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Abstract Background Evaluation of company clinical trial reports could provide information for meta-analysis at the commercial introduction of a new technology. Methods Clinical trial reports of sildenafil for erectile dysfunction from September 1997 were used for meta-analysis of randomised trials (at least four weeks duration) and using fixed or dose optimisation regimens. The main outcome sought was an erection, sufficiently rigid for penetration, followed by successful intercourse, and conducted at home. Results Ten randomised controlled trials fulfilled the inclusion criteria (2123 men given sildenafil and 1131 placebo). NNT or NNH were calculated for important efficacy, adverse event and discontinuation outcomes. Dose optimisation led to at least 60% of attempts at sexual intercourse being successful in 49% of men, compared with 11% with placebo; the NNT was 2.7 (95% confidence interval 2.3 to 3.3). For global improvement in erections the NNT was 1.7 (1.6 to 1.9). Treatment-related adverse events occurred in 30% of men on dose optimised sildenafil compared with 11% on placebo; the NNH was 5.4 (4.3 to 7.3). All cause discontinuations were less frequent with sildenafil (10%) than with placebo (20%). Sildenafil dose optimisation gave efficacy equivalent to the highest fixed doses, and adverse events equivalent to the lowest fixed doses. Conclusion This review of clinical trial reports available at the time of licensing agreed with later reviews that had many more trials and patients. Making reports submitted for marketing approval available publicly would provide better information when it was most needed, and would improve evidence-based introduction of new technologies.

This paper explores the relationship between trade growth and long-run trends in real GDP growth from a purely empirical perspective. Its novelty lies in the way that it models trade growth: as a function of cyclical trends in real GDP growth. The main finding is that trade growth responds asymmetrically to deviations from long-run GDP growth. Generally, trade growth is positive and statistically significant when GDP growth is above the long-run trend. On the other hand, trade growth ceases but does not become negative when GDP growth falls below its long-run trend. While this behavior holds true broadly, individual countries' trade growth may respond differently when GDP growth is above or below trend. Comparatively, low-income countries' trade growth takes the greatest hit when economic growth slows, while lower-middle and high-income countries are least affected. These findings have potential implications for trade policy-making in the twentyfirst Century especially given the current atmosphere of anti-globalization and slow trade growth. [ABSTRACT FROM AUTHOR]

Stone MB, Merrick MA, Ingersoll CD, Edwards JE. Clin J Sport Med 2002;12:373-378. OBJECTIVE The purpose of this study was to determine whether a common bromelain regimen or common ibuprofen [...]

Background: Invasive infection with Candida species is an important cause of morbidity and mortality in intensive care unit (ICU) patients. Optimal preventive strategies have not been clearly defined.Objective: To see whether empirical fluconazole improves clinical outcomes more than placebo in adult ICU patients at high risk for invasive candidiasis.Design: Double-blind, placebo-controlled, randomized trial conducted from 1995 to 2000.Setting: 26 ICUs in the United States.Patients: 270 adult ICU patients with fever despite administration of broad-spectrum antibiotics. All had central venous catheters and an Acute Physiology and Chronic Health Evaluation II score greater than 16.Intervention: Patients were randomly assigned to either intravenous fluconazole, 800 mg daily, or placebo for 2 weeks and were followed for 4 weeks thereafter. Two hundred forty-nine participants were available for outcome assessment.Measurements: A composite primary outcome that defined success as all 4 of the following: resolution of fever; absence of invasive fungal infection; no discontinuation because of toxicity; and no need for a nonstudy, systemic antifungal medication (as assessed by a blinded oversight committee).Results: Only 44 of 122 (36%) fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.78]). The main reason for failure was lack of resolution of fever (51% for fluconazole and 57% for placebo). Documented invasive candidiasis occurred in 5% of fluconazole recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.49]). Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse events resulting in discontinuation of the study drug. Discontinuation because of abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%) placebo recipients.Limitations: Twenty-one randomly assigned patients were not included in the analysis because they either did not meet entry criteria or did not have postbaseline assessments. Fewer fungal infections than anticipated occurred in the control group. Confidence bounds were wide and did not exclude potentially important differences in outcomes between groups.Conclusion: In critically ill adults with risk factors for invasive candidiasis, empirical fluconazole did not clearly improve a composite outcome more than placebo. [ABSTRACT FROM AUTHOR]

The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from seven randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over six and eight hours and global evaluations of treatment effect after eight hours were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity. [ABSTRACT FROM AUTHOR]

Many pitching injuries occur during deceleration of the upper extremity when the muscles of the shoulder and arm are acting eccentrically. Published information regarding eccentric muscular strength in baseball pitchers is nonexistent. The purpose of this study was to assess bilateral isokinetic eccentric and concentric muscular strength of the shoulder's external and internal rotator muscles and the elbow's flexor and extensor muscles in a group of collegiate baseball pitchers (N = 25). Isokinetic strength was assessed at 1.6, 3.7, and 5.2 rad/sec. Our findings indicate that the internal rotator muscles were always stronger than the external rotator muscles and that the concentric and eccentric external-to-internal strength ratios ranged from 62% to 81%. The eccentric strength of the shoulder rotator muscles averaged 114% that of concentric strength. The concentric and eccentric elbow extension-to-flexion strength ratios ranged from 71% to 110%; eccentric strength averaged 33% higher than concentric strength. No differences were noted between dominant and nondominant limbs for any of the strength measures or ratios. Clinically, the findings of this study can serve as a reference during the evaluation, rehabilitation, and conditioning of throwing athletes. [ABSTRACT FROM AUTHOR]

Abstract Background Sequencing-by-ligation (SBL) is one of several next-generation sequencing methods that has been developed for massive sequencing of DNA immobilized on arrayed beads (or other clonal amplicons). SBL has the advantage of being easy to implement and accessible to all because it can be performed with off-the-shelf reagents. However, SBL has the limitation of very short read lengths. Results To overcome the read length limitation, research groups have developed complex library preparation processes, which can be time-consuming, difficult, and result in low complexity libraries. Herein we describe a variation on traditional SBL protocols that extends the number of sequential bases that can be sequenced by using Endonuclease V to nick a query primer, thus leaving a ligatable end extended into the unknown sequence for further SBL cycles. To demonstrate the protocol, we constructed a known DNA sequence and utilized our SBL variation, cyclic SBL (cSBL), to resequence this region. Using our method, we were able to read thirteen contiguous bases in the 3' - 5' direction. Conclusions Combining this read length with sequencing in the 5' - 3' direction would allow a read length of over twenty bases on a single tage. Implementing mate-paired tags and this SBL variation could enable > 95% coverage of the genome.

Abstract Background The isolated northern region of Nicaragua has one of the highest rates of diarrheal disease in Central America. Political and environmental hardships faced by inhabitants of this region are contributing factors to this health inequity. The aim of this study was to assess the relationship between water and latrine infrastructure and the prevalence of diarrhea in this region. Methods A population-based, cross-sectional survey of women of reproductive age was conducted in the Sahsa region of northern Nicaragua in July, 2009. Households were selected by two stage cluster sampling methodology. A questionnaire was administered in Spanish and Miskito with assessment of household and socioeconomic conditions, sanitation practices, and health care access. Diarrhea prevalence differences at the household level over a two week reporting period were estimated with a standardized instrument which included assessment of water treatment and latrine use and maintenance. Results There were 189 women enrolled in the current study. The use of water purification methods, such as chlorine and filters, and latrine ownership were not associated with reduced prevalence of household diarrhea in the two week reporting period. Latrine overflow, however, was associated with an increased prevalence of diarrhea during the same two week period [adjusted prevalence difference and 95% CI: 0.19 (0.03, 0.36)]. Conclusions Simple, low cost interventions that improve water and latrine infrastructure may reduce the prevalence of diarrheal disease in the isolated regions of Nicaragua and Central America.

Abstract Background Microorganisms have been associated with many types of human diseases; however, a significant number of clinically important microbial pathogens remain to be discovered. Methods We have developed a genome-wide approach, called Digital Karyotyping Microbe Identification (DK-MICROBE), to identify genomic DNA of bacteria and viruses in human disease tissues. This method involves the generation of an experimental DNA tag library through Digital Karyotyping (DK) followed by analysis of the tag sequences for the presence of microbial DNA content using a compiled microbial DNA virtual tag library. Results To validate this technology and to identify pathogens that may be associated with human cancer pathogenesis, we used DK-MICROBE to determine the presence of microbial DNA in 58 human tumor samples, including brain, ovarian, and colorectal cancers. We detected DNA from Human herpesvirus 6 (HHV-6) in a DK library of a colorectal cancer liver metastasis and in normal tissue from the same patient. Conclusion DK-MICROBE can identify previously unknown infectious agents in human tumors, and is now available for further applications for the identification of pathogen DNA in human cancer and other diseases.

