A Randomized Crossover Trial Evaluating the Impact of Cultural Dexterity Training on Surgical Residents' Knowledge, Cross-Cultural Care, Skills, and Beliefs: The Provider Awareness and Cultural dexterity Training for Surgeons (PACTS) Trial.

OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. SUMMARY BACKGROUND DATA: Cross-cultural training of providers may reduce healthcare outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between Periods 1 and 2, while the Delayed group ("Delayed") received PACTS between Periods 2 and 3. Residents were assessed pre- and post-intervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. Chi-square and Fisher's exact tests were conducted to evaluate within- and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6% to 88.2%, P<0.0001), Self-Assessed Skills (74.5% to 85.0%, P<0.0001), and Beliefs (89.6% to 92.4%, P=0.0028) improved after PACTS; Knowledge scores (71.3% to 74.3%, P=0.0661) were unchanged. Delayed resident scores pre- to post-PACTS showed minimal improvements in all domains. When comparing the two groups at Period 2, Early residents had modest improvement in all 4 assessment areas, with statistically significant increase in Beliefs (92.4% vs 89.9%, P=0.0199). CONCLUSION: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.

National ABSITE Preparation Practices: A Survey of General Surgery Residency Program Directors.

OBJECTIVE: The American Board of Surgery In-Training Examination (ABSITE) was designed as a low-stakes, medical knowledge examination for US general surgery residency programs. However, in practice, this exam has been utilized for higher stakes purposes, such as resident promotion or remediation, and fellowship selection. Several studies have demonstrated the efficacy of ABSITE preparation resources, but best practices for ABSITE preparation and national preparatory habits are currently unknown. The aim of this work was to determine current residency programs' strategies for ABSITE preparation. DESIGN: We distributed an electronic survey to program directors or program coordinators of US general surgery programs asking them to anonymously report program ABSITE educational practices and ABSITE scores. We analyzed the proportion of responses using descriptive statistics and compared the effect of various strategies using the Mann-Whitney testing for nonparametric data. An average ABSITE percentile score was calculated for each residency based on program self-reported scores. SETTING: Association of Program Directors (APDS) Listserv PARTICIPANTS: General surgery residency programs participating at the time of distribution (278). RESULTS: Response rate was 24% (66/278); 41 programs (62.1%) identified as university-affiliated, and 25 (37.9%) were community-based. Median intern class size was 8 (range: 3-14), including preliminary interns. Average ABSITE percentile score was 52.8% (range 36.9%-67.6%). There were no significant differences in ABSITE scores based on affiliation or program size. Educational resources utilized for ABSITE preparation included SCORE (89.3%), Q-banks (50%), and surgical textbooks (25.8%). The majority (56.1%) of programs reported using a year-long curriculum for ABSITE preparation, and 66.6% used a time-limited curriculum completed in the months immediately prior to ABSITE. Most programs reported that ABSITE scores were a low priority (63.6%) or not a priority (13.6%). The existence of a year-long curriculum for ABSITE was positively correlated with score as compared to programs without a year-long curricula (53.9% vs 48.5%, p <0.01). Programs using a time-limited curriculum demonstrated lower scores as compared to programs without time-limited curricula (51.3% v 56.1%, p < 0.01). CONCLUSION: General surgery programs use a variety of strategies to prepare residents for the ABSITE. Despite reporting that they utilize ABSITE scores for a variety of high stakes purposes including evaluation for promotion and as a predictor of the preparedness for the ABS QE, many programs reported that they consider ABSITE scores as a low priority. A year-long focused curriculum was the only strategy correlated with increased scores, which may reflect the value of encouraging consistent studying and spaced repetition. Additional work is needed to guide programs in optimal utilization of ABSITE scores for remediation and resident evaluation, as well as understanding how ABSITE preparatory strategies correlate with clinical performance.

An Analysis of Diversity Statements and Support of Special Interest Societies by General Surgery Residency Programs.

OBJECTIVE: The purpose of this study was to characterize the nondiscrimination and diversity, equity, and inclusion (DEI) statements found on the websites of general surgery residency programs, as well as to measure programmatic commitment to diversity through their involvement with special interest surgical societies (SISS). DESIGN: The authors evaluated the relationship between DEI statements and SISS participation, and performed a natural language processing analysis of general surgery residency DEI statements. SETTING: The residency program websites from 319 non-military general surgery residency programs within the United States were analyzed. PARTICIPANTS: This study evaluated the DEI statement and SISS participation in general surgery residency programs. RESULTS: Of the 319 general surgery residency websites reviewed, 127 (39.8%) featured an identifiable statement of nondiscrimination or commitment to diversity. Compared to programs without diversity statements, programs with statements were more likely to be involved with special interest surgical societies (53.5% vs 30.7%, p < 0.001). Natural language processing analysis revealed that the diversity statements of programs with SISS involvement had higher word counts (p = 0.001), higher clout scores (measure of confidence conveyed, p = 0.001), and higher positive tone scores (p = 0.006) compared with the statements of those without special interest society involvement. CONCLUSIONS: In the era of virtual interviewing, applicants are forced to rely heavily on surgery residency websites as their main source of information. Less than 40% of programs participating in the Match in 2022 feature diversity statements on their websites. Programs with some degree of involvement with special interest societies were more likely to have statements that score higher in confidence and positivity in natural language processing analysis, which may potentially reflect a more earnest commitment to diversity, equity, and inclusion. Residency programs should continue to improve the visibility of their DEI efforts to recruit a diverse resident class.

Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102.

PURPOSE: To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. EXPERIMENTAL DESIGN: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. RESULTS: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. CONCLUSIONS: These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408.

Standardized oral examinations allow for assessment of medical student clinical knowledge and decrease racial grading differences in a surgery clerkship.

BACKGROUND: Oral examinations are not consistently included in third-year medical student clerkships. When included, they are often unstructured, leaving room for variations in difficulty or scoring. Previous research has demonstrated differences in clinical grade achievement, with underrepresented in medicine students receiving significantly lower grades than White students. METHODS: We designed a structured oral examination for third-year medical students on the surgery clerkship. Students completed 2 oral examination scenarios and were evaluated on their ability to complete a history and diagnostic workup, interpret laboratory and imaging results, and devise a treatment plan. Scores from our examination were compared to previous, unstructured oral examination scores and to student demographics. Students and faculty were surveyed regarding their experience. RESULTS: Third-year medical students demonstrated strong knowledge of multiple surgical diseases. The greatest number of errors occurred in treatment planning (P < .001). Third-year medical students receiving honors clerkship grades achieved higher percentages of correct items on their oral examination. (94.8% vs 90.4%) (P = .02). Evaluation of prior unstructured oral examinations found underrepresented in medicine students received lower scores than White students (P = .04). After implementation of our structured examination, no difference was seen between the scores of underrepresented in medicine and White students (P = .99). CONCLUSION: We implemented a standardized oral examination for third-year medical students on the surgery clerkship with student and faculty satisfaction and demonstrated the ability to determine domains of knowledge weakness. The application of our structured oral examination helped to address nonspecific grading practices and eliminate oral examination grade differences between underrepresented in medicine and White students.

Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer.

PURPOSE: FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). RESULTