to study the dynamic structure of the liquid-ordered (Lo) phase versus that of the liquid-crystalline (Lc) phase in multibilayer phospholipid vesicles without (Lc) and with (Lo) cholesterol, using end-chain and headgroup labels and spin-labeled cholestane. The spectra are in most cases found to be dramatically different for these two phases. Thus, visual inspection of the 2D-ELDOR spectra provides a convenient way to distinguish the two phases in membranes. Detailed analysis shows these observations are due to increased ordering in the Lo phase and modified reorientation rates. In the Lo phase, acyl chains undergo a faster rotational diffusion and higher ordering than in the Lc phase, whereas spin-labeled cholestane exhibits slower rotational diffusion and higher ordering. On the other hand, the choline headgroup in the Lo phase exhibits faster motion and reduced but realigned ordering versus the Lc phase. The microscopic translational diffusion rates in the Lo phase are significantly reduced in the presence of cholesterol. These results are compared with previous studies, and a consistent model is provided for interpreting them in terms of the differences in the dynamic structure of the Lo and Lc phases.


Sensorineural hearing loss due to Toxoplasma gondii in children: a case-control study.
Sensorineural hearing loss (SNHL) can follow congenital toxoplasmosis. Treatment in the first year of life is associated with diminished occurrence of this sequel. In various parts of Iran, the prevalence of antibodies to Toxoplasma gondii ranges from 24% to 57.7%. We evaluate the possible role of Toxoplasma gondii infection on the occurrence of SNHL in children. This case-control study was performed in a tertiary care center in Tehran between 2002 and 2003. This study was carried out based on diagnostic parameters of the American Academy of Otolaryngology criteria for SNHL and a healthy control group. We compared the specific Toxoplasma gondii antibodies (IgM & IgG) measured by ELISA in 95 blood samples of infants with SNHL and 63 healthy matched infants. Acute (IgM) and previous (IgG) immunity to Toxoplasma gondii was found in 12 and 21.2% of SNHL children, respectively. Most cases with previous infections (IgG positive) were children aged less than 1 year old (i.e. maternal immunity), but acute infection (IgM positive) was higher in 3-5 year old age group. Acute infection (IgM) was significantly more frequent in the SNHL group, and previous immunity was higher in the controls (CI 95%, P-value = 0.01; 0.01). With respect to seropositive children, as we were unable to differentiate congenital from acquired cases, we recommend prevention of congenital toxoplasmosis by treatment of Toxoplasma infection in pregnant women and treatment of acquired Toxoplasma gondii infection after birth to minimise the risk of SNHL in children.


The GRADE system for classification of the level of evidence and grade of recommendations in clinical guideline reports.
There is great inconsistency on how "Clinical Guideline Developers" worldwide rate the quality of evidence and strength of recommendations because there are several classification systems in use. Therefore, medical guideline users face profound challenges in understanding articles on Clinical Guidelines. Many researchers are adopting the GRADE system to classify the quality of the available evidence and the strength of recommendations when preparing a manuscript on Clinical Guidelines. The GRADE system has advantages over previous rating systems including being developed by a representative group of guideline developers, patent separation between quality of evidence and strength of recommendations, explicit evaluation of the importance of outcomes of alternative management strategies, and others. Consequently, in this brief review, we describe the reasons underlying the adoption of GRADE.


Duty of Confidentiality and HIV/AIDS: PD v Harvey.
The issue of doctor-patient confidentiality in situations where the doctor can reasonably foresee that third parties associated with the patient could be put at risk by the patient's medical status is a continuing conundrum. In a case heard in the New South Wales Supreme Court in 1999, BT v Oei (1999) NSWSC 1082, the court held that a medical practitioner owed a duty of care to the sexual partner/s of a patient. Where there were signs/symptoms consistent with a diagnosis of HIV infection, the doctor had a duty to strongly advise the patient to be tested. Where the patient's results were positive, the doctor could not inform the partner/s directly; however, there was an obligation to counsel the patient to inform their partner/s of their HIV status, and to instruct the patient regarding the patient's own statutory responsibility to inform partner/s before engaging in sexual intercourse with them. A second case revolving around the issue of risk to third parties is the case of PD v Dr Nicholas Harvey & I Ors (2003) NSWSC 487, heard in the Supreme Court of NSW in 2003. The facts and the law discussed in this report are drawn from and summarised from the judgment of Cripps AJ.


The human polyomavirus BK (BKPyV): virological background and clinical implications.
Polyomavirus BK (BKPyV) infects most people subclinically during childhood and establishes a lifelong infection in the renourinary tract. In most immunocompetent individuals, the infection is completely asymptomatic, despite frequent episodes of viral reactivation with shedding into the urine. In immunocompromised patients, reactivation followed by high-level viral replication can lead to severe disease: 1-10% of kidney transplant patients develop polyomavirus-associated nephropathy (PyVAN) and 5-15% of allogenic hematopoietic stem cell transplant patients develop polyomavirus-associated haemorrhagic cystitis (PyVHC). Other conditions such as ureteric stenosis, encephalitis, meningoencephalitis, pneumonia and vasculopathy have also been associated with BKPyV infection in immunocompromised individuals. Although BKPyV has been associated with cancer development, especially in the bladder, definitive evidence of a role in human malignancy is lacking. Diagnosis of PyVAN and PyVHC is mainly achieved by quantitative PCR of urine and plasma, but also by cytology, immunohistology and electron microscopy. Despite more than 40 years of research on BKPyV, there is still no effective antiviral therapy. The current treatment strategy for PyVAN is to allow reconstitution of immune function by reducing or changing the immunosuppressive medication. For PyVHC, treatment is purely supportive. Here, we present a summary of the accrued knowledge regarding BKPyV.


Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker.
We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1. Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.


Acetylcholine receptor in a C2 muscle cell variant is retained in the endoplasmic reticulum.
We have examined the properties and intracellular localization of acetylcholine receptors in the C2 muscle cell line and in a variant (T-) that accumulates AChR intracellularly. On immunoblots, the subunit structures of the AChR from wild-type and T- cells were similar except that the gamma and delta subunits of the variant AChR had altered mobilities. Digestion with endoglycosidases H and F demonstrated that this difference results from a failure of high-mannose N-linked oligosaccharides on AChR subunits to be processed to complex forms in the variant. N-linked glycosylation of other proteins in the variant was normal. When examined by immunocytochemistry, the distribution of internal AChR in wild-type cells was consistent with a location both in the endoplasmic reticulum and in the Golgi. Variant cells, however, showed no evidence of Golgi staining. Subcellular fractionation experiments also demonstrated AChR in the Golgi fractions of wild-type cells, but not in those derived from T- cells. We conclude that in T- myotubes most of the AChR fails to be transported out of the endoplasmic reticulum.


A randomised controlled trial comparing palate surgery at 6 months versus 12 months of age (the TOPS trial): a statistical analysis plan.
Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, hearing, dental development, and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. The Timing Of Primary Surgery for cleft palate (TOPS) trial aims to determine whether, in infants with cleft palate, it is better to perform primary surgery at age 6 or 12 months (corrected for gestational age). The TOPS trial is an international, two-arm, parallel group, randomised controlled trial. The primary outcome is insufficient velopharyngeal function at 5 years of age. Secondary outcomes, measured at 12 months, 3 years, and 5 years of age, include measures of speech development, safety of the procedure, hearing level, middle ear function, dentofacial development, and growth. The analysis approaches for primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The TOPS protocol has been published previously. This paper provides details of the planned statistical analyses for the TOPS trial and will reduce the risk of outcome reporting bias and data-driven results. ClinicalTrials.gov NCT00993551 . Registered on 9 October 2009.


An adaptive multi-frame parallel iterative method for accelerating real-time magnetic particle imaging reconstruction.
Objective. Real-time reconstruction of magnetic particle imaging (MPI) shows promising clinical applications. However, prevalent reconstruction methods are mainly based on serial iteration, which causes large delay in real-time reconstruction. In order to achieve lower latency in real-time MPI reconstruction, we propose a parallel method for accelerating the speed of reconstruction methods.Approach. The proposed method, named adaptive multi-frame parallel iterative method (AMPIM), enables the processing of multi-frame signals to multi-frame MPI images in parallel. To facilitate parallel computing, we further propose an acceleration strategy for parallel computation to improve the computational efficiency of our AMPIM.Main results. OpenMPIData was used to evaluate our AMPIM, and the results show that our AMPIM improves the reconstruction frame rate per second of real-time MPI reconstruction by two orders of magnitude compared to prevalent iterative algorithms including the Kaczmarz algorithm, the conjugate gradient normal residual algorithm, and the alternating direction method of multipliers algorithm. The reconstructed image using AMPIM has high contrast-to-noise with reducing artifacts.Significance. The AMPIM can parallelly optimize least squares problems with multiple right-hand sides by exploiting the dimension of the right-hand side. AMPIM has great potential for application in real-time MPI imaging with high imaging frame rate.