Abstract Background We report the development of a microarray platform for rapid and cost-effective genetic mapping, and its evaluation using rice as a model. In contrast to methods employing whole-genome tiling microarrays for genotyping, our method is based on low-cost spotted microarray production, focusing only on known polymorphic features. Results We have produced a genotyping microarray for rice, comprising 880 single feature polymorphism (SFP) elements derived from insertions/deletions identified by aligning genomic sequences of the japonica cultivar Nipponbare and the indica cultivar 93-11. The SFPs were experimentally verified by hybridization with labeled genomic DNA prepared from the two cultivars. Using the genotyping microarrays, we found high levels of polymorphism across diverse rice accessions, and were able to classify all five subpopulations of rice with high bootstrap support. The microarrays were used for mapping of a gene conferring resistance to Magnaporthe grisea, the causative organism of rice blast disease, by quantitative genotyping of samples from a recombinant inbred line population pooled by phenotype. Conclusion We anticipate this microarray-based genotyping platform, based on its low cost-per-sample, to be particularly useful in applications requiring whole-genome molecular marker coverage across large numbers of individuals.

Abstract Background The ErbB family of receptors are dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore a detailed understanding of the mechanisms of receptor activation is critical. However, despite a plethora of biochemical studies and recent single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Herein, we describe a spatially distributed Monte Carlo based simulation framework to enable the simulation of in vivo receptor diffusion and dimerization. Results Our simulation results are in agreement with the data from single particle tracking and biochemical experiments on EGFR. Furthermore, the simulations reveal that the sequence of receptor-receptor and ligand-receptor reaction events depends on the ligand concentration, receptor density and receptor mobility. Conclusion Our computer simulations reveal the mechanism of EGF binding on EGFR. Overall, we show that spatial simulation of receptor dynamics can be used to gain a mechanistic understanding of receptor activation which may in turn enable improved cancer treatments in the future.

Abstract Background Despite intense effort the treatment options for the invasive astrocytic tumors are still limited to surgery and radiation therapy, with chemotherapy showing little or no increase in survival. The generation of Serial Analysis of Gene Expression (SAGE) profiles is expected to aid in the identification of astrocytoma-associated genes and highly expressed cell surface genes as molecular therapeutic targets. SAGE tag counts can be easily added to public expression databases and quickly disseminated to research efforts worldwide. Methods We generated and analyzed the SAGE transcription profiles of 25 primary grade II, III and IV astrocytomas 1. These profiles were produced as part of the Cancer Genome Anatomy Project's SAGE Genie 2, and were used in an in silico search for candidate therapeutic targets by comparing astrocytoma to normal brain transcription. Real-time PCR and immunohistochemistry were used for the validation of selected candidate target genes in 2 independent sets of primary tumors. Results A restricted set of tumor-associated genes was identified for each grade that included genes not previously associated with astrocytomas (e.g. VCAM1, SMOC1, and thymidylate synthetase), with a high percentage of cell surface genes. Two genes with available antibodies, Aquaporin 1 and Topoisomerase 2A, showed protein expression consistent with transcript level predictions. Conclusions This survey of transcription in malignant and normal brain tissues reveals a small subset of human genes that are activated in malignant astrocytomas. In addition to providing insights into pathway biology, we have revealed and quantified expression for a significant portion of cell surface and extra-cellular astrocytoma genes.

Abstract Background Quantification of variations of human gene expression is complicated by the small differences between different alleles. Recent work has shown that variations do exist in the relative allelic expression levels in certain genes of heterozygous individuals. Herein, we describe the application of an immobilized polymerase chain reaction technique as an alternative approach to measure relative allelic differential expression. Results Herein, we report a novel assay, based on immobilized polymerase colonies, that accurately quantifies the relative expression levels of two alleles in a given sample. Mechanistically, this was accomplished by PCR amplifying a gene in a cDNA library in a thin polyacrylamide gel. By immobilizing the PCR, it is ensured that each transcript gives rise to only a single immobilized PCR colony, or "polony". Once polony amplified, the two alleles of the gene were differentially labeled by performing in situ sequencing with fluorescently labeled nucleotides. For these sets of experiments, silent single nucleotide polymorphisms (SNPs) were used to discriminate the two alleles. Finally, a simple count was then performed on the differentially labeled polonies in order to determine the relative expression levels of the two alleles. To validate this technique, the relative expression levels of PKD2 in a family of heterozygous patients bearing the 4208G/A SNP were examined and compared to the literature. Conclusions We were able to reproduce the results of allelic variation in gene expression using an accurate technology known as polymerase colonies. Therefore, we have demonstrated the utility of this method in human gene expression analysis.

