Publications by authors named "Samantha Lane"

27 Publications

  • Page 1 of 1

General Surgery Residency Application Evaluation in a USMLE Step 1 Pass/Fail World: A Retrospective Comparison.

J Surg Res 2021 May 7;265:317-322. Epub 2021 May 7.

Department of General Surgery, Geisinger Medical Center, 100 N Academy Ave, Danville, 17822, Pennsylvania.

Introduction The United States Medical Licensure Exam (USMLE) Step 1 has been used as both a licensing exam and a way for residency programs to evaluate applicants. It has had significant impact upon the match process over time. With the 2020 decision to make the exam pass/fail due to its unclear validity as an evaluation for future physician performance, programs will go through the match without the Step 1 score. We set out to better understand the effects of the exam score on our selection process, with the hypothesis that without the step 1 score, the ranking of our applicants would be significantly altered. Methods We performed a retrospective analysis of applications to a single General Surgery residency program with 4 categorial residents per year at a physician led, academic, tertiary care medical center from 2017-2020. Important applicant factors including USMLE Step 1 and 2, AOA status, science grades, clerkship scores, audition rotations, volunteer activities, research activities, letters of recommendation, and personal statements were given points and evaluated through our equation, the sum of which was used to create a rank list and offer interviews. The standard deviation of scores was calculated with and without Step 1, and the distribution of scores compared. The range and average of applicants' change in point scores were examined. Results The applications of 653 students were reviewed. After removal of USMLE step 1 points, 40% of all applicants decreased in rank, 35% remained the same, and 24% increased. Specifically, 18.8% of the top third dropped to the middle third, and 11.7% of the bottom third jumped to the middle third, while the middle third changed little (0.2% dropped and 0.9% jumped out of middle third). The points given for USMLE step 1 created a wider distribution of scores with a negative skewness, suggesting there were more applicants below the mean than above. After removing those points, applicants' scores had a narrower distribution and skewness closer to 0, showing fewer upper outliers and more applicants near the mean. Conclusions The USMLE Step 1 score significantly affected the evaluation of applicants, and the removal of it from the recruitment criteria tightened applicant rankings. The elimination of the USMLE Step 1 score in the assessment of applicants will allow for its replacement with variables that better reflect the core values of residency programs.
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http://dx.doi.org/10.1016/j.jss.2021.03.056DOI Listing
May 2021

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology.

Drug Saf 2021 May 7. Epub 2021 May 7.

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.

In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect.
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http://dx.doi.org/10.1007/s40264-021-01074-yDOI Listing
May 2021

How to Investigate a Serious Adverse Event Reported During a Clinical Trial for a COVID-19 Vaccine.

Drug Saf 2021 01 21;44(1):1-5. Epub 2020 Nov 21.

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, Hampshire, SO31 1AA, UK.

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http://dx.doi.org/10.1007/s40264-020-01018-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680067PMC
January 2021

Lopinavir-Ritonavir in the Treatment of COVID-19: A Dynamic Systematic Benefit-Risk Assessment.

Drug Saf 2020 08;43(8):809-821

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.

Introduction And Objective: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile.

Methods: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.

Results: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.

Conclusions: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.
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http://dx.doi.org/10.1007/s40264-020-00966-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309686PMC
August 2020

Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment.

Drug Saf 2020 07;43(7):645-656

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.

Introduction: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available.

Methods: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.

Results: Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%).

Conclusions: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.
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http://dx.doi.org/10.1007/s40264-020-00952-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255634PMC
July 2020

Application Factors May Not Be Predictors of Success Among General Surgery Residents as Measured by ACGME Milestones.

J Surg Res 2020 09 19;253:34-40. Epub 2020 Apr 19.

Geisinger Medical Center, Danville, Pennsylvania.

Background: Can factors within the Electronic Residency Application Service application be used to predict the success of general surgery residents as measured by the Accreditation Council for Graduate Medical Education (ACGME) general surgery milestones?

Methods: This is a retrospective study of 21 residents who completed training at a single general surgery residency program. Electronic Residency Application Service applications were reviewed for objective data, such as age, US Medical Licensing Examination scores, and authorship of academic publications as well as for letters of recommendation, which were scored using a standardized grading system. These factors were correlated to resident success as measured by ACGME general surgery milestone outcomes using univariate and multivariate analyses. This study was conducted at a single academic tertiary care and level 1 trauma facility. Residents who completed general surgery residency training from the years of 2012-2018 were included in the study.