Bioinspired Struvite Mineralization for Fire-Resistant Wood.
High-performance wood materials have attracted significant attention in recent years because of excellent property profiles achieved by relatively easy top-down processing of a renewable resource. A crucial flaw of the renewable wood scaffolds is the low flame retardancy, which we tackled by bioinspired mineralization in an eco-friendly processing step. The formation of the biomineral struvite, commonly found in urinary tract stones, was used for the infiltration of hierarchical wood structures with the necessary ions followed by an in situ synthesis of struvite by ammonium steam fumigation. Struvite decomposes prior to wood, which absorbs heat and releases nonflammable gas and amorphous MgHPO4 resulting from the degradation, which promotes insulating char formation. As a result, the mineralized wood can hardly be ignited and the treatment strongly suppresses the heat release rate and smoke production.


Abdominal imaging ordering patterns by referring provider specialty.
Prior work has demonstrated marked growth in the volume of abdominal imaging performed by radiologists. However, decisions to pursue imaging are largely driven by referring providers. In this study, we take the novel approach of investigating abdominal imaging utilization patterns by referring provider specialty. Data on imaging services were obtained from the 2014 DocGraph Medicare Referring Provider Utilization for Procedures (MrPUP) public use file. MrPUP contains aggregated transaction data for combinations of unique referring provider and service code. Imaging services were classified by modality and body region using the Neiman Institute Types of Service (NITOS). Each referring provider's specialty was determined using Medicare Physician Compare. Abdominal imaging ordering patterns were summarized by referring specialty. The final dataset included 5,824,754 abdominal imaging transactions. The most common ordering specialties of abdominal imaging were as follows: (1) internal medicine; (2) urology; (3) emergency medicine; (4) family practice; and (5) gastroenterology. The most common ordering specialties by abdominal imaging modality were emergency medicine for CT; gastroenterology for MRI and nuclear medicine; and internal medicine for ultrasound and radiography. While numerous specialties commonly ordered abdominal radiography and CT, urologists also commonly ordered retroperitoneal ultrasound and retrograde urography, and gastroenterologists also commonly ordered abdominal ultrasound, abdominal MRI, and esophagrams. Internal medicine, family practice, and emergency medicine providers ordered a much broader mix of imaging, including many non-abdominal imaging examinations. Referring specialty abdominal imaging ordering patterns are varied but distinct. Awareness of these patterns may facilitate focused educational and policy initiatives to improve abdominal imaging appropriateness and utilization.


In vivo hydraulic conductivity of muscle: effects of hydrostatic pressure.
We and others have shown that the loss of fluid and macromolecules from the peritoneal cavity is directly dependent on intraperitoneal hydrostatic pressure (Pip). Measurements of the interstitial pressure gradient in the abdominal wall demonstrated minimal change when Pip was increased from 0 to 8 mmHg. Because flow through tissue is governed by both interstitial pressure gradient and hydraulic conductivity (K), we hypothesized that K of these tissues varies with Pip. To test this hypothesis, we dialyzed rats with Krebs-Ringer solution at constant Pip of 0.7, 1.5, 2.2, 3, 4.4, 6, or 8 mmHg. Tracer amounts of 125I-labeled immunoglobulin G were added to the dialysis fluid as a marker of fluid movement into the abdominal wall. Tracer deposition was corrected for adsorption to the tissue surface and for local loss into lymphatics. The hydrostatic pressure gradient in the wall was measured using a micropipette and a servo-null system. The technique requires immobilization of the tissue by a porous Plexiglas plate, and therefore a portion of the tissue is supported. In agreement with previous results, fluid flux into the unrestrained abdominal wall was directly related to the overall hydrostatic pressure difference across the abdominal wall (Pip = 0), but the interstitial pressure gradient near the peritoneum increased only approximately 40% over the range of Pip = 1.5-8 mmHg (20-28 mmHg/cm). K of the abdominal wall varied from 0.90 +/- 0.1 x 10(-5) cm2.min-1.mmHg-1 at Pip = 1.5 mmHg to 4.7 +/- 0.43 x 10(-5) cm2.min-1.mmHg-1 on elevation of Pip to 8 mmHg. In contrast, for the same change in Pip, abdominal muscle supported on the skin side had a significantly lower range of fluid flux (0.89-1.7 x 10(-4) vs. 1.9-10.1 x 10(-4) ml.min-1.cm-2 in unsupported tissue). The differences between supported and unsupported tissues are likely explained in part by a reduced pressure gradient across the supported tissue. In conclusion, the in vivo hydraulic conductivity of the unsupported abdominal wall muscle in anesthetized rats varies with the superimposed hydrostatic pressure within the peritoneal cavity.


A Smart Card-Based Electronic School Absenteeism System for Influenza-Like Illness Surveillance in Hong Kong: Design, Implementation, and Feasibility Assessment.
School-aged children have the highest incidence of respiratory virus infections each year, and transmission of respiratory viruses such as influenza virus can be a major concern in school settings. School absenteeism data have been employed as a component of influenza surveillance systems in some locations. Data timeliness and system acceptance remain as key determinants affecting the usefulness of a prospective surveillance system. The aim of this study was to assess the feasibility of implementing an electronic school absenteeism surveillance system using smart card-based technology for influenza-like illness (ILI) surveillance among a representative network of local primary and secondary schools in Hong Kong. We designed and implemented a surveillance system according to the Protocol for a Standardized information infrastructure for Pandemic and Emerging infectious disease Response (PROSPER). We employed an existing smart card-based education and school administration platform for data capture, customized the user interface, and used additional back end systems built for other downstream surveillance steps. We invited local schools to participate and collected absenteeism data by the implemented system. We compared temporal trend of the absenteeism data with data from existing community sentinel and laboratory surveillance data. We designed and implemented an ILI surveillance system utilizing smart card-based attendance tracking approach for data capture. We implemented the surveillance system in a total of 107 schools (including 66 primary schools and 41 secondary schools), covering a total of 75,052 children. The system successfully captured information on absences for 2 consecutive academic years (2012-2013 and 2013-2014). The absenteeism data we collected from the system reflected ILI activity in the community, with an upsurge in disease activity detected up to 1 to 2 weeks preceding other existing surveillance systems. We designed and implemented a novel smart card technology-based school absenteeism surveillance system. Our study demonstrated the feasibility of building a large-scale surveillance system riding on a routinely adopted data collection approach and the use of simple system enhancement to minimize workload implication and enhance system acceptability. Data from this system have potential value in supplementing existing sentinel influenza surveillance for situational awareness of influenza activity in the community.


Regulation of dipeptide transport in Saccharomyces cerevisiae by micromolar amino acid concentrations.
Prototrophic Saccharomyces cerevisiae X2180, when grown on unsupplemented minimal medium, displayed little sensitivity to ethionine- and m-fluorophenylalanine-containing toxic dipeptides. We examined the influence of the 20 naturally occurring amino acids on sensitivity to toxic dipeptides. A number of these amino acids, at concentrations as low as 1 microM (leucine and tryptophan), produced large increases in sensitivity to leucyl-ethionine, alanyl-ethionine, and leucyl-m-fluorophenylalanine. Sensitivity to ethionine and m-fluorophenylalanine remained high under either set of conditions. The addition of 0.15 mM tryptophan to a growing culture resulted in the induction of dipeptide transport, as indicated by a 25-fold increase in the initial rate of L-leucyl-L-[3H]leucine accumulation. This increase, which was prevented by the addition of cycloheximide, began within 30 min and peaked approximately 240 min after a shift to medium containing tryptophan. Comparable increases in peptidase activity were not apparent in crude cell extracts from tryptophan-induced cultures. We concluded that S. cerevisiae possesses a specific mechanism for the induction of dipeptide transport that can respond to very low concentrations of amino acids.


