Rapid Sequence Intubation Using the SEADUC Manual Suction Unit in a Contaminated Airway.

The case presented here highlights the utility/feasibility of the SEADUC (EM Innovations, Galloway, OH) manual suction unit in clearing a contaminated airway during rapid sequence intubation. The case also highlights the importance of intubation in a patient with declining mental status in the prehospital environment. A 75-year-old woman suffered a head injury, and a helicopter emergency medical service team staffed with a physician and nurse was tasked with retrieval and transfer back to the tertiary care center. As the flight team rendezvoused with ground emergency medical services and the patient, a decision to intubate was made because of the patient's declining mental status and inability to protect her own airway. While in preparation for intubation, it was noted that the ambulance's electrical suction system was not working, and the flight crew had to resort to a SEADUC manual suction unit to clear the patient's airway of contaminants. The patient's airway was cleared, and she was successfully intubated and transported to a tertiary care center where the patient underwent an emergent neurosurgery procedure/decompression and was discharged home a few weeks later.

Documentation from trained medical students has a low rate of relative downcoding for emergency medicine encounters.

Background: Since 2018, the Centers for Medicare & Medicaid Services (CMS) guidelines have allowed teaching physicians to bill for evaluation and management services based on medical student documentation. Limited previous data suggest that medical student documentation suffers from a high rate of downcoding relative to faculty documentation. We sought to compare the coding outcomes of documentation performed by medical students, and not edited by faculty, with documentation edited and submitted by faculty. Methods: A total of 104 randomly selected notes from real patient encounters written by senior medical students were compared to the revised notes submitted by faculty. The note pairs were then split and reviewed by blinded professional coders and assigned level of service (LoS) codes 1-5 (corresponding to E&M CPT codes 99281-99285). Results: We found that the LoS agreement between student and faculty note versions was 63%, with 23% of all student notes receiving lower LoS compared to faculty notes (downcoded). This was found to be similar to baseline variability in professional coder LoS designations. Conclusions: Notes from medical students who have completed a focused documentation curriculum have less LoS downcoding than in previous reports.

Curriculum to Develop Documentation Proficiency Among Medical Students in an Emergency Medicine Clerkship.

INTRODUCTION: Documenting a clinical encounter is a core skill for entering residency, but medical students often receive scant dedicated documentation training, leading to a high rate of inadequate information. Utilizing adult experiential learning theory, we created and implemented an educational resource to train medical students on how to proficiently document an emergency department (ED) patient encounter. METHODS: One hundred and five third- and fourth-year medical students participating in an emergency medicine clerkship took part in a brief orientation day documentation curriculum that included a group didactic, a review of reference materials, a standardized patient activity, a sample patient note writing assignment with individualized feedback, and supervising faculty physician feedback on real patient notes. Students were subsequently entrusted with primary documentation responsibility for all ED patients whose care they participated in. RESULTS: After completing this curriculum, students' self-rated comfort with writing a high-quality note increased from 4.1 to 5.9 (p < .001) and knowledge about billing and coding increased from 2.9 to 5.5 (p < .001) on a 7-point scale. Among faculty physicians, 93% found student notes to always, usually, or frequently be clinically useful, and 86% reported that student notes always, usually, or frequently contained enough information for billing and coding. DISCUSSION: This curriculum was effective at training medical students on proficient patient care documentation in emergency medicine. The relatively short amount of synchronous learning time required could aid in implementation, and the allowance of medical student notes to count for billing purposes could facilitate student and faculty buy-in.

Integration of Lung Point-of-care Ultrasound into Clinical Decision Making for Medical Students in Simulated Cases.

BACKGROUND: Point-of-care ultrasound (POCUS) has an emerging presence in medical student education; however, there is limited evidence that this translates into appropriate clinical care. We aimed to evaluate the ability of medical students to integrate newly obtained POCUS knowledge into simulated clinical cases. METHODS: We conducted an observational study of medical students participating in a mandatory rotation during their clinical years. Students in small groups underwent formalized lung POCUS lectures and hands-on training. Students participated in simulated "dyspnea" cases focused on either congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). They were observed for critical actions including elements related to medical decision-making and ultrasound use and interpretation. Ultrasound-specific written knowledge was gauged with a short assessment after the first lecture and at week 4. RESULTS: A total of 62 students participated and were observed during simulations. All groups correctly identified and treated CHF in the simulated case. Most groups (7 out of 9) attempted to use ultrasound in the CHF case; five groups correctly recognized B-lines; and four groups correctly interpreted B-lines as pulmonary edema. No groups used ultrasound in the COPD case. CONCLUSION: Most students attempted to use ultrasound during simulated CHF cases after a brief didactic intervention; however, many students struggled with clinical application. Interestingly, no students recognized the need to apply ultrasound for diagnosis and management of COPD. Future studies are needed to better understand how to optimize teaching for medical students to improve translation into POCUS skills and improved clinical practice.