Results: There were few correlations between application factors and resident success determined by the ACGME milestones.

Conclusions: Application factors alone do not account for ongoing growth and development throughout residency. Unlike the results presented in the literature for other surgical subspecialties, predicting general surgery resident success based on application factors is not straightforward.
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http://dx.doi.org/10.1016/j.jss.2020.03.029DOI Listing
September 2020

How Applicants to General Surgery Residency Define Resilience.

J Surg Educ 2020 Jul - Aug;77(4):799-804. Epub 2020 Mar 17.

Geisinger Medical Center, Danville, Pennsylvania.

Objective: Resilience is a vital quality for the successful completion of any residency training program. Resilience is a commonly used but poorly understood term and is defined in multiple ways by people during different times of their lives. The transition from medical student to general surgical resident (GSR) is one of the most formative times in a young surgeon's professional career. The purpose of this study is to determine how a cohort of aspiring surgical residents define resilience.

Design: This is a qualitative study where interviews were conducted prospective GSRs over 2 application seasons. During the institution's standard interview process, applicants were asked to provide a definition of resilience. Responses were documented. Qualitative content analysis was conducted by the research team. Initial codes were developed and defined. Research team members independently coded the responses, and then an iterative group consensus process was used to develop the final themes.

Setting: This study was conducted at Geisinger Medical Center, an academic tertiary care hospital in Danville, PA with 5 categorical GSR positions per year.

Participants: All applicants who underwent an in-person interview were included in this study.

Results: A total of 261 comments about resilience were available from 117 interviews. These responses were categorized into 5 themes: support, learning from failure, adaptability, self-reflection, and perseverance.

Conclusion: Resilience as defined by applicants to a general surgery residency program is a multifaceted term. The thematic categories suggest that resilience can be viewed through the framework of the 5 components of emotional intelligence: self-aware, self-regulation, motivation, empathy, and social skills.
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http://dx.doi.org/10.1016/j.jsurg.2020.02.011DOI Listing
March 2020

Meaningful autonomy in general surgery training: Exploring for gender bias.

Am J Surg 2020 02 27;219(2):240-244. Epub 2019 Nov 27.

Department of General Surgery, Geisinger Medical Center, 100 North Academy Ave, Danville, PA, 17822, USA.

Background: Resident autonomy is essential to the development of a surgical resident. This study aims to analyze gender differences in meaningful autonomy (MA) given to general surgery trainees intraoperatively.

Methods: This is a retrospective study of general surgery residents at an academic-affiliated tertiary care facility. Attending surgeons completed post-operative evaluations based on the Zwisch model (4-point scale, ≥3 indicating MA).

Results: Attending faculty members (37 males, 15 females) completed evaluations of 35 residents (18 males, 17 females). A total of 3574 evaluations were analyzed (1380 female, 2194 male residents) over 28 months. Multivariate analysis revealed case complexity, post graduate year level and rater gender were significantly associated with MA. Resident gender and faculty experience did not impact MA.

Conclusions: In contrast to published literature, resident gender did not influence MA. This may be encouraging to surgical programs seeking strategies to address gender bias.
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http://dx.doi.org/10.1016/j.amjsurg.2019.11.035DOI Listing
February 2020

Low skeletal muscle capillarization limits muscle adaptation to resistance exercise training in older adults.

Exp Gerontol 2019 11 10;127:110723. Epub 2019 Sep 10.

Department of Nutrition & Metabolism, School of Health Professions, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX, USA. Electronic address:

Objectives: Adequate muscle perfusion supports the transport of nutrients, oxygen and hormones into muscle fibers. Aging is associated with a substantial decrease in skeletal muscle capillarization, fiber size and oxidative capacity, which may be improved with regular physical activity. The aim of this study was to investigate the relationship between muscle capillarization and indices of muscle hypertrophy (i.e. lean mass; fiber cross sectional area (CSA)) in older adults before and after 12 weeks of progressive resistance exercise training (RET).

Design: Interventional study SETTING AND PARTICIPANTS: 19 subjects (10 male and 9 female; 71.1 ± 4.3 years; 27.6 ± 3.2 BMI) were enrolled in the study and performed a whole body RET program for 12 weeks. Subjects where then retrospectively divided into a LOW or HIGH group, based on their pre-RET capillary-to-fiber perimeter exchange index (CFPE). Physical activity level, indices of capillarization (capillaries-to-fiber ratio, C:Fi; CFPE index and capillary-to-fiber interface, LC-PF index), muscle hypertrophy, muscle protein turnover and mitochondrial function were assessed before and after RET.

Results: Basal capillarization (C:Fi; CFPE and LP-CF index) correlates with daily physical activity level (C:Fi, r = 0.57, p = 0.019; CFPE index, r = 0.55, p = 0.024; LC-PF index, r = 0.56, p = 0.022) and CFPE and LC-PF indices were also positively associated with oxidative capacity (respectively r = 0.45, p = 0.06; r = 0.67, p = 0.004). Following RET, subjects in the HIGH group underwent hypertrophy with significant improvements in muscle protein synthesis and muscle fiber CSA (p < 0.05). However, RET did not promote muscle hypertrophy in the LOW group, but RET significantly increased muscle capillary density (p < 0.05).

Conclusion/implications: Muscle fiber capillarization before starting an exercise training program may be predictive of the muscle hypertrophic response to RET in older adults. Increases in muscle fiber size following RET appear to be blunted when muscle capillarization is low, suggesting that an adequate initial capillarization is critical to achieve a meaningful degree of muscle adaptation to RET.
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http://dx.doi.org/10.1016/j.exger.2019.110723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904952PMC
November 2019

The Value of Surgical Graduate Medical Education (GME) Programs Within An Integrated Health Care System.

J Surg Educ 2019 Nov - Dec;76(6):e173-e181. Epub 2019 Aug 26.

Department of Surgery, Geisinger Medical Center, Danville, Pennsylvania. Electronic address:

Objective: Surgical graduate medical education (GME) programs add both significant cost and complexity to the mission of teaching hospitals. While expenses tied directly to surgical training programs are well tracked, overall cost-benefit accounting has not been performed. In this study, we attempt to better define the costs and benefits of maintaining surgical GME programs within a large integrated health system.

Design: We examined the costs, in 2018 US dollars, associated with the surgical training programs within a single health system. Total health system expenses were calculated using actual and estimated direct GME expenses (salary, benefits, supplies, overhead, and teaching expenses) as well as indirect medical education (IME) expenses. IME expenses for each training program were estimated by using both Medicare percentages and the Medicare Payment Advisor Commission study. The projected cost to replace surgical trainees with advanced practitioners or hospitalists was obtained through interviews with program directors and administrators and was validated by our system's business office.

Setting: A physician lead, integrated, rural health system consisting of 8 hospitals, a medical school and a health insurance company.

Participants: GME surgical training programs within a single health system's department of surgery.

Results: Our health system's department of surgery supports 8 surgical GME programs (2 general surgery residencies along with residencies in otolaryngology, ophthalmology, oral-maxillofacial surgery, urology, pediatric dentistry, and vascular surgery), encompassing 89 trainees. Trainees work an average of 64.4 hours per week. Total health system cost per resident ranged from $249,657 to $516,783 based on specialty as well as method of calculating IME expenses. After averaging program costs and excluding IME and overhead expenses, we estimated the average annual cost per trainee to be $84,171. We projected that replacing our surgical trainees would require hiring 145 additional advanced practitioners at a cost of $166,500 each per year, or 97 hospitalists at a cost of $346,500 each per year. Excluding overhead, teaching and IME expenses, these replacements would cost the health system an estimated additional $16,651,281 or $26,119,281 per year, respectively.

Conclusions: Surgical education is an integral part of our health system and ending surgical GME programs would require large expansion of human resources and significant additional fiscal capital.
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http://dx.doi.org/10.1016/j.jsurg.2019.08.006DOI Listing
October 2020

Investigation assessing the publicly available evidence supporting postmarketing withdrawals, revocations and suspensions of marketing authorisations in the EU since 2012.

BMJ Open 2018 01 23;8(1):e019759. Epub 2018 Jan 23.

Drug Safety Research Unit, Southampton, Hampshire, UK.

Objectives: To assess the sources of publicly available evidence supporting withdrawal, revocation or suspension of marketing authorisations ('regulatory actions') due to safety reasons in the EU since 2012 and to investigate the time taken since initial marketing authorisation to reach these regulatory decisions.

Setting: This investigation examined the sources of evidence supporting 18 identified prescription medicinal products which underwent regulatory action due to safety reasons within the EU in the period 1 July 2012 to 31 December 2016.

Results: Eighteen single or combined active substances ('medicinal products') withdrawn, revoked or suspended within the EU for safety reasons between 2012 and 2016 met the inclusion criteria. Case reports were most commonly cited, supporting 94.4% of regulatory actions (n=17), followed by randomised controlled trial, meta-analyses, animal and in vitro, ex vivo or in silico study designs, each cited in 72.2% of regulatory actions (n=13). Epidemiological study designs were least commonly cited (n=8, 44.4%). Multiple sources of evidence contributed to 94.4% of regulatory decisions (n=17). Death was the most common adverse drug reaction leading to regulatory action (n=5; 27.8%), with four of these related to medication error or overdose. Median (IQR) time taken to reach a decision from the start of regulatory review was found to be 204.5 days (143, 535 days) and decreased across the study period. Duration of marketing prior to regulatory action, from the medicinal product's authorisation date, increased across the period 2012-2016.

Conclusions: The sources of evidence supporting pharmacovigilance regulatory activities appear to have changed since implementation of Directive 2010/84/EU and Regulation (EU) No. 1235/2010. This, together with a small improvement in regulatory efficiency, suggests progress towards more rapid regulatory decisions based on more robust evidence. Future research should continue to monitor sources of evidence supporting regulatory decisions and the time taken to reach these decisions over time.
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http://dx.doi.org/10.1136/bmjopen-2017-019759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786078PMC
January 2018

Ten Year Projections for US Residency Positions: Will There be Enough Positions to Accommodate the Growing Number of U.S. Medical School Graduates?

J Surg Educ 2018 May - Jun;75(3):546-551. Epub 2017 Sep 14.

Department of General Surgery, Geisinger Medical Center, Danville, Pennsylvania.

Objective: Recently, a multitude of new U.S. medical schools have been established and existing medical schools have expanded their enrollments. The National Residency Match Program (NRMP) reports that in 2016 there were 23,339 categorical residency positions offered in the match and 26,836 overall applicants with 17,789 (66.29%) of the total candidates being U.S. allopathic graduates. In view of the rapid growth of medical school graduates, the aim of this study is to determine if current trends suggest a shortage of residency positions within the next ten years.

Design: The total number of graduates from U.S. medical schools was obtained from the Association of American Medical Colleges (AAMC) for 2005-2014 academic years and was trended linearly for a 10-year prediction for the number of graduates. The yearly number of categorical positions filled by U.S. graduates for calendar years 2006-2015 was obtained from the NRMP and was trended longitudinally 10 years into the future. Analysis of subspecialty data focused on the comparison of differences in growth rates and potential foreseeable deficits in available categorical positions in U.S. residency programs.

Results: According to trended data from AAMC, the total number of graduates from U.S. medical schools has increased 1.52 percent annually (15,927 in 2005 to 18,705 in 2014); with a forecast of 22,280 U.S. medical school graduates in 2026. The growth rate of all categorical positions available in U.S. residency programs was 2.55 percent annually, predicting 29,880 positions available in 2026. In view of these results, an analysis of specific residencies was done to determine potential shortages in specific residencies. With 17.4 percent of all U.S. graduates matching into internal medicine and a 3.17 percent growth rate in residency positions, in 2026 the number of internal medicine residency positions will be 9,026 with 3,874 U.S. graduates predicted to match into these positions. In general surgery, residency positions note a growth rate of 1.55 percent. Of all U.S. graduates, 5.6 percent match into general surgery. Overall this projects 1,445 general surgery residency positions in 2026 with 1,257 U.S. graduates matching. In orthopedics with a growth rate of 1.35 percent and a match rate of 3.75 percent, there are projected to be 827 positions available with 836 U.S. graduates projected to match.

Conclusions: Despite the increasing number of medical school graduates, our model suggests the rate of growth of residency positions continues to be higher than the rate of growth of U.S. medical school graduates. While there is no apparent shortage of categorical positions overall, highly competitive subspecialties like orthopedics may develop a shortage within the next ten years.
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http://dx.doi.org/10.1016/j.jsurg.2017.08.021DOI Listing
September 2019

Characterizing the Relationship Between Surgical Resident and Faculty Perceptions of Autonomy in the Operating Room.

J Surg Educ 2017 Nov - Dec;74(6):e31-e38. Epub 2017 Jun 13.

Department of General Surgery, Geisinger Medical Center, Danville, Pennsylvania. Electronic address:

Objective: Characterize the concordance among faculty and resident perceptions of surgical case complexity, resident technical performance, and autonomy in a diverse sample of general surgery procedures using case-specific evaluations.