Comparison of basic elements of human performance scores between urologists with various extents of experience.
An objective evaluation of innate ability and its ability to predict potential success as a surgical trainee is an appealing concept for the selection process of residency applications. The objective of this study was to evaluate whether basic elements of performance (BEP) could discriminate among resident applicants and urologists with various extents of surgical experience. One hundred forty-five participants were divided into four study groups: group A, 57 urology residency applicants to the 2002 and 2003 interview process; group B, 8 post-internship urology residents; group C, 19 urologists tested with BEP within 10 years of graduation from their residency training program; and group D, 61 urologists who had graduated from their residency training program more than 10 years prior to testing. The BEP measures consisted of 13 basic performance resources (BPR) including visual-information processing speed, visual-spatial immediate-recall capacity, and neuromotor channel capacity. The four study groups differed significantly in their mean age: group A=27.6 years, group B=29.1 years, group C=37.1 years, and group D=48.9 years (P<0.0005). There was essentially no significant difference between the groups with regard to immediate-recall memory, reaction time simple, or reaction time complicated. The younger participants (groups A and B) were faster than the older surgeons (groups C and D) (P<0.02). However, the older surgeons (groups C and D) were significantly more accurate than the younger groups (A and B) (P<0.0005). The only sex differences noted were in hand-grip strength and shoulder-strength scores, which were all higher in the men. There generally appears to be a lack of direct correlation between innate abilities and surgical experience. Urology resident applicants with no surgical experience and urology residents with limited surgical experience are faster but less accurate in innate skills testing than experienced practicing urologists.


Systematic Review of Costs and Effects of Self-Management Interventions for Chronic Musculoskeletal Pain: Spotlight on Analytic Perspective and Outcomes Assessment.
Evidence for the cost-effectiveness of self-management interventions for chronic musculoskeletal pain (CMP) lacks consensus, which may be due to variability in the costing methods employed. The purposes of the study were to identify how costs and effects have been assessed in economic analysis of self-management interventions for CMP and to identify the effect of the chosen analytical perspective on cost-effectiveness conclusions. Five databases were searched for all study designs using relevant terms. Two independent researchers reviewed all titles for predefined inclusion criteria: adults (≥18 years of age) with CMP, interventions with a primary aim of promoting self-management, and conducted a cost analysis. Descriptive data including population, self-management intervention, analytical perspective, and costs and effects measured were collected by one reviewer and checked for accuracy by a second reviewer. Fifty-seven studies were identified: 65% (n = 37) chose the societal perspective, of which 89% (n = 33) captured health care utilization, 92% (n = 34) reported labor productivity, 65% (n = 24) included intervention delivery, and 59% (n = 22) captured patient/family costs. Types of costs varied in all studies. Eight studies conducted analyses from both health service and societal perspectives; cost-effectiveness estimates varied with perspective chosen, but in no case was the difference sufficient to change overall policy recommendations. Chronic musculoskeletal pain conditions where self-management is recommended, but not as a primary treatment, were excluded. Gray literature was excluded. Substantial heterogeneity in the cost components captured in the assessment of self-management for CMP was found; this was independent of the analytic perspective used. Greater efforts to ensure complete and consistent costings are required if reliable cost-effectiveness evidence of self-management interventions is to be generated and to inform the most appropriate perspective for economic analyses in this field.


Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks.
Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle arrest in G2 /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes. Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by PE may be exploited for sensitization of tumors to anticancer drugs.


Prevention of pressure ulcers in elderly nursing home residents: are special support surfaces the answer?
This article describes a research study that compared the effectiveness of two pressure-reducing devices in a group of elderly nursing home residents. The results obtained revealed no significant differences between the two devices--an air-filled overlay and a gel mattress--in terms of pressure ulcer incidence, severity, and healing. Several factors contributed to these results and illustrate the problems encountered when preventing pressure ulcer development in a group of elderly, debilitated nursing home residents. These factors include ease of use of the pressure-reducing device, caregiver and facility characteristics, and critical patient variables. Until these variables are addressed, it is impossible for any device to be effective in preventing pressure ulcer development in nursing homes.


Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study.
Most studies on the primary prevention of cardiovascular disease (CVD) have been limited to patients at high CVD risk. We assessed the achievement of treatment goals for CVD risk factors among patients with a substantial variation in CVD risk. This study was conducted with 7641 outpatients aged ≥50 years, free of clinical CVD and with at least one major CVD risk factor, selected from 12 European countries in 2009. Risk factor definition and treatment goals were based on the 2007 European guidelines on CVD prevention. Cholesterol fractions and glycated haemoglobin (HbA1c) were measured in a central laboratory. Cardiovascular disease risk was estimated with the SCORE equation. Patients' mean age was 63 years (48% men), and 40.1% had a high CVD risk. Among treated hypertensives (94.2%), only 38.8% achieved the blood pressure target of <140/90 mmHg [between-country range (BCR): 32.1-47.5%]. Among treated dyslipidaemic patients (74.4%), 41.2% attained both the total- and LDL-cholesterol target of <5 and <3 mmol/L, respectively (BCR: 24.3-68.4%). Among treated type 2 diabetic patients (87.2%), 36.7% achieved the <6.5% HbA1c target (BCR: 23.4-48.4%). Among obese patients on non-pharmacological treatment (92.2%), 24.7% reached the body mass index target of <30 kg/m(2) (BCR: 12.7-37.1%). About one-third of controlled patients on treatment were still at high remaining CVD risk. Although most patients were advised to reduce excess weight and to follow a low-calorie diet, less than half received written recommendations. In Europe, a large proportion of patients in primary prevention have CVD risk factors that remain uncontrolled, and lifestyle counselling is not well implemented; moreover, there is substantial between-country variation, which indicates additional room for improvement. Raised residual CVD risk is relatively frequent among patients despite control of their primary risk factors and should be addressed.


Cyclooxygenase-2 inhibitors: are they really atherothrombotic, and if not, why not?
BACKGROUND AND SUMMARY: Selective cyclooxygenase (COX)-2 inhibitors are increasingly being used in place of "conventional" nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2 inhibitors has been questioned because they selectively reduce prostacyclin production, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns appear to be supported by the results of clinical trials demonstrating an increased risk of myocardial infarction with COX-2 inhibitors compared with a conventional NSAID, and indirect comparisons of the rates of myocardial infarction among patients treated with a selective COX-2 inhibitor compared with aspirin in different trials. However, emerging data from animal, experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic, and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of randomized trials of selective COX-2 inhibitors compared with placebo have demonstrated no excess of cardiovascular events among patients allocated COX-2 inhibitors, and preliminary data from a randomized controlled trial of the selective COX-2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with aspirin, demonstrated a reduction in cardiovascular events among patients allocated the COX-2 inhibitor. Continuing uncertainty regarding the direction and magnitude of any cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and increasing use, mandates prospective randomized evaluation of their efficacy and safety in patients at increased risk of future cardiovascular events.


A Two Parameters for the Evaluation of Hypovolemia in Patients with Septic Shock: Inferior Vena Cava Collapsibility Index (IVCCI), Delta Cardiac Output.
BACKGROUND The aim of this study was to determine the correlation between inferior vena cava collapsibility index and changes in cardiac output measured during passive leg raising test in patients with spontaneous breathing and septic shock. MATERIAL AND METHODS Fifty-six patients were included in the study. All of these 56 patients were diagnosed with septic shock and had spontaneous breathing under continuous positive airway pressure. Patients exclusions included: patients with cardiac pathology, not septic shock, pregnant, spontaneous breathing, increased intra-abdominal pressure, inferior vena cava could not be visualized, arrhythmia and pulmonary hypertension. Exclusion criteria for the study were as follows: 1) left ventricular systolic dysfunction, 2) cardiomyopathy, 3) medium severe heart valve disease, 4) patients with arrhythmia; 5) pulmonary hypertension, 6) patients without spontaneous breathing (for inferior vena cava collapsibility index, it is not evaluated), 7) patients with >60 mmHg CO₂ in arterial blood gas; 8) pregnant patients; 9) patients with neurogenic shock, cerebrovascular incident or traumatic brain injury, 10) patients whose inferior vena cava and parasternal long axis cannot be visualized, and 11) patients with increased intra-abdominal pressure. Patients were placed in neutral supine position, and the inferior vena cava collapsibility index and cardiac output 1 were recorded. In passive leg raising test, after which the cardiac output 2 is recorded in terms of L/min. The percentage increase between the 2 cardiac outputs was calculated and recorded. RESULTS A moderately positive correlation was also observed between the inferior vena cava collapsibility index and delta cardiac output (r=0.459; r2=0.21), which was statistically significant (P<0.001). The cutoff value for the delta cardiac output was 29.5. CONCLUSIONS In conclusion, we found that the inferior vena cava collapsibility index, which is one of the dynamic parameters used in the diagnosis of hypovolemia in patients with septic shock, is correlated with delta cardiac output after leg raising test. We believe that, based on a clinician's experience, looking at 1 of these 2 parameters is sufficient for the identification of hypovolemia in patients diagnosed with septic shock.