Abstract Background The identification of known mutations in a cell population is important for clinical applications and basic cancer research. In this work an immobilized form of the polymerase chain reaction, referred to as polony technology, was used to detect mutations as well as gene deletions, resulting in loss of heterozygosity (LOH), in cancer cell lines. Specifically, the mutational hotspots in p53, namely codons 175, 245, 248, 249, 273, and 282, and K-ras2, codons 12, 13 and 61, were genotyped in the pancreatic cell line, Panc-1. In addition LOH analysis was also performed for these same two genes in Panc-1 by quantifying the relative gene copy number of p53 and K-ras2. Results Using polony technology, Panc-1 was determined to possess only one copy of p53, which possessed a mutation in codon 273, and two copies of K-ras2, one wildtype and one with a mutation in codon 12. To further demonstrate the general approach of this method, polonies were also used to detect K-ras2 mutations in the pancreatic cell lines, AsPc-1 and CAPAN-1. Conclusions In conclusion, we have developed an assay that can detect mutations in hotspots of p53 and K-ras2 as well as diagnose LOH in these same genes.

Abstract Background Genome sequencing and bioinformatics are producing detailed lists of the molecular components contained in many prokaryotic organisms. From this 'parts catalogue' of a microbial cell, in silico representations of integrated metabolic functions can be constructed and analyzed using flux balance analysis (FBA). FBA is particularly well-suited to study metabolic networks based on genomic, biochemical, and strain specific information. Results Herein, we have utilized FBA to interpret and analyze the metabolic capabilities of Escherichia coli. We have computationally mapped the metabolic capabilities of E. coli using FBA and examined the optimal utilization of the E. coli metabolic pathways as a function of environmental variables. We have used an in silico analysis to identify seven gene products of central metabolism (glycolysis, pentose phosphate pathway, TCA cycle, electron transport system) essential for aerobic growth of E. coli on glucose minimal media, and 15 gene products essential for anaerobic growth on glucose minimal media. The in silico tpi-, zwf, and pta- mutant strains were examined in more detail by mapping the capabilities of these in silico isogenic strains. Conclusions We found that computational models of E. coli metabolism based on physicochemical constraints can be used to interpret mutant behavior. These in silica results lead to a further understanding of the complex genotype-phenotype relation. Supplementary information: http://gcrg.ucsd.edu/supplementary_data/DeletionAnalysis/main.htm

Context: Exposure of the human body to cold is perceived as a stressor and results in a sympathetic response geared at maintaining core temperature. Application of ice to the periphery may lead to a decrease in core temperature, which may counteract the therapeutic effects of cryotherapy.Objective: To determine if core temperature is lowered by the application of an ice bag to the ankle joint complex. Design: A within-subjects, repeated-measures design. Setting: The University of Virginia General Clinical Research Center.Patients or Other Participants: Twenty-three healthy adults aged 19 to 39 years.Intervention(s): Subjects were admitted to the hospital on 2 separate occasions. During one admission, subjects had a 20minute ice treatment applied to their ankles; in the other admission, a bag of marbles was applied. Temperature measurements were recorded at 6 time intervals: baseline (before ice application), immediately after ice application, 10 and 20 minutes after ice application, and 10 and 20 minutes after ice removal.Main Outcome Measure(s): We measured core temperature and ankle and soleus muscle surface temperatures. A mixedeffects model analysis of variance with repeated measures was used to determine if differences existed in core temperature and ankle and soleus surface temperatures between conditions (cryotherapy and control) and over time.Results: Core temperature did not change after ice application or ice removal (P > 0.05). The average core temperatures during the cryotherapy and control conditions were 36.72 degreesC 0.42 degreesC and 36.45 degreesC +/- 1.23 degreesC, respectively.Conclusions: A 20-minute cryotherapy treatment applied to the ankle did not alter core temperature. [ABSTRACT FROM AUTHOR]

Objective: To find out which type of dressing (semipermeable film, hydrocolloid, conventional method, or no dressing) allowed abrasions to heal in the least amount of time and had the greatest decrease in wound area. Design and Setting: A 4 x 9 factorial was used for this study. There were two independent variables with four levels and two dependent variables. Research was performed at the Athletic Training Research Laboratory at Indiana State University. Subjects: Fourteen subjects (eight males, six females), ages 23 to 34 years, participated in this study. Measurements: From daily photographs, the day the wounds were healed was determined. The photographs were also used to measure wound area on the first and last days of the study. Subjects received four treatments (dressings and control), and placement of the dressings was determined by random assignment. Results: Data were analyzed using a repeated-measures multivariate analysis of variance to determine if differences existed among treatment groups for healing time and change in area. Student-Newman-Keuls post hoc testing was performed to determine specifically where the differences occurred. Our results indicate that healing time is affected by covering the wound, and area is decreased by using DuoDerm or Bioclusive. Conclusions: Bioclusive should be used in the athletic training setting. Bioclusive and DuoDerm are equally effective, but Bioclusive is less expensive. Bioclusive is more expensive than Coverlet, but it is also more effective in reducing the area of the wound. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of Competing Interest All authors have completed the ICMJE Disclosure Form and have nothing to disclose.