Design: A prospective study was conducted in which a faculty surgeon and surgical resident independently completed a postoperative assessment examining case complexity, resident operative performance (Milestone assessment) and autonomy (Zwisch model). Pearson correlation coefficients (r) reaching statistical significance (p < 0.05) were further classified as moderate (r ≥ 0.40), strong (r ≥ 0.60), or very strong (r ≥ 0.80).

Setting: This study was conducted in the General Surgery Residency Program at an academic tertiary care facility (Geisinger Medical Center, Danville, PA).

Participants: Participants included 6 faculty surgeons, in addition to 5 postgraduate year (PGY) 1, 6 midlevel (PGY 2-3), and 4 chief (PGY 4-5) residents.

Results: In total, 75 surgical cases were analyzed. Midlevel residents accounted for the highest number of cases (35, 46.6%). Overall, faculty and resident perceptions of case complexity demonstrated a strong correlation (r = 0.76, p < 0.0001). Technical performance scores were also strongly correlated (r = 0.66, p < 0.0001), whereas perceptions of autonomy demonstrated a moderate correlation (r = 0.56, p < 0.0001). Subgroup analysis revealed very strong correlations among faculty perceptions of case complexity and the perceptions of PGY 1 (r = 0.80, p < 0.0001) and chief residents (r = 0.82, p < 0.0001). All other intergroup correlations were strong with 2 notable exceptions as follows: midlevel and chief residents failed to correlate with faculty perceptions of autonomy and operative performance, respectively.

Conclusions: General surgery residents generally demonstrated high correlations with faculty perceptions of case complexity, technical performance, and operative autonomy. This generalized accord supports the use of the Milestone and Zwisch assessments in residency programs. However, discordance among perceptions of midlevel resident autonomy and chief resident operative performance suggests that these trainees may need more direct communication from the faculty.
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http://dx.doi.org/10.1016/j.jsurg.2017.05.021DOI Listing
August 2018

The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism.

J Biol Chem 2016 Feb 23;291(7):3254-67. Epub 2015 Dec 23.

From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and

Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCV-infected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein·SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.
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http://dx.doi.org/10.1074/jbc.M115.694059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751372PMC
February 2016

Comparative analysis of optogenetic actuators in cultured astrocytes.

Cell Calcium 2014 Sep 23;56(3):208-14. Epub 2014 Jul 23.

School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, BS8 1TD, UK. Electronic address:

Astrocytes modulate synaptic transmission via release of gliotransmitters such as ATP, glutamate, D-serine and L-lactate. One of the main problems when studying the role of astrocytes in vitro and in vivo is the lack of suitable tools for their selective activation. Optogenetic actuators can be used to manipulate astrocytic activity by expression of variants of channelrhodopsin-2 (ChR2) or other optogenetic actuators with the aim to initiate intracellular events such as intracellular Ca(2+) ([Ca(2+)]i) and/or cAMP increases. We have developed an array of adenoviral vectors (AVV) with ChR2-like actuators, including an enhanced ChR2 mutant (H134R), and a mutant with improved Ca(2+) permeability (Ca(2+) translocating channelrhodopsin, CatCh). We show here that [Ca(2+)]i elevations evoked by ChR2(H134R) and CatCh in astrocytes are largely due to release of Ca(2+) from the intracellular stores. The autocrine action of ATP which is released under these conditions and acts on the P2Y receptors also contributes to the [Ca(2+)]i elevations. We also studied effects evoked using light-sensitive G-protein coupled receptors (opto-adrenoceptors). Activation of optoα1AR (Gq-coupled) and optoβ2AR (Gs-coupled) resulted in astrocytic [Ca(2+)]i increases which were suppressed by blocking the corresponding intracellular signalling cascade (phospholipase C and adenylate cyclase, respectively). Interestingly, the bulk of [Ca(2+)]i responses evoked using either optoAR was blocked by an ATP degrading enzyme, apyrase, or a P2Y1 receptor blocker, MRS 2179, indicating that they are to a large extent triggered by the autocrine action of ATP. We conclude that, whilst optimal tools for control of astrocytes are yet to be generated, the currently available optogenetic actuators successfully initiate biologically relevant signalling events in astrocytes.
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http://dx.doi.org/10.1016/j.ceca.2014.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169180PMC
September 2014

Hemophagocytic lymphohistiocytosis (HLH) in a 25-year-old presenting with multisystem organ failure.