Columnar islands in Barrett's esophagus: Do they impact Prague C&M criteria and dysplasia grade?
The standard for classifying Barrett's metaplasia on endoscopy, the Prague C&M criteria, ignores all islands of metaplastic-appearing tissue. The aims of the present study were to measure the prevalence of columnar islands, quantify their impact on metaplasia extent, and determine if they harbor advanced dysplasia. Data from two prospective patient cohorts were retrospectively analyzed. They included adults who underwent upper endoscopy to evaluate for gastroesophageal reflux disease, Barrett's esophagus (BE), dysplasia, or adenocarcinoma between 2003 and 2012 at tertiary care centers in the USA and Germany. The BE pattern, location, and pathology were examined. The extent of BE as defined by the Prague criteria (disregarding the location of islands) was compared with the complete maximal extent of BE (incorporating the location of islands). A total of 555 patients underwent endoscopy (mean age 60.1 years, 67.2% male, 91.9% white). Among those patients, 191 (34.4%) showed metaplastic-appearing mucosa in islands. Endoscopically, in 101 (52.9%) cases, islands were proximal to the farthest segment of BE as defined by the Prague M location. Histologically, intestinal metaplasia was confirmed in 60 (58.8%) of the 102 esophagogastroduodenoscopies (EGDs) where islands were biopsied. In 41 (40.2%) cases, the histologically confirmed BE islands extended farther than the maximal segment based on the Prague criteria. Pathology from biopsies of islands either changed the diagnosis or worsened the BE dysplasia grade in 16 (15.7%) of the 102 patients. Columnar islands are commonly seen on EGD. The Prague C&M criteria may underestimate the maximal extent of BE and overlook the area of highest dysplasia grade.


Discordant QuantiFERON-TB Gold test results among US healthcare workers with increased risk of latent tuberculosis infection: a problem or solution?
In late 2006, our hospital implemented use of the QuantiFERON-TB Gold (QFT-G) assay, a whole-blood interferon-gamma release assay, for detection of tuberculosis infection. All newly hired healthcare workers (HCWs) with positive Mantoux tuberculin skin test (TST) results were routinely tested with the QFT-G assay, to take advantage of its higher specificity. We then undertook a quality assurance review to evaluate the QFT-G test results in HCWs with multiple risk factors for latent tuberculosis infection (LTBI). The clinical records for TST-positive HCWs tested with the QFT-G assay were reviewed. HCWs with 2 or more risk factors commonly associated with LTBI were classified as "increased risk" (IR). IR HCWs who had negative QFT-G test results underwent repeat QFT-G testing and were offered testing with a different interferon-gamma release assay (T-SPOT.TB) and with extended T cell stimulation assays. Of 143 TST-positive HCWs tested with the QFT-G assay, 26 (18%) had positive results, 115 (81%) had negative results, and 2 (1%) had indeterminate results. Of 82 IR HCWs, 23 (28%) had positive QFT-G test results, and 57 (70%) had negative results. Of the 57 IR HCWs with negative results, 43 underwent repeat QFT-G testing: 41 had negative results again, and 2 had positive results. These 43 HCWs were also offered additional testing with the T-SPOT.TB diagnostic, and 36 consented: 31/36 tested negative, and 5/36 tested positive. Extended assays using the antigens ESAT-6 and CFP-10 confirmed the positive results detected by the overnight assays and yielded positive results for an additional 7/36 (19%) of individuals; strikingly, all 36 HCWs had strongly positive test results with assays using purified protein derivative. The extreme discordance between the results of our clinical diagnostic algorithm and the results of QFT-G testing raises concern about the sensitivity of the QFT-G assay for detection of LTBI in our HCWs. Results of extended stimulation assays suggest that many of our IR HCWs have indeed been sensitized to Mycobacterium tuberculosis. It is possible that the QFT-G assay identifies those at higher reactivation risk rather than all previously infected, but, in the absence of long-term follow-up data, we should interpret negative QFT-G results with some caution.


Timing of Creatine Supplementation around Exercise: A Real Concern?
Creatine has been considered an effective ergogenic aid for several decades; it can help athletes engaged in a variety of sports and obtain performance gains. Creatine supplementation increases muscle creatine stores; several factors have been identified that may modify the intramuscular increase and subsequent performance benefits, including baseline muscle Cr content, type II muscle fibre content and size, habitual dietary intake of Cr, aging, and exercise. Timing of creatine supplementation in relation to exercise has recently been proposed as an important consideration to optimise muscle loading and performance gains, although current consensus is lacking regarding the ideal ingestion time. Research has shifted towards comparing creatine supplementation strategies pre-, during-, or post-exercise. Emerging evidence suggests greater benefits when creatine is consumed after exercise compared to pre-exercise, although methodological limitations currently preclude solid conclusions. Furthermore, physiological and mechanistic data are lacking, in regard to claims that the timing of creatine supplementation around exercise moderates gains in muscle creatine and exercise performance. This review discusses novel scientific evidence on the timing of creatine intake, the possible mechanisms that may be involved, and whether the timing of creatine supplementation around exercise is truly a real concern.


Next generation of antibody therapy for cancer.
Monoclonal antibodies (mAbs) have become a major class of therapeutic agents providing effective alternatives to treating various human diseases. To date, 15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs. mAb-based regimens have brought clinical benefits, including improvements in overall survival, to patients with a variety of cancers. Many challenges still remain, however, to fully realize the potential of these new medicines. With our further understanding of cancer biology, mechanism of antibody action, and advancement of antibody engineering technologies, many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics. Carefully designed and engineered, they retain the advantage of specificity and selectivity of original antibodies, but in the meantime acquire additional special features such as improved pharmacokinetics, increased selectivity, and enhanced anticancer efficacy. Promising clinical results are being generated with these newly improved antibody-based therapeutics.


VariantTools: an extensible framework for developing and testing variant callers.
Variant calling is the complex task of separating real polymorphisms from errors. The appropriate strategy will depend on characteristics of the sample, the sequencing methodology and on the questions of interest. We present VariantTools, an extensible framework for developing and testing variant callers. There are facilities for reproducibly tallying, filtering, flagging and annotating variants. The tools are extensible, modular and flexible, so that they are tunable to particular use cases, and they interoperate with existing analysis software so that they can be embedded in established work flows. VariantTools is available from http://www.bioconductor.org/. email@example.com. Supplementary data are available at Bioinformatics online.


Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer.
We assess risks, toxicity and side effects of multiple and repeat in situ suicide gene therapy in patients with localized prostate cancer. The study population comprised patients with localized prostate cancer receiving multiple and/or repeat intraprostatic injections of a replication deficient adenovirus containing the herpes simplex virus thymidine kinase (HSV-tk) gene. Intravenous ganciclovir or oral valaciclovir was given for 14 days after injection. Patients were recruited from 4 different clinical protocols in studies of toxicity and efficacy of suicide gene therapy, and closely monitored for toxicity and side effects during and after treatment. Toxicity was graded according to the Cancer Therapy Evaluation Program common toxicity criteria published by the National Cancer Institute. A total of 52 patients were treated under these clinical protocols with a total of 76 gene therapy cycles. Toxic events were recorded in 16 of 29 patients (55.2%) who were given multiple viral injections into the prostate, 7 of 20 (35%) who received 2 cycles of "suicide" gene therapy and 3 of 4 (75%) who received a third course of gene therapy. All toxic events after multiple or repeat injections were mild (grades 1 to 2) and resolved completely once the therapy course was terminated. No additive toxicity was noted in patients receiving repeat gene therapy cycles. Mean followup was 12.8 months (range 3 to 34). Preliminary results for 28 patients in 2 clinical protocols indicated a mean decrease of 44% in PSA in 43%. Direct injection into the prostate of a replication defective adenovirus containing the HSV-tk gene followed by intravenous ganciclovir is safe even in repeat cycles.


