The Danish-American Research Exchange (DARE): a cross-sectional study of a binational research education program.

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'. METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. RESULTS: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network. CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

Intertwined: What makes food and wine pairings appropriate?

This study sought to identify sensory attributes of appropriate food and wine pairings and relate them to balance, consumer liking, sensory complexity, and expected price. A descriptive analysis panel (n = 8) evaluated four Australian Shiraz wines along with four complex food samples, yielding 16 wine and food combinations. Based on the sensory profiles, distinct food and wine pairings (n = 6) were selected for consumer preference tests, comprising a real life, pseudo-three course meal with two wines. According to American consumers (n = 108), in the most appropriate pairings, flavour intensities increased and wine taste attributes changed in relation to individual components. Appropriate pairings positively correlated with liking, sensory complexity, and expected price to pay, and negatively with balance as a slight wine dominance was preferred. Pairings had an increase in liking and sensory complexity over the individual wine but not the food component. To account for individual variability, consumers were segmented by their liking of the pairing. Key drivers of successful pairings across consumer clusters were similar to the average consumer results, however, the preferred pairings differed by cluster. The findings suggest, the quality of food and wine pairings might be better measured with a combination of direct (dominance/balance, appropriateness of pairing) and indirect methods (sensory complexity, liking), instead of a single scale, and consumer segmentation may better account for the variability of results. The outcome of this study enhanced the understanding of the relationship between consumer behaviour and food and wine pairings.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

Rapid Bedside Evaluation of Seizures in the ICU by Listening to the Sound of Brainwaves: A Prospective Observational Clinical Trial of Ceribell's Brain Stethoscope Function.

BACKGROUND: Patients suffering from non-convulsive seizures experience delays in diagnosis and treatment due to limitations in acquiring and interpreting electroencephalography (EEG) data. The Ceribell EEG System offers rapid EEG acquisition and conversion of EEG signals to sound (sonification) using a proprietary algorithm. This study was designed to test the performance of this EEG system in an intensive care unit (ICU) setting and measure its impact on clinician treatment decision. METHODS: Encephalopathic ICU patients at Stanford University Hospital were enrolled if clinical suspicion for seizures warranted EEG monitoring. Treating physicians rated suspicion for seizure and decided if the patient needed antiepileptic drug (AED) treatment at the time of bedside evaluation. After listening to 30 s of EEG from each hemisphere in each patient, they reevaluated their suspicion for seizure and decision for additional treatment. The EEG waveforms recorded with Ceribell EEG were subsequently analyzed by three blinded epileptologists to assess the presence or absence of seizures within and outside the sonification window. Study outcomes were EEG set up time, ease of use of the device, change in clinician seizure suspicion, and change in decision to treat with AED before and after sonification. RESULTS: Thirty-five cases of EEG sonification were performed. Mean EEG setup time was 6 ± 3 min, and time to obtain sonified EEG was significantly faster than conventional EEG (p < 0.001). One patient had non-convulsive seizure during sonification and another had rhythmic activity that was followed by seizure shortly after sonification. Change in treatment decision after sonification occurred in approximately 40% of patients and resulted in a significant net reduction in unnecessary additional treatments (p = 0.01). Ceribell EEG System was consistently rated easy to use. CONCLUSION: The Ceribell EEG System enabled rapid acquisition of EEG in patients at risk for non-convulsive seizures and aided clinicians in their evaluation of encephalopathic ICU patients. The ease of use and speed of EEG acquisition and interpretation by EEG-untrained individuals has the potential to improve emergent clinical decision making by quickly detecting non-convulsive seizures in the ICU.

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing.

Citrobacter rodentium is a Gram-negative, murine-specific enteric pathogen that infects epithelial cells in the colon. It is closely related to the clinically relevant human pathogen, enterohemorrhagic Escherichia coli (EHEC), a leading cause of haemorrhagic colitis and haemolytic uremic syndrome. We have previously reported that a novel antimicrobial peptide, wrwycr, compromises bacterial DNA repair and significantly reduces the survival of acid-stressed EHEC, suggesting an antimicrobial strategy for targeting the survival of ingested EHEC. This study examines the impact of peptide pretreatment on survival of the closely related murine pathogen, C. rodentium, before and after acid stress, using both in vitro and in vivo investigations. Peptide pretreatment of C. rodentium significantly and dramatically increases acid-stress-induced killing in a peptide-dose-dependent and time-dependent manner. Reduction in survival rates after brief pretreatment with peptide (25-65 µM) followed by 1 h at pH 3.5 ranges from 6 to 8 log fold relative to untreated C. rodentium, with no detectable bacteria after 65 µM peptide-acid treatment. Using a C57BL/6 mouse model of infection, peptide pretreatment of C. rodentium with wrwycr prior to orogastric gavage eliminates evidence of infection based on C. rodentium colonization levels, faecal scores, colonic histology, faecal microbiome and visual observation of overall animal health. These findings provide compelling evidence for the role of the peptide wrwycr as a potential strategy to control the growth and colonization of enteric pathogens.