W V Med J 2013 Nov-Dec;109(6):22-3

CAMC, Dept. of Hematology Oncology, Charleston, WV, USA.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of extreme inflammation caused by pathologic activation of the immune system. Diagnosis of HLH is challenging as the clinical presentation is similar to common medical entities such as sepsis. When a source of the extreme inflammation is not found, HLH should be considered in the differential diagnosis. In HLH, inflammatory markers such as soluble CD25 and ferritin levels are elevated. Ferritin assay is widely available at most institutions; a level greater than 10,000 is highly suggestive of HLH.2 Delayed diagnosis and failure to initiate cytotoxic chemotherapy will result in a fatal outcome.
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January 2014

Astrocytes control breathing through pH-dependent release of ATP.

Science 2010 Jul 15;329(5991):571-5. Epub 2010 Jul 15.

Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, UK.

Astrocytes provide structural and metabolic support for neuronal networks, but direct evidence demonstrating their active role in complex behaviors is limited. Central respiratory chemosensitivity is an essential mechanism that, via regulation of breathing, maintains constant levels of blood and brain pH and partial pressure of CO2. We found that astrocytes of the brainstem chemoreceptor areas are highly chemosensitive. They responded to physiological decreases in pH with vigorous elevations in intracellular Ca2+ and release of adenosine triphosphate (ATP). ATP propagated astrocytic Ca2+ excitation, activated chemoreceptor neurons, and induced adaptive increases in breathing. Mimicking pH-evoked Ca2+ responses by means of optogenetic stimulation of astrocytes expressing channelrhodopsin-2 activated chemoreceptor neurons via an ATP-dependent mechanism and triggered robust respiratory responses in vivo. This demonstrates a potentially crucial role for brain glial cells in mediating a fundamental physiological reflex.
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http://dx.doi.org/10.1126/science.1190721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160742PMC
July 2010

Astroglia are a possible cellular substrate of angiotensin(1-7) effects in the rostral ventrolateral medulla.

Cardiovasc Res 2010 Aug 3;87(3):578-84. Epub 2010 Mar 3.

Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.

Aims: Angiotensin(1-7) (Ang1-7) acting at the level of the rostral ventrolateral medulla (RVLM) affects arterial pressure. The cellular substrate of Ang1-7 remains unknown. We sought to determine which cell types in RVLM could mediate its actions and whether these are altered in the spontaneously hypertensive rat (SHR).

Methods And Results: Astrocytes, catecholaminergic (CA-ergic) and non-CA-ergic neurones were targeted with adenoviral vectors in organotypic slice cultures from Wistar rats and SHR. Astrocytic Ca(2+) signalling was monitored using a genetically engineered Ca(2+) sensor Case12. CA-ergic neurones expressed enhanced green fluorescent protein (EGFP) under control of the PRS x 8 promoter, whereas non-CA-neurones expressed EGFP under control of the synapsin-1 promoter. Neurones were recorded in whole cell mode while [Ca(2+)](i) was monitored using Rhod-2. RVLM astrocytes responded to Ang1-7 (200-1000 nM) with concentration-dependent [Ca(2+)](i) elevation. In SHR, the response to 1000 nM was significantly attenuated. The competitive Ang1-7 receptor antagonist A779, but not the AT(1) receptor blocker (losartan), suppressed Ang1-7-induced [Ca(2+)](i) elevations, which were also antagonized by blocking intracellular Ca(2+) stores. Ang1-7 evoked no consistent changes in [Ca(2+)](i) or membrane excitability in CA-ergic or non-CA-ergic neurones in either rat strain.

Conclusion: Astroglia are a plausible cellular target of Ang1-7 in RVLM. Our data suggest that astrocytic responsiveness to Ang1-7 is reduced in SHR. We hypothesise that Ang1-7 modulates astrocytic signalling which in vivo may affect local metabolism and microcirculation, resulting in changes in activity of RVLM pre-sympathetic neurones and hence blood pressure.
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http://dx.doi.org/10.1093/cvr/cvq059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904658PMC
August 2010

Activation and repression of prion protein expression by key regions of intron 1.

Cell Mol Life Sci 2009 Dec;66(23):3809-20

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.