Use of graded responsibility and common entrustment considerations among United States emergency medicine residency programs.

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) requires all residency programs to provide increasing autonomy as residents progress through training, known as graded responsibility. However, there is little guidance on how to implement graded responsibility in practice and a paucity of literature on how it is currently implemented in emergency medicine (EM). We sought to determine how emergency medicine (EM) residency programs apply graded responsibility across a variety of activities and to identify which considerations are important in affording additional responsibilities to trainees. METHODS: We conducted a cross-sectional study of EM residency programs using a 23-question survey that was distributed by email to 162 ACGME-accredited EM program directors. Seven different domains of practice were queried. RESULTS: We received 91 responses (56.2% response rate) to the survey. Among all domains of practice except for managing critically ill medical patients, the use of graded responsibility exceeded 50% of surveyed programs. When graded responsibility was applied, post-graduate year (PGY) level was ranked an "extremely important" or "very important" consideration between 80.9% and 100.0% of the time. CONCLUSION: The majority of EM residency programs are implementing graded responsibility within most domains of practice. When decisions are made surrounding graded responsibility, programs still rely heavily on the time-based model of PGY level to determine advancement.

Misunderstanding the Match: Do Students Create Rank Lists Based on True Preferences?

INTRODUCTION: The "stable marriage" algorithm underlying the National Residency Match Program (NRMP) has been shown to create optimal outcomes when students submit true preference lists. Previous research has shown students may allow external information to affect their rank lists. The objective of this study was to determine whether medical students consistently make rank lists that reflect their true preferences. METHODS: A voluntary online survey was sent to third-year students at a single midwestern medical school. Students were given hypothetical scenarios that either should or should not affect their true residency preferences and rated the importance of six factors to their final rank list. The survey was edited by a group of education scholars and revised based on feedback from a pilot with current postgraduate year 1 residents. RESULTS: Of 175 students surveyed, 140 (80%) responded; 63% (88/140) reported that their "perceived competitiveness" would influence their rank list at least a "moderate amount. Of 135 students, 31 (23%) moved a program lower on their list if they learned they were ranked "low" by that program, while 6% (8/135) of respondents moved a program higher if they learned they were ranked "at the top of the list." Participants responded similarly (κ = 0.71) when presented with scenarios asking what they would do vs what a classmate should do. CONCLUSION: Students' hypothetical rank lists did not consistently match their true residency preferences. These results may stem from a misunderstanding of the Match algorithm. Medical schools should consider augmenting explicit education related to the NRMP Match algorithm to ensure optimal outcomes for students.

Reactive oxygen species regulate caspase activation in tumor necrosis factor-related apoptosis-inducing ligand-resistant human colon carcinoma cell lines.

The effects of reactive oxygen species (ROS) on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in solid cancers have yet to be clearly defined. In this study, we found that the classic uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a reduction in DeltaPsim and generation of ROS. This uncoupling effect enhanced TRAIL-induced apoptosis in TRAIL-resistant human colon carcinoma cell lines (RKO, HT29, and HCT8). Sensitization was inhibited by benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone, indicating the requirement for caspase activation. CCCP per se did not induce apoptosis or release of proapoptotic factors from mitochondria. Generation of ROS by CCCP was responsible for TRAIL-induced Bax and caspase activation because scavenging ROS completely abrogated apical caspase-8 activation and further downstream events leading to cell death. Overexpression of Bcl-2 did not prevent the initial loss of DeltaPsim and ROS generation following CCCP treatment, but did prevent cell death following TRAIL and CCCP exposure. Uncoupling of mitochondria also facilitated TRAIL-induced release of proapoptotic factors. X-linked inhibitor of apoptosis overexpression abrogated TRAIL-induced apoptosis in the presence of CCCP and decreased initiator procaspase-8 processing, indicating that additional processing of caspase-8 required initiation of a mitochondrial amplification loop via effector caspases. Of interest, depletion of caspase-9 in RKO cells did not protect cells from TRAIL/CCCP-induced apoptosis, indicating that apoptosis occurred via a caspase-9-independent pathway. Data suggest that in the presence of mitochondrial-derived ROS, TRAIL induced mitochondrial release of Smac/DIABLO and inactivation of X-linked inhibitor of apoptosis through caspase-9-independent activation of caspase 3.

Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C.

Signaling pathways involved in survival responses may attenuate the apoptotic response to the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human colon carcinomas. In six lines examined, three were sensitive (GC(3)/c1, VRC(5)/c1, HCT116), HT29 demonstrated intermediate sensitivity, and RKO and HCT8 were resistant to TRAIL-induced apoptosis. Calphostin c [an inhibitor of classic and novel isoforms of protein kinase C (PKC)] sensitized five of six cell lines to TRAIL, whereas Go6976, (inhibitor of classic PKC isoforms), did not influence TRAIL sensitivity. Rottlerin, an inhibitor of novel isoforms of PKC, specifically PKC delta, sensitized five of six cell lines to TRAIL-induced apoptosis, suggesting that PKC delta may be involved in the mechanism of TRAIL resistance. Transfection of HCT116 with a proapoptotic cleaved fragment of PKC delta or an antiapoptotic full-length PKC delta did not influence the sensitivity of HCT116 to TRAIL. Furthermore, the incubation of HCT116 or RKO with phorbol myristate acetate for 16 h, which down-regulated the expression of novel PKC isoforms, also did not influence sensitivity to TRAIL either in the absence or presence of rottlerin. However, after 15-min incubation with rottlerin, mitochondrial membrane potential (Delta psi m) was dramatically reduced in RKO cells, and, in cells subsequently treated with TRAIL, rapid apoptosis was evident within 8 h. Calphostin c, but not Go6976, also caused a decrease in Delta psi m. In RKO, rottlerin induced the release of cytochrome c, HtrA2/Omi, Smac/DIABLO, and AIF from the mitochondria, potentiated in combination with TRAIL, with concomitant caspase activation and down-regulation of XIAP. In HT29, the release of proapoptotic factors was demonstrated only when rottlerin and TRAIL were combined, and Bcl-2 overexpression inhibited this release and the induction of apoptosis. TRAIL-induced apoptosis was not influenced by rottlerin or Bcl-2 overexpression in type I (GC(3)/c1) cells. Data suggest that rottlerin affects mitochondrial function independent of PKC delta, thereby sensitizing cells to TRAIL, and that mitochondria constitute an important target in overcoming inherent resistance to TRAIL in colon carcinomas.

Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin.

We have demonstrated previously a Fas-dependent component in thymineless death of human colon carcinoma cells. Importantly, the cytotoxic effects of thymidine deprivation induced by 5-fluorouracil (FUra) combined with leucovorin (LV) was enhanced by IFN-gamma, and the synergism was shown to be dependent on Fas, FUra-induced DNA damage, and independent of p53. Subsequently we examined the potential for synergistic interactions between IFN-gamma and the specific thymidylate synthase inhibitor, ZD9331. IFN-gamma sensitized colon carcinomas to ZD9331-induced apoptosis and loss in clonogenic survival, also dependent on ZD9331-induced DNA damage, independent of p53. Synergism occurred in HCT116, demonstrating previously RNA-mediated FUra/LV cytotoxicity that could not be potentiated by IFN-gamma. Manipulation of the Fas death receptor pathway from the level of the receptor (Nok1/Nok2, Fas overexpression, and DN-FADD) to the mitochondria (Bcl-xL and Bcl-2) did not modulate ZD9331 +/- IFN-gamma-induced cytotoxicity in HT29, with the exception that Nok1/Nok2-blocking antibodies partially protected HT29 from the cytotoxic activity of ZD9331 alone. However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2. Additionally, IFN-gamma increased the activity of the proteasome in HT29, leading to selective down-regulation of the antiapoptotic protein survivin, whereas simultaneously increasing Fas expression. However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma. Data demonstrate that IFN-gamma combined with ZD9331 is synergistic in additional cell lines that demonstrate RNA-mediated FUra/LV cytotoxicity, and that a major target of interaction is at the level of caspases, downstream of Fas, and independent of involvement of either the mitochondria or survivin.

Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin.