Factors associated with health care access and outcome.
This study aims to (1) assess ethnic differences in health care access and health outcome between Asian Americans and whites and between Asian American subgroups, (2) examine effects of cultural factors, and (3) investigate moderating effects of health risk behaviors between cultural characteristics and health care access and outcome. Data were derived from the 2007 California Health Interview Survey. Asian Americans (n = 4,462) and whites (n = 4,470) were included. There were significant ethnic differences in health care access and health perception between Asian Americans and Whites and across Asian American subgroups. Health risk behaviors moderated relationships between cultural factors and health care access and outcome. Findings reveal that ethnicity affects an individual's health care access and health perception, and their health behaviors are an important factor that may improve or worsen outcomes. This study may increase our knowledge base of research and interventions to enhance ethnic minority populations' health care accessibility and perceptions.


Location is everything: let-7b microRNA and TLR7 signaling results in a painful TRP.
Extracellular let-7b, a microRNA found in the central nervous system, affects neurons through its interaction with Toll-like receptor 7 (TLR7), but with divergent outcomes in different neurons. Lehmann et al. found that let-7b stimulation of cortical and hippocampal neurons led to neuronal apoptosis, whereas Park et al. report that let-7b activation of TLR7 stimulated the cation channel transient receptor potential A1 (TRPA1) on dorsal root ganglia sensory neurons and induced pain responses. The primary difference that may influence these distinct responses to let-7b is the localization of TLR7 to the endosome in the cortical and hippocampal neurons or the plasma membrane in the sensory neurons. These studies suggest that different types of neurons traffic TLR7 to distinct membrane locations, affecting the functional response of neurons to let-7b stimulation.


Social networking between mobile introns and their host genes.
Homing endonucleases have long been known as the orchestrators of intron mobility. However, the extent of their influence on the intron and its genetic and cellular environment is still being elucidated. The accompanying paper emphasizes the importance of temporal control of endonuclease expression on splicing, expression of the host gene and cellular metabolism, while it raises questions to guide future inquiry.


Iron hydroxyphosphate electro-Fenton catalyst for efficient removal of sulfamethoxazole and resource recycling into slow-release fertilizer ammonium ferrous phosphate.
Although the electro-Fenton (EF) process is effective for wastewater treatment, recycling spent catalysts remain a major challenge. Therefore, we introduce a reuse strategy for spent catalysts where an iron hydroxyphosphate [Fe5(PO4)4(OH)3·2H2O] catalyst is utilized. Fe5(PO4)4(OH)3·2H2O obtained •OH and •O2- by activating in-situ produced H2O2, and the degradation rate of sulfamethoxazole reached 94.5% after 120 min and showed excellent stability (maintained above 90%) for 10 cycles. Finally, the used catalyst was converted into slow-release ammonium ferrous phosphate (NH4FePO4·H2O) fertiliser at a conversion rate of 85.6%. NH4FePO4·H2O significantly promoted plant and seed growth within 6 days, highlighting the contribution of the resource recycling of the spent catalyst. This study serves as a valuable reference for the efficient utilization of spent catalysts. This study successfully applied EF catalysts and explored the recycling of spent catalysts.


Long-term comparison of cryoballoon and radiofrequency ablation of paroxysmal atrial fibrillation: a propensity score matched analysis.
Although radiofrequency (RF) and cryoballoon (CB) based technologies for pulmonary vein isolation (PVI) have both individually been demonstrated to be effective and safe for the treatment of paroxysmal AF, head-to-head comparisons are lacking. The purpose of this study was to compare the outcome of cryoballoon versus radiofrequency ablation in patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation. Out of a prospective registry of 327 patients undergoing PVI, 208 patients (age 58±11 years, ejection fraction 59±6%, left atrial size 39±6 mm) with paroxysmal AF were identified. The presented dataset was obtained by 1:1 propensity score matching and contained 142 patients undergoing CB-PVI or RF-PVI in conjunction with a 3D mapping system, respectively. We compared single procedure efficacy of the two methods using a Cox proportional hazards model. After a mean follow-up of 28 months and a single procedure, AF recurred in 37 of 71 (52%) in the CB-PVI group and in 31 of 71 patients (44%) in the RF-PVI group (HR [95% CI]=1.19 [0.74, 1.92], p=0.48). Recurrence of AF for PVI using solely the CB was observed in 23 of 51 (45%) patients and in 23 of 51 (45%) patients in the corresponding RF-PVI group (HR [95% CI]=0.93 [0.52, 1.66], p=0.81). Complication rate was not different between the groups. A propensity score matched comparison between CB-PVI and RF-PVI using a 3D-mapping system for AF ablation showed similar long-term success rates.


Residual renal function and dialysis modality: is it really beneficial to preserve residual renal function in dialysis patients?
Residual renal function (RRF) contributes to the achievement of treatment adequacy in stage 5 chronic kidney disease (CKD-5) patients. It may facilitate patients' acceptance of renal replacement therapy (RRT) in allowing reduction of treatment time duration and minimising dietary and fluid restriction. It has been confirmed to improve dialysis patient outcomes. Attempts to preserve RRF in incident Stage 5 chronic kidney disease patients are still subject to intense controversies in the nephrology community. The aim of this review is to analyse the role of renal replacement modalities in the maintenance of RRF in dialysis patients. Under the scope of this manuscript, four questions are explored: Is the preservation of residual renal function an objective for dialysis adequacy? Does dialysis modality affect the decline of RRF? What are the factors implicated by this loss of RRF? At what expense can the maintenance of RRF be achieved in dialysis patients? Preservation of RRF is undoubtedly an interesting means to enhance the efficacy of renal replacement therapy and reduce dietary fluid restriction but it should not be considered as a goal of dialysis adequacy in dialysis patients. Further, preservation of RRF must be considered as a permanent trade-off between patient comfort and chronic fluid volume overload.


Trends in immune cell function assay and donor-specific HLA antibodies in kidney transplantation: A 3-year prospective study.
The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.


Development of the Pre-gnathal Segments in the Milkweed Bug Oncopeltus fasciatus Suggests They Are Not Serial Homologs of Trunk Segments.
The three anterior-most segments in arthropods contain the ganglia that make up the arthropod brain. These segments, the pre-gnathal segments (PGS), are known to exhibit many developmental differences to other segments, believed to reflect their divergent morphology. We have analyzed the expression and function of the genes involved in the conserved segment-polarity network, including genes from the Wnt and Hedgehog pathways, in the PGS, compared with the trunk segments, in the hemimetabolous insect Oncopeltus fasciatus. Gene function was tested by manipulating expression through RNA interference against components of the two pathways. We show that there are fundamental differences in the expression patterns of the segment polarity genes, in the timing of their expression and in the interactions among them in the process of pre-gnathal segment generation, relative to all other segments. We argue that given these differences, the PGS should not be considered serially homologous to trunk segments. This realization raises important questions about the differing evolutionary ancestry of different regions of the arthropod head.


Presentation of 3D Scenes Through Video Example.
Using synthetic videos to present a 3D scene is a common requirement for architects, designers, engineers or Cultural Heritage professionals however it is usually time consuming and, in order to obtain high quality results, the support of a film maker/computer animation expert is necessary. We introduce an alternative approach that takes the 3D scene of interest and an example video as input, and automatically produces a video of the input scene that resembles the given video example. In other words, our algorithm allows the user to "replicate" an existing video, on a different 3D scene. We build on the intuition that a video sequence of a static environment is strongly characterized by its optical flow, or, in other words, that two videos are similar if their optical flows are similar. We therefore recast the problem as producing a video of the input scene whose optical flow is similar to the optical flow of the input video. Our intuition is supported by a user-study specifically designed to verify this statement. We have successfully tested our approach on several scenes and input videos, some of which are reported in the accompanying material of this paper.


Relatively random: context effects on perceived randomness and predicted outcomes.
This article concerns the effect of context on people's judgments about sequences of chance outcomes. In Experiment 1, participants judged whether sequences were produced by random, mechanical processes (such as a roulette wheel) or skilled human action (such as basketball shots). Sequences with lower alternation rates were judged more likely to result from human action. However, this effect was highly context-dependent: A moderate alternation rate was judged more likely to indicate a random physical process when encountered among sequences with lower alternation rates than when embedded among sequences with higher alternation rates. Experiment 2 found the same effect for predictions of the next outcome following a streak: A streak of 3 at the end of the sequence was judged less likely to continue by participants who had encountered shorter terminal streaks in previous trials than by those who had encountered longer ones. These contrast effects (a) help to explain variability in the types of sequences that are judged to be random and that elicit the gambler's fallacy, and urge caution about attempts to establish universal parameterizations of these effects; (b) are congruent with theories of sequence judgment that emphasize the importance of people's actual experiences with sequences of different kinds; (c) provide a link between models of sequence judgment and broader accounts of psychophysical/economic judgment; and (d) may offer new insight into individual differences in randomness judgments and sequence predictions.


What patient assessment skills are required by pharmacists prescribing systemic anti-cancer therapy? A consensus study.
In the UK, pharmacist independent prescribers can prescribe for any condition within their clinical competence including systemic anti-cancer therapy. Competency frameworks have been developed but contain little detail on the patient assessment skills pharmacist independent prescribers require to prescribe systemic anti-cancer therapy with concern in the literature over current training on these skills. To gain consensus on the patient assessment skills required by pharmacist independent prescribers prescribing systemic anti-cancer therapy for genitourinary cancer (prostate and renal) and lung cancer across National Health Service Scotland. Two phases were performed to generate patient assessment skill consensus. Initially, the Nominal Group Technique was performed within a local cancer network by discussion and participant ranking within genitourinary and lung cancer multi-disciplinary teams. Where consensus was achieved, patient assessment skills were carried forward to try to achieve national (National Health Service Scotland) consensus using a two-round Delphi questionnaire. Of the 27 patient assessment skills, consensus was gained for 21 and 23 patient assessment skills in the genitourinary and lung Nominal Group Technique groups, respectively. Within the genitourinary and lung national groups, 13/21 and 18/23 patient assessment skills were agreed as required for a pharmacist independent prescriber to prescribe systemic anti-cancer therapy in genitourinary and lung cancer, respectively. Eight common patient assessment skills were identified as core skills. Reasons for not reaching consensus included pharmacist independent prescriber competence, knowledge, skills and the roles and responsibilities of pharmacist independent prescribers within the multi-disciplinary team. We identified the core and specific patient assessment skills required to prescribe systemic anti-cancer therapy within two tumour groups. Further work is necessary to develop patient assessment skill competency frameworks, training and assessment methods and to redefine the roles of pharmacist independent prescribers within the multi-disciplinary team.


Pilot evaluation of mirtazapine for the treatment of hot flashes.
This prospective, single-arm, pilot clinical trial, developed to evaluate the efficacy and tolerability of mirtazapine for alleviating hot flashes, was conducted between May 2001 and January 2002. Patients' baseline characteristics were collected during the first week of the study. At the beginning of the second week, patients were started on mirtazapine at a dose of 7.5 mg at bedtime. The dose of mirtazapine was then increased to 15 mg at week 3 and to 30 mg at week 4. For week 5, patients could choose whether to take 15 mg/d or 30 mg/d. Data were obtained primarily from patient-completed questionnaires. Data from 22 evaluable women were available. For the 16 patients who completed the study, the median reductions in total daily hot flashes and weekly hot-flash scores from their baselines were 52.5% and 59.5%, respectively. Patients reported improvements in tension, trouble sleeping, abnormal sweating, distress from hot flashes, satisfaction with hot-flash control, overall quality of life, and impact of hot flashes on quality of life. Patients also reported increases in appetite and dry mouth. Although data from a double-blind, placebo-controlled clinical trial would be necessary to more definitively elucidate the efficacy and toxicity of mirtazapine in patients with hot flashes, the available data suggest that mirtazapine is a reasonable treatment to consider in patients with hot flashes, particularly in those with anxiety and sleep disturbances.


[Latest progress in internal medicine].
Internal medicine continues de evolve as a result of further insight and evidence for the efficacy of given interventions. Although numerous studies have addressed issues concerning the SARS-COV-2 epidemic, multiple novelties concerning other frequent pathologies have also been presented. Management strategies of cardiovascular disease, infectious diseases and venous thromboembolism are particularly concerned.


Diagnostic delay, comorbid hidradenitis suppurativa and the prognostic value of bacterial culture in folliculitis decalvans: A cohort study.
Folliculitis decalvans (FD) is a type of primary neutrophilic cicatricial alopecia often leading to irreversible hair loss. Data on its epidemiology, clinical features, outcomes, and prognostic factors are limited. To evaluate a cohort of patients with FD and identify characteristics of severe disease and prognostic factors which impede remission. This retrospective cohort study included 192 patients diagnosed with FD and followed for at least six months at a tertiary center between 2010 and 2020. There was a diagnostic delay averaging 22.2 (± 29.7) months. Comorbid follicular occlusion disorders were common. Bacterial cultures were positive in 45.6% of the cases, with Staphylococcus (S.) aureus being the most common pathogen. Severe disease was associated with comorbid hidradenitis suppurativa and a positive bacterial culture, particularly S. aureus. 50.7% of patients experienced complete remission: 32% within the first six months of treatment and 18.7% later during follow-up. Relapses were frequent. Negative prognostic factors for achieving remission included younger age and a positive bacterial culture. There is a need for the education of dermatologists to reduce the diagnostic delay. Screening FD patients for comorbid hidradenitis suppurativa and obtaining bacterial cultures is important for treatment planning.


A one year pay-as-you-speed trial with economic incentives for not speeding.
The objective was to identify whether it was possible to change driver behavior by economic incentives and thereby reduce crash risk. Furthermore, the objective was to evaluate the participants' attitudes toward the pay-as-you-speed (PAYS) concept. A one-year PAYS trial with economic incentives for keeping speed limits using intelligent speed assistance (ISA) was conducted in Sweden during 2011-2012. The full incentive was a 30 percent discount off the insurance premium. The participants were private insurance customers and were randomized into a test group (initial n = 152, final n = 128) and a control group (initial n = 98, final n = 68). When driving, the drivers in the test group were informed and warned visually when the speed limit was exceeded. They could also follow their driving results on a personal website. The control group was not given any feedback at all. To reflect the impact of the PAYS concept the proportion of distance driven above the speed limit was compared between the 2 groups. The introduction of a PAYS concept shows that the test group significantly reduced the proportion of distance driven above the speed limit. The proportion of driving at a speed exceeding 5 km/h over the speed limit was 6 percent for the test group and 14 percent for the control group. It also showed that the effect was higher the higher the violation of speed. The result remained constant over time. It was shown that a PAYS concept is an effective way to reduce speed violations. Hence, it has the possibility to reduce crash severity and thereby to save lives. This could be an important step toward a safer road transport system. The majority of the participants were in favor of the concept, which indicates the potential of a new insurance product in the future.


Localizing and estimating causal relations of interacting brain rhythms.
Estimating brain connectivity and especially causality between different brain regions from EEG or MEG is limited by the fact that the data are a largely unknown superposition of the actual brain activities. Any method, which is not robust to mixing artifacts, is prone to yield false positive results. We here review a number of methods that allow for addressing this problem. They are all based on the insight that the imaginary part of the cross-spectra cannot be explained as a mixing artifact. First, a joined decomposition of these imaginary parts into pairwise activities separates subsystems containing different rhythmic activities. Second, assuming that the respective source estimates are least overlapping, yields a separation of the rhythmic interacting subsystem into the source topographies themselves. Finally, a causal relation between these sources can be estimated using the newly proposed measure Phase Slope Index (PSI). This work, for the first time, presents the above methods in combination; all illustrated using a single, simulated data set.


Prediction of Spasticity through Upper Limb Active Range of Motion in Stroke Survivors: A Generalized Estimating Equation Model.
We aim to study the association between spasticity and active range of motion (ROM) during four repetitive functional tasks such as cone stacking (CS), fast flexion-extension (FFE), fast ball squeezing (FBS), and slow ball squeezing (SBS), and predicted spasticity models. An experimental study with control and stroke groups was conducted in a Medical Center. A total of sixty-four participants, including healthy control (n = 22; average age (years) = 54.68 ± 9.63; male/female = 12/10) and chronic stroke survivors (n = 42; average age = 56.83 ± 11.74; male/female = 32/10) were recruited. We employed a previously developed smart glove device mounted with multiple inertial measurement unit (IMU) sensors on the upper limbs of healthy and chronic stroke individuals. The recorded ROMs were used to predict subjective spasticity through generalized estimating equations (GEE) for the affected side. The models have significant (p ≤ 0.05 *) prediction of spasticity for the elbow, thumb, index, middle, ring, and little fingers. Overall, during SBS and FFE activities, the maximum number of upper limb joints attained the greater average ROMs. For large joints, the elbow during CS and the wrist during FFE have the highest average ROMs, but smaller joints and the wrist have covered the highest average ROMs during FFE, FBS, and SBS activities. Thus, it is concluded that CS can be used for spasticity assessment of the elbow, FFE for the wrist, and SBS, FFE, and FBS activities for the thumb and finger joints in chronic stroke survivors.