The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors.

The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).

Can evidence-based medicine and clinical quality improvement learn from each other?

The considerable gap between what we know from research and what is done in clinical practice is well known. Proposed responses include the Evidence-Based Medicine (EBM) and Clinical Quality Improvement. EBM has focused more on 'doing the right things'--based on external research evidence--whereas Quality Improvement (QI) has focused more on 'doing things right'--based on local processes. However, these are complementary and in combination direct us how to 'do the right things right'. This article examines the differences and similarities in the two approaches and proposes that by integrating the bedside application, the methodological development and the training of these complementary disciplines both would gain.

Problems and promises of innovation: why healthcare needs to rethink its love/hate relationship with the new.

Innovation is often regarded as uniformly positive. This paper shows that the role of innovation in quality improvement is more complicated. The authors identify three known paradoxes of innovation in healthcare. First, some innovations diffuse rapidly, yet are of unproven value or limited value, or pose risks, while other innovations that could potentially deliver benefits to patients remain slow to achieve uptake. Second, participatory, cooperative approaches may be the best way of achieving sustainable, positive innovation, yet relying solely on such approaches may disrupt positive innovation. Third, improvement clearly depends upon change, but change always generates new challenges. Quality improvement systems may struggle to keep up with the pace of innovation, yet evaluation of innovation is often too narrowly focused for the system-wide effects of new practices or technologies to be understood. A new recognition of the problems of innovation is proposed and it is argued that new approaches to addressing them are needed.

Hypermethylated genes as biomarkers of cancer in women with pathologic nipple discharge.

PURPOSE: In a pilot study of women with pathologic nipple discharge (PND) undergoing ductoscopy, we tested quantitative assessment of gene promoter hypermethylation using quantitative multiplex methylation-specific PCR (QM-MSP) to enhance detection of duct carcinoma in situ (DCIS). EXPERIMENTAL DESIGN: Women with PND underwent ductoscopy; ducts with significant lesions were surgically resected (36 ducts in 33 women) and those with minimal findings were not (28 ducts in 16 women). QM-MSP was done on ductoscopy cell samples. Results were compared with cytology and tissue histology. RESULTS: Cells from ducts with significant lesions on ductoscopy had significantly higher levels of methylation than those with minimal findings. Furthermore, cells from ducts with DCIS displayed higher levels of methylation than those with benign lesions such as papilloma (P = 0.006); or ducts with minimal findings on ductoscopy (P = 0.0001). Cumulative RASSF1A, TWIST1, and HIN1 gene methylation accurately distinguished ducts with cancerous versus benign lesions (100% sensitivity, 72% specificity, and area under the curve of 0.91 according to receiving operating characteristic analyses). QM-MSP analysis was more informative than cytology (100% versus 29% sensitivity, respectively), for detecting DCIS. In a validation set of paraffin-embedded DCIS and papilloma samples from women presenting with PND, QM-MSP was significantly higher in DNA from DCIS than papilloma sections (P = 0.002). CONCLUSION: The positive predictive value of ductoscopy was more than doubled (19% versus 47%) with the addition of QM-MSP, demonstrating the benefit of targeting ducts having both high methylation and significant abnormalities on ductoscopy for surgical excision. Future large-scale studies to validate this approach are needed.

Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients.

BACKGROUND & AIMS: Somatic mutations provide uniquely specific markers for the early detection of neoplasia that can be detected in DNA purified from plasma or stool of patients with colorectal cancer. The primary purpose of the present investigation was to determine the parameters that were critical for detecting mutations using a quantitative assay. A secondary purpose was to compare the results of plasma and stool DNA testing using the same technology. METHODS: We examined DNA purified from the stool of 25 patients with colorectal cancers before surgery. In 16 of these cases, plasma samples also were available. Mutations in stool or plasma were assessed with an improved version of the BEAMing technology. RESULTS: Of the 25 stool DNA samples analyzed, 23 (92%) contained mutations that were present in the corresponding tumors from the same patients. In contrast, only 8 of the 16 (50%) plasma DNA samples analyzed had detectable levels of mutated DNA. We found that the DNA fragments containing mutations in both stool and plasma DNA typically were smaller than 150 bases in size. The sensitivity of the new method was superior to a widely used technique for detecting mutations, using single base extension and sequencing, when assessed on the same samples (92% vs 60%; P = .008, exact McNemar test). CONCLUSIONS: When assessed with sufficiently sensitive methods, mutant DNA fragments are detectable in the stool of more than 90% of colorectal cancer patients. DNA purified from stool provides a better template for mutation testing than plasma.

Multiple host-switching of Haemosporidia parasites in bats.

BACKGROUND: There have been reported cases of host-switching in avian and lizard species of Plasmodium (Apicomplexa, Haemosporidia), as well as in those infecting different primate species. However, no evidence has previously been found for host-swapping between wild birds and mammals. METHODS: This paper presents the results of the sampling of blood parasites of wild-captured bats from Madagascar and Cambodia. The presence of Haemosporidia infection in these animals is confirmed and cytochrome b gene sequences were used to construct a phylogenetic analysis. RESULTS: Results reveal at least three different and independent Haemosporidia evolutionary histories in three different bat lineages from Madagascar and Cambodia. CONCLUSION: Phylogenetic analysis strongly suggests multiple host-switching of Haemosporidia parasites in bats with those from avian and primate hosts.

An open label study to establish dosing recommendations for nabumetone in juvenile rheumatoid arthritis.

OBJECTIVE: Once-a-day dosing with nabumetone has been shown to be effective in adults with rheumatoid arthritis. We establish dosing recommendations for nabumetone in children and adolescents with juvenile rheumatoid arthritis (JRA). METHODS: An open label, multicenter study was conducted in children with JRA aged 2-16 years, weighing > 14 kg, and requiring nonsteroidal antiinflammatory drugs (NSAID) for control of symptoms. NSAID were discontinued one day prior to study initiation to minimize disease flare. Patients received nabumetone 30 mg/kg once daily (as a tablet or a slurry) for 12 weeks. Efficacy assessment evaluations were performed at Weeks 1, 3, 6, and 12, based on the mean change from baseline at the study endpoint for 6 standard rheumatology variables. An overall assessment of efficacy was determined based on the percentage of patients who did not experience a flare, using the 6 rheumatology variables. Since this was an open label study, only descriptive statistics were obtained for efficacy variables. Routine safety assessments were completed for all patients. RESULTS: In total, 99 patients with JRA were enrolled and 89 completed the study; mean age was 9.2 years. The proportion of nabumetone treated patients with no flare in disease activity during the nabumetone treatment period was 92/99 (93%). Improvement was noted in each efficacy assessment, although statistical evaluations were not performed. The adverse event profile was similar to that reported for nabumetone in adults with RA. CONCLUSION: Nabumetone 30 mg/kg/day (up to 2000 mg/day) demonstrated a safe profile with no loss of efficacy compared to previous treatment in children with JRA. The dose can be administered by suspending tablets in warm water to create a slurry.

Natural transformation and DNA uptake signal sequences in Actinobacillus actinomycetemcomitans.

Actinobacillus actinomycetemcomitans is a member of the family Pasteurellaceae and a major causative agent of periodontitis. While several genera from this family are known to be competent for transformation, A. actinomycetemcomitans has yet to be fully characterized. Here we show that the competence of A. actinomycetemcomitans is remarkably similar to that of Haemophilus influenzae. In addition to having a similar frequency of transformation as H. influenzae, A. actinomycetemcomitans competence could also be induced at least 100-fold by cyclic AMP, suggesting that, as in H. influenzae, at least some competence genes are regulated by catabolite repression. Even more intriguing was the discovery of a putative A. actinomycetemcomitans DNA uptake signal sequence (USS) virtually identical to the USS of H. influenzae. Moreover, we provide evidence that this sequence functions in the same capacity as that from H. influenzae; the sequence appears to be required and sufficient for DNA uptake in a variety of assays. Finally, we have taken advantage of this system to develop a simple, highly efficient competence-based method for generating site-directed mutations in the wild-type fimbriated A. actinomycetemcomitans.