Purpose: Accurate assessment of chronic pain and functional disability in children and adolescents is imperative for guiding pain management interventions. Parents have multifaceted roles in their child's pain experience and frequently provide parent-proxy reports of pain-related functioning. However, cross-informant variance is often observed with limited understanding of contributing factors. This study aims to examine the degree of alignment between child and parent-proxy reports for Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference domain among children with chronic pain and to identify factors associated with improved child-parent agreement., Methods: This study includes a sample of 127 youth (66.1% female) with mixed etiology chronic pain, ranging in age from 8 to 17 (M = 12.24; SD = 1.598), and their parent. Data was collected at an interdisciplinary pediatric pain clinic and online peer support groups. Measures of demographic, pain intensity, and functioning were collected., Results: Means of parent-proxy reports were significantly lower than child self-reports on the PROMIS (p < 0.05). A statistically significant association between child's pain intensity (β = 0.953, P < 0.05) and the difference between child self-reported and parent-proxy reported PROMIS functional interference scores was found., Conclusion: Parents underestimated pain-related functional disability relative to children's self-reports. The difference between the paired child self-report and parent-proxy report of functional disability was significantly associated with greater child self-reported pain intensity. Although parent-proxy reports in pediatric chronic pain is often used in research and practice, findings underscore the importance of incorporating child and adolescent self-report, when possible, to comprehensively capture the child's pain experience and best inform clinical interventions., (© 2024. The Author(s).)

The movement ecology of European seabass, Dicentrarchus labrax, remains poorly understood, especially in the northern ranges of its distribution. To investigate migration patterns of seabass from the southern North Sea, we combined data from different projects from four countries using various tagging techniques. This resulted in 146 recaptures (out of 5598 externally marked seabass), 138 detected animals (out of 162 seabass fitted with an acoustic transmitter) and 76 archived depth and temperature series (out of 323 seabass with an archival tag). Using geolocation modelling, we distinguished different migration strategies, whereby individual fish migrated to the eastern English Channel (15.1%), the western English Channel (28.3%), the Celtic Sea and the norther part of the Bay of Biscay (17.0%), or stayed in the North Sea (39.6%). A high number of seabass exhibited fidelity to the North Sea (90.5% of recaptures, 55.3% for acoustic transmitters and 44.7% of archival tags). Although seabass are generally considered to migrate southwards in winter, a large number of individuals (n = 62) were observed in the southern North Sea, where spawning might potentially occur in a particular deep location along the coast of Norfolk in the UK. Our results highlight the need to consider fine-scaled population structuring in fisheries assessment, and indicate that current seasonal fisheries closures are not aligned with the ecology of seabass in the North Sea., (© 2024. The Author(s).)

Recovery coaches are individuals with lived experience with recovery from substance use disorder who typically engender a greater sense of trust than found with other types of healthcare providers. However, there currently are no validated tools that measure the connection between recovery coaches and their participants. The purpose of this study was to describe the initial development of the Scales for Participant Alliance with Recovery Coach (SPARC) to measure recovery coach connection or alliance, including initial psychometric analyses. Measurement development began with five scales of the Client Evaluation of Self Treatment (treatment participation, treatment satisfaction, rapport, peer support, and social support). Adapted items were pre-tested with focus groups ( n = 8) to ensure they were meaningful and accurately reflected the domains (Study 1). After modifications, the SPARC has six scales (engagement, satisfaction, rapport, motivation and encouragement, role model and community linkage). The survey was piloted with 100 individuals (Study 2) age 18 or over who had met with a recovery coach within the last six months. Most study participants were male (60%) and white (87%) with less than two years in recovery. After removing two low performing items, the items for five of the domains had acceptable internal consistency. The items for the engagement domain had a slightly lower reliability. Findings suggest that items cover relevant recovery coach roles, are internally consistent within domains, and can be easily administered to individuals engaging in recovery coaching services. Additional research is needed with a larger, more heterogenous sample to further refine items.