Hereditary colon cancer: lynch syndrome.
Lynch syndrome is the most common familial colorectal cancer syndrome. It is linked to germline mutations in one of four DNA mismatch repair (MMR) genes. A comprehensive family history is one important way to identify at-risk individuals. The elucidation of the molecular genetics of this syndrome has made it possible to screen for the disorder with molecular tests. Microsatellite instability and/or immunohistochemistry followed by germline testing for mutations in MMR genes is now a standard approach for clinically suspected cases. Correctly recognizing Lynch syndrome is essential for the application of appropriate screening and surveillance measures. Close surveillance and risk-reducing operations can decrease cancer-related mortality. In addition, counseling is an important component of the management of any family with Lynch syndrome.


Peer-based interventions targeting suicide prevention: A scoping review.
Peers of individuals at risk for suicide may be able to play important roles in suicide prevention. The aim of the current study is to conduct a scoping review to characterize the breadth of peer-delivered suicide prevention services and their outcomes to inform future service delivery and research. Articles were selected based on search terms related to peers, suicide, or crisis. After reviews of identified abstracts (N = 2681), selected full-text articles (N = 286), and additional references (N = 62), a total of 84 articles were retained for the final review sample. Types of suicide prevention services delivered by peers included being a gatekeeper, on-demand crisis support, crisis support in acute care settings, and crisis or relapse prevention. Peer relationships employed in suicide prevention services included fellow laypersons; members of the same sociodemographic subgroup (e.g., racial minority), workplace, or institution (e.g., university, correctional facility); and the shared experience of having a mental condition. The majority of published studies were program descriptions or uncontrolled trials, with only three of 84 articles qualifying as randomized controlled trials. Despite a lack of methodological rigor in identified studies, peer support interventions for suicide prevention have been implemented utilizing a diverse range of peer provider types and functions. New and existing peer-delivered suicide prevention services should incorporate more rigorous evaluation methods regarding acceptability and effectiveness.


Renal excretion of fluoride in renal failure and after renal transplantation.
We have compared the renal excretion of fluoride in a variety of patients with chronic renal failure maintained with and without protein restriction before and during regular dialysis treatment and after transplantation. The patients tended to continue to excrete normal dietary loads of fluoride quite well until renal function was seriously reduced. From a regression of function on excretion the mean level of creatinine clearance when a normal dietary load of fluoride 0.0526 plus or minus 0.019 mmol/2 h (1.0 plus or minus 0.36 mg/24h) has a 90% chance of being excreted lies around 16 ml/min, a level when most patients with renal failure will be symptomatic. Acute loading of such patients with additional fluoride in the form of sodium fluoride from 40 mg to 60 mg/day showed a twofold to threefold increase of serum fluoride concentrations, slight increases in urinary fluoride excretion, and heavy tissue absorption, suggesting that prior fluoride loading of the skeleton had not taken place. These effects contrasted with those in one patient with normal renal function and with those in one patient with skeletal saturation due to prolonged loading. After renal transplantation fluoride excretion increased but reached normal levels within three months of satisfactory function, suggesting that fluoride loading in renal failure and during regular dialysis therapy had not been excessive.


Compost as a soil supplement increases the level of antioxidant compounds and oxygen radical absorbance capacity in strawberries.
Compost as a soil supplement significantly enhanced levels of ascorbic acid (AsA) and glutathione (GSH) and ratios of AsA/dehydroascorbic acid (DHAsA) and GSH/oxidized glutathione (GSSG) in fruit of two strawberry (Fragaria x ananassa Duch.) cultivars, Allstar and Honeoye. The peroxyl radical (ROO(*)) as well as the superoxide radical (O(2)(*)(-)), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH(*)), and singlet oxygen ((1)O(2)) absorbance capacity in strawberries increased significantly with increasing fertilizer strength and compost use. The planting medium (compost) x fertilizer interaction for phenolics and flavonoids was significant. Fruit from plants grown in full-strength fertilizer with 50% soil plus 50% compost and 100% compost yielded fruit with the highest levels of phenolics, flavonol, and anthocyanin content. A positive relationship between antioxidant activities and contents of AsA and GSH and ratios of AsA/DHAsA and GSH/GSSG existed in fruit of both strawberry cultivars. Correlation coefficients for the content of antioxidant components versus antioxidant activity [against ROO(*), O(2)(*)(-), H(2)O(2), OH(*), or (1)O(2)] ranged from r( )()= 0.7706 for H(2)O(2) versus GSH/GSSH in cv. Allstar to r = 0.9832 for O(2)(*)(-) versus total flavonoids in cv. Allstar.


Three types of tobacco calmodulins characteristically activate plant NAD kinase at different Ca2+ concentrations and pHs.
We previously reported that three types of tobacco calmodulin (CaM) isoforms originated from 13 genes are differently regulated at the transcript and protein levels in response to wounding and tobacco mosaic virus-induced hypersensitive reaction (HR); wound-inducible type I and HR-inducible type III levels increased after wounding and HR, respectively, while type II, whose expression is constitutive and wound responsible, remained unchanged. Here, we show that these CaMs differentially activate target enzymes; rat NO synthase was activated most effectively by type III, moderately by type I and weakly by type II, and plant NAD kinase (NADK) was activated in the inverse order. Furthermore, we found that a suitable Ca2+ concentration differs by type; type II activated NADK at lower Ca2+ of around 0.1 microM, which is the cytosolic concentration in unstimulated cells, type I did so at 1-5 microM, which is the increased Ca2+ concentration in stimulated cells, while type III did not at any Ca2+ level. NADK activation was highest over a pH range of 7.1-6.8 for which the cytosolic pH reportedly changed from 7.5 after being stimulated. Thus, tobacco CaMs, especially type I, effectively activate NADK in stimuli-induced conditions.


Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity.
Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1-PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1-GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.


Outcomes of enhanced recovery protocols and tranexamic acid on double-incision versus periareolar gender-affirming mastectomy: A retrospective study of postoperative outcomes.
The effects of enhanced recovery protocols and use of tranexamic acid (TXA) to reduce postoperative complications after periareolar and double-incision (DIM) gender-affirming mastectomies have not been previously described. We sought to evaluate the efficacy of our ERP including use of liposomal bupivacaine [Exparel] in these cases, assess the efficacy of TXA in reducing postoperative complications, and compare need for revisionary surgery between periareolar and DI mastectomy techniques. A retrospective review from November 2017 to June 2022 was performed. Data were collected on patient demographics, operative data, and postoperative outcomes including complications and revisions. Morphine milligram equivalent was used to assess opioid use after surgery. Overall, 260 patients were included: 240 (92.3%) patients in the DI and 20 (7.7%) patients in the periareolar group. Thirty-five (7.3%) breasts in the DIM group and five (12.5%) breasts in the periareolar cohort developed complications (p = 0.220). Significantly more breasts in the periareolar cohort developed hematomas (12.5% vs. 2.9%, p = 0.011). Sixteen (3.3%) breasts in the DIM group developed seromas. Significantly more breasts in the periareolar group required revisionary surgery (15.0% vs. 5.2%, p = 0.025). Patients who received intraoperative liposomal bupivacaine [Exparel] had fewer opioids intraoperatively (p = 0.019) and at discharge (p < 0.001). Use of TXA did not affect rates of complications including hematoma or seroma. Overall, complication rates for periareolar and DIM are similar. However, the periareolar technique results in a significantly higher rate of hematomas and revisionary surgery. Use of intraoperative liposomal bupivacaine [Exparel] resulted in significantly lower opioid use. Lastly, use of topical TXA did not lower the risk of postoperative hematoma or seroma.


A commentary on the medicinal use of marijuana.
Lately, the number of people using marijuana in the USA has dramatically increased. In 2018, many states have legalized marijuana use for both medical and recreational purposes, thus exploring the evidence behind medical marijuana use became essential. Muslim majority countries enforce rigorous rules as marijuana has been a long-debated issue due to the stigma associated with its use as a treatment. Marijuana has a high beneficial effect in managing chronic pain in adults and relieving spasticity symptoms in multiple sclerosis, obstructive sleep apnea syndrome, and fibromyalgia. As well as, used as pain management, and as anti-emetic in treatment of chemotherapy-induced vomiting and nausea. Marijuana is requested from more than one-third of posttraumatic stress disorder patients due to its significant clinical improvement in nightmares and subsidence disorder symptoms.Marijuana adversely affects the body's resistance to many infections, compromising their immune response. Its recreational use has led to an increasing trend in the occurrence of major acute cardiovascular events as stroke, epilepsy, acute myocardial infarction, congestive heart failure, and arrhythmia. Many countries started to allow medicinal use of marijuana due to its beneficial effect in managing chronic pain, spasticity symptoms in multiple sclerosis, obstructive sleep apnea syndrome, fibromyalgia, and posttraumatic stress disorder. But literature lacks benefit-harm analysis for marijuana usage in medicine. Therefore, evidence-based report of short- and long-term health effects of marijuana use-both harmful and beneficial effects-is crucial for further marijuana prescription in healthcare settings.


Institutional review board variability in minimal-risk multicenter urogynecology studies.
To investigate variability among local institutional review boards (IRBs) in the review process of standardized multicenter urogynecologic studies with common protocols. Descriptive study of the IRB review and approval process for common urogynecologic protocols of 4 minimal-risk multicenter studies conducted within the Fellow's Pelvic Research Network (FPRN), including prospective cohort, retrospective review, and case-control studies. Most of the 22 network sites (73%) were in academic institutions. The level of IRB review varied by site and study design. Institutional review boards had local requirements regarding standard format and language that resulted in 86% of consent documents and 33% of protocols being changed before submission. Institutional review boards queried most (55%) submissions, with significantly more queries for prospective studies compared to retrospective studies (78.6% vs 35.3%; P = 0.03). After submission, IRB requirements necessitated changes for 71% of consents and 28% of protocols. There were no substantive changes made to any consent document or protocol. There was considerable variability in time between IRB submission and approval (10 ± 3 days; range, 7-12 days for exempt; 22 ± 17 days; range, 1-57 days for expedited; and 34 ± 32 days; range, 13-81 days for full board reviews). We detected considerable variability in IRB review of standardized multicenter protocols across minimal-risk study designs. Reduction in variability may improve expediency of multicenter studies while maintaining the highest level of protections for research participants.


Molecular cloning of the endogenous rat C-type helper virus DNA sequence: structural organization and functional analysis of some restricted DNA fragments.
Recently, we have identified and purified the integrated and proviral DNA sequences specific for two endogenous rat type C leukaemia helper viruses: WR-RaLV which originated from a fibrosarcoma induced in a feral rat and RHHV from the cell line HTC-H1 which originated from a Buffalo rat hepatoma. The rat leukaemia helper virus DNA sequences have previously been shown to be 8.4 to 8.8 kilobases (kb) in size. In this communication, we report the molecular cloning of the 8.8 kb DNA of RHHV by ligation at the BamHI site of the vector pBR322, cultured in an Escherichia coli RR1 host. After screening 5750 clones for ampicillin resistance and tetracycline sensitivity and testing by colony hybridization using 32P-labelled RHHV cDNA, four clones were isolated, two of which carried the total 8.8 kb DNA. A detailed restriction endonuclease map of the cloned RHHV DNA was deduced by sequential digestions of either 3'- or 5'-labelled DNA. Of the 14 restriction enzymes tested, EcoRI, BamHI, PstI, KpnI, TaqI, PvuII and SmaI gave informative cleavage patterns. At least two copies of long terminal repeated sequences (LTR) flanking the 3' and 5' termini of the proviral DNA were identified by TaqI and PstI cleavages. LTR in the rat endogenous leukaemia helper virus DNA measured 780 +/- 20 nucleotides in length. The genetic information encoded by the cloned DNA was also analysed by hybridization selection of RHHV mRNA, which was then used in cell-free protein synthesis in a rabbit reticulocyte lysate system. Essentially all major RaLV-specific proteins precipitable by anti-RaLV serum were synthesized in vitro, confirming that the RHHV genomic DNA was successfully cloned with little fidelity loss or scrambling of the genetic information.


Molecular Imaging of Brain Tumor-Associated Epilepsy.
Epilepsy is a common clinical manifestation and a source of significant morbidity in patients with brain tumors. Neuroimaging has a pivotal role in neuro-oncology practice, including tumor detection, differentiation, grading, treatment guidance, and posttreatment monitoring. In this review, we highlight studies demonstrating that imaging can also provide information about brain tumor-associated epileptogenicity and assist delineation of the peritumoral epileptic cortex to optimize postsurgical seizure outcome. Most studies focused on gliomas and glioneuronal tumors where positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques can detect metabolic and biochemical changes associated with altered amino acid transport and metabolism, neuroinflammation, and neurotransmitter abnormalities in and around epileptogenic tumors. PET imaging of amino acid uptake and metabolism as well as activated microglia can detect interictal or peri-ictal cortical increased uptake (as compared to non-epileptic cortex) associated with tumor-associated epilepsy. Metabolic tumor volumes may predict seizure outcome based on objective treatment response during glioma chemotherapy. Advanced MRI, especially glutamate imaging, can detect neurotransmitter changes around epileptogenic brain tumors. Recently, developed PET radiotracers targeting specific glutamate receptor types may also identify therapeutic targets for pharmacologic seizure control. Further studies with advanced multimodal imaging approaches may facilitate development of precision treatment strategies to control brain tumor-associated epilepsy.


A 9-cis beta-carotene-enriched diet inhibits atherogenesis and fatty liver formation in LDL receptor knockout mice.
Our aim was to study the effect of 9-cis beta-carotene-rich powder of the alga Dunaliella bardawil on lipid profile, atherogenesis, and liver steatosis in high-fat diet-fed LDL receptor knockout mice. In 4 sets of experiments, mice were distributed into the following groups: control, fed an unfortified diet; Dunaliella 50, fed a diet composed of 50% 9-cis and 50% all-trans beta-carotene; Dunaliella 25, fed a diet containing 25% 9-cis and 75% all-trans beta-carotene; beta-carotene-deficient Dunaliella, fed beta-carotene-deficient Dunaliella powder; and all-trans beta-carotene, fed a synthetic all-trans beta-carotene. All fortified diets contained 0.6% total beta-carotene. Algal 9-cis beta-carotene was absorbed by the mice and accumulated in the liver. Synthetic all-trans beta-carotene was not converted to 9-cis beta-carotene. Dunaliella 50 inhibited high-fat diet-induced plasma cholesterol elevation by 40-63% and reduced cholesterol concentrations in the atherogenic VLDL and LDL. Atherosclerotic lesion area in mice treated with Dunaliella 50 was 60-83% lower compared with mice fed the high-fat diet alone. beta-Carotene-deficient Dunaliella did not influence plasma cholesterol and atherogenesis, suggesting that beta-carotene is essential for a Dunaliella protective effect. Moreover, by administrating Dunaliella powder containing different levels of 9-cis and all-trans beta-carotene isomers, we found that the effect on plasma cholesterol concentration and atherogenesis is 9-cis-dependent. Dunaliella 50 also inhibited fat accumulation and inflammation in the livers of mice fed a high-fat diet, which was accompanied by reduced mRNA levels of inflammatory genes. These results in mice suggest that 9-cis beta-carotene may have the potential to inhibit atherogenesis in humans.


Myosin-Va and dynamic actin oppose microtubules to drive long-range organelle transport.
In animal cells, microtubule and actin tracks and their associated motors (dynein, kinesin, and myosin) are thought to regulate long- and short-range transport, respectively. Consistent with this, microtubules extend from the perinuclear centrosome to the plasma membrane and allow bidirectional cargo transport over long distances (>1 μm). In contrast, actin often comprises a complex network of short randomly oriented filaments, suggesting that myosin motors move cargo short distances. These observations underpin the "highways and local roads" model for transport along microtubule and actin tracks. The "cooperative capture" model exemplifies this view and suggests that melanosome distribution in melanocyte dendrites is maintained by long-range transport on microtubules followed by actin/myosin-Va-dependent tethering. In this study, we used cell normalization technology to quantitatively examine the contribution of microtubules and actin/myosin-Va to organelle distribution in melanocytes. Surprisingly, our results indicate that microtubules are essential for centripetal, but not centrifugal, transport. Instead, we find that microtubules retard a centrifugal transport process that is dependent on myosin-Va and a population of dynamic F-actin. Functional analysis of mutant proteins indicates that myosin-Va works as a transporter dispersing melanosomes along actin tracks whose +/barbed ends are oriented toward the plasma membrane. Overall, our data highlight the role of myosin-Va and actin in transport, and not tethering, and suggest a new model in which organelle distribution is determined by the balance between microtubule-dependent centripetal and myosin-Va/actin-dependent centrifugal transport. These observations appear to be consistent with evidence coming from other systems showing that actin/myosin networks can drive long-distance organelle transport and positioning.