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN-gamma in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of < or =50 micro g/m2 and > or =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma correlated with a 2-3-fold up-regulation of Fas expression at 24 h in CD15+ cells in peripheral blood samples. Furthermore, clinically relevant IFN-gamma concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity. On the basis of the modulation of Fas signaling, FUra/LV combined with IFN-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.

Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer.

PURPOSE: The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-gamma) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN-gamma exposures and Fas upregulation in vivo and in vitro. METHODS: Patients received IFN-gamma (10, 25, 50, 75, and 100 microg/m(2)) with LV and 5-FU, and serial samples were collected after the first dose. IFN-gamma concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN-gamma plasma concentration-time data. To examine the relationship between IFN-gamma systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments. RESULTS: The median (range) apparent IFN-gamma clearance was 46 l/m(2) per hour (2.6-92 l/m(2) per hour). With increasing IFN-gamma dosages, the area under the concentration-time curve (AUC(0--> infinity )) and C(max) increased; however, significant interpatient variability was observed. IFN-gamma AUC(0--> infinity ) and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4(+) and CD56(+) cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN-gamma concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo. CONCLUSIONS: We characterized IFN-gamma disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN-gamma upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN-gamma pharmacokinetics/pharmacodynamics may be warranted in IFN-gamma clinical use.

Uncommon causes of leg ulceration and lesions not to be missed.

While the vast majority of cases of leg ulceration are the result of venous and/or arterial disease, and occur in older people, there are several other, less common conditions that can lead to leg ulceration, often in younger people. This article examines the diagnosis and management of some of these conditions, almost all of which will require referral for specialist assessment and treatment.

Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial.

To generate sufficient clinical-grade vector to support a phase I/II clinical trial of adeno-associated virus serotype 8 (AAV8)-mediated factor IX (FIX) gene transfer for hemophilia B, we have developed a large-scale, good manufacturing practice (GMP)-compatible method for vector production and purification. We used a 293T-based two-plasmid transient transfection system coupled with a three-column chromatography purification process to produce high-quality self-complementary AAV2/8 FIX clinical-grade vector. Two consecutive production campaigns using a total of 432 independent 10-stack culture chambers produced a total of ∼2 × 10(15) vector genomes (VG) by dot-blot hybridization. Benzonase-treated microfluidized lysates generated from pellets of transfected cells were purified by group separation on Sepharose beads followed by anion-exchange chromatography. The virus-containing fractions were further processed by gel filtration and ultrafiltration, using a 100-kDa membrane. The vector was formulated in phosphate-buffered saline plus 0.25% human serum albumin. Spectrophotometric analysis suggested ∼20% full particles, with only low quantities of nonviral proteins were visible on silver-stained sodium dodecyl sulfate-polyacrylamide gels. A sensitive assay for the detection of replication-competent AAV was developed, which did reveal trace quantities of such contaminants in the final product. Additional studies have confirmed the long-term stability of the vector at -80°C for at least 24 months and for at least 24 hr formulated in the clinical diluent and stored at room temperature within intravenous bags. This material has been approved for use in clinical trials in the United States and the United Kingdom.

A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups.

Psoriasis is a chronic skin disorder with multifactorial aetiology. Genome-wide scans have provided unambiguous evidence for a major disease susceptibility locus on chromosome 6p21 (PSORS1). A minimal PSORS1 interval has been defined which encompasses three genes (HLA-C, HCR and CDSN) carrying psoriasis-associated SNPs. On the basis of this genetic evidence, we have undertaken an assessment of CDSN allele functional impact. A comparison of CDSN intragenic haplotypes showed that SNPs exclusive to disease-associated chromosomes are located in regions implicated in the stabilization of RNA transcripts. As CDSN is over-expressed in psoriatic lesions, we hypothesised that disease-associated intragenic SNPs may alter the rate of its mRNA decay. Here, we demonstrate that mRNAs transcribed from a CDSN risk haplotype present a 2-fold increase in stability, compared with those transcribed from a neutral haplotype (t-test P=0.004). Site-directed mutagenesis revealed that a single synonymous SNP (CDSN*971T) accounts for the observed increase in RNA stability. CDSN*971T maps to a RNA stability motif and UV cross-linking analysis demonstrated that the SNP affects the transcript affinity for a 39 kDa RNA binding protein. Association analyses show that haplotypes bearing CDSN*971T confer psoriasis susceptibility in a wide range of ethnic groups. These results demonstrate the effect of synonymous variation upon allele specific gene expression, a finding of relevance to future studies of the pathogenesis of common and complex traits.

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.