Expression of the prion protein is necessary for infection with prion diseases. Altered expression levels may play an important role in susceptibility to infection. Therefore, understanding the mechanisms that regulate prion protein expression is of great importance. It was previously shown that expression of the prion protein is to some degree regulated by an alternative promoter within intron 1. Studies using GFP and luciferase reporter systems were undertaken to determine key sites for the repression and activation of expression of the prion protein driven by intron 1. We identified a region within intron 1 sufficient to drive prion protein expression. Our findings highlight two potential repressor regions. Both regions have binding sites for the known repressor Hes-1. Hes-1 overexpression caused a dramatic decrease in PrP protein expression. Additionally, we have identified Atox-1 as a transcription factor that upregulates prion protein expression. These findings clearly indicate that intron 1 plays a key role in regulation of prion protein expression levels.
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http://dx.doi.org/10.1007/s00018-009-0154-8DOI Listing
December 2009

The bacterial profile of cotton lint from worldwide origins, and links with occupational lung disease.

Am J Ind Med 2007 Jan;50(1):42-7

School of Science and the Environment, Bath Spa University, Bath, UK.

Background: Byssinosis, the cotton worker's lung disease persists today in many countries. Several agents have been investigated with respect to causality; among these are Gram-negative bacteria. These organisms are a source of lipopolysaccharide toxins, which are potentially hazardous to the respiratory tract. Despite byssinosis being most prevalent in countries where adequate preventive procedures are lacking, the majority of past studies have been conducted on cotton from the United States.

Methods: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions.

Results: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions.

Conclusions: Building a bacterial profile of cotton samples with worldwide origins will be useful in isolating sources of these organisms, assessing the risk posed to industry, workers and ultimately assisting the prevention of byssinosis and related conditions.
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http://dx.doi.org/10.1002/ajim.20412DOI Listing
January 2007

The fungal profile of cotton lint from diverse sources and implications for occupational health.

J Occup Environ Hyg 2006 Sep;3(9):508-12

Welsh School of Pharmacy-Pharmacology, Cardiff University, Wales.

There is mounting evidence that inhalation of fungal spores and their fragments and toxins may cause respiratory illness, particularly in indoor environments and industrial settings. However, analysis of these organisms on cotton has not been carried out in detail and, hence, further examination may prove important in identifying sources of these organisms and assessing the risks posed to cotton workers. This study identified fungi from cotton lint samples originating in 12 world regions and revealed six different fungal genera, with the following rank order of sample isolation incidence: Aspergillus > Cladosporium > Fusarium > Rhizopus > Penicillium > Alternaria. Aspergillus was the most common genus and Aspergillus niger in particular was the pecies most frequently identified. Improved understanding of the variety of organisms that contaminate cotton may help to reduce prevalence of organic dust-related lung diseases.
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http://dx.doi.org/10.1080/15459620600872567DOI Listing
September 2006

Correlative measurement of four biological contaminants on cotton lint, and their implications for occupational health.

Int J Occup Environ Health 2006 Apr-Jun;12(2):120-5

Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.

Four biological contaminants of cotton fibers (gram-negative bacterial cells, endotoxin, fungal cells, and (1-3)-beta-D-glucan) were measured in 13 cotton lint samples from international origins, using traditional microbiological spread plating and adaptation of the Limulus amoebocyte lysate (LAL) assay. Correlations were evaluated using Spearman's rank correlation analyses. Contamination levels ranged from 713 +/- 212 to 216,830 +/- 30,413 CFU/g gram-negative bacteria; 281 +/- 29 to 9,250 +/- 820 CFU/g fungal cells; 8.30 +/- 0.89 to 137.89 +/- 21.55 ng/g endotoxin; and 15.96 +/- 5.18 to 2,964.42 +/- 313.90 LAL-reactive units/g glucan. Positive correlations existed between all contaminants; however, they were significant only between fungal cells and glucan (p < 0.05) and between endotoxin and glucan (p < 0.01). The highly significant positive correlation between endotoxin and glucan has implications for the health risk posed by the cotton-production environment, as simultaneous inhalation of these agents may cause or exacerbate lung inflammation.
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http://dx.doi.org/10.1179/oeh.2006.12.2.120DOI Listing
December 2006

Amplicon secondary structure prevents target hybridization to oligonucleotide microarrays.

Biosens Bioelectron 2004 Nov;20(4):728-35

Department of Veterinary Microbiology and Pathology, Washington State University, 402 Bustad Hall, P.O. Box 647040, Pullman, WA 99164-7040, USA.

DNA microarrays that are used as end-point detectors for PCR assays are typically composed of short (15-25 mer) oligonucleotide probes bound to glass. When designing these detectors, we have frequently encountered situations where a probe would not hybridize to its complementary, terminally labeled PCR amplicon. To determine if failures could be explained by general phenomenon such as secondary structure, we designed a microarray to detect eight regions of the Escherichia coli 16S rDNA gene. We then amplified eight amplicons of different lengths using a biotin conjugated, antisense primer. Amplicons were then hybridized to the microarray and detected using a combination of signal amplification and fluorescence. In most cases, probe sequences complementary to the 5' region of the amplified products (sense orientation) did not hybridize to their respective amplicon. We tested for positional bias and showed that a biotin conjugated sense primer mirrored the same probe failures. Nick translated products, however, hybridized to all probes. Because nick translation generates many labeled fragments of random length, we concluded that this method disrupted secondary structure that otherwise prevented the amplicons from hybridizing to their respective probes. We also show that nick translation does not compromise detector sensitivity even when used with long PCR amplicons (ca. 1.5 kbp). Despite the increased cost of the nick translation, we concluded that this labeling strategy will reduce the time needed to design new assays as well as avoid possible false negatives during field applications. Alternative labeling strategies are also discussed.
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http://dx.doi.org/10.1016/j.bios.2004.04.014DOI Listing
November 2004

The measurement and health impact of endotoxin contamination in organic dusts from multiple sources: focus on the cotton industry.

Inhal Toxicol 2004 Apr;16(4):217-29

Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom.

Endotoxin is derived from Gram-negative bacterial membranes, and its inflammatory effects following inhalation are well characterized. The significance of this fact becomes apparent when the wide-ranging environments containing high levels of this microbial product are considered. Endotoxin is present in numerous industrial environments, especially where organic fibers are processed. Microbial contamination of these fibers mainly occurs at the agricultural stage. Materials such as flax and hemp are affected in this way, but the most important product in this context is cotton, from which chronic dust inhalation causes the disease byssinosis. Despite the fact that endotoxin constitutes a significant threat to public health, there are currently no occupational exposure limits for this toxicant. This communication describes the toxicology of endotoxin, and its role in inhalation-induced disease, focusing on measurement of airborne endotoxin in the occupational and domestic environments using the Limulus amebocyte lysate (LAL) enzyme assay. Following the success of the LAL assay for measuring endotoxin in dusts, our laboratory has examined its application to aqueous washes from cotton fibers. Reproducibility of the results was high, and data are presented displaying levels of endotoxin contamination in fibers from different cotton producing countries. Hence, worldwide comparison of industrial endotoxin concentrations can be readily made using this test. It would be highly desirable if the performance of the LAL assay facilitated introduction of industrial endotoxin safety limits, and in spite of minor surmountable shortcomings, the test is accurate, reliable, and well field-tested, so its continued widespread use may achieve this goal.
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http://dx.doi.org/10.1080/08958370490277164DOI Listing
April 2004

Current trends in research into the waterborne parasite Giardia.

Crit Rev Microbiol 2002 ;28(2):123-47

School of Biosciences, Microbiology, Cardiff University, Wales, UK.

The waterborne flagellated parasite Giardia intestinalis continues to be the most frequent protozoan agent of intestinal disease world-wide, causing an estimated 2.8 x 10(8) cases per annum. Severe symptoms of diarrhea and sickness can be persistent and even life threatening in the immunocompromised, in infants, and in the aged, although self-limiting in the majority of patients. Despite a growing awareness and intensified research many uncertainties remain, especially with respect to the risk of potential zoonotic transmission. Water supplies can be monitored for cysts using automated cytofluorimetric immunoassays, but this does not measure infectivity. Filtration provides the best protection, because cysts are highly resistant to chlorine and ozone. Other incompletely elucidated aspects include mechanisms of pathogenicity, host reaction to infection, immunity and parasite control using vaccines or antigiardial compounds; the 5-nitroimidazole metronidazole is the most effective of these. Molecular typing of various isolates indicates that most animal parasites are not infective to humans, but those that are can be genotypically classified as assemblage A or B. The phylogeny of the organism remains uncertain, but there is a growing opinion that Giardia is not an ancient primitive eukaryote, but that it is derived from a more complex mitochondria-containing protozoon.
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http://dx.doi.org/10.1080/1040-840291046713DOI Listing
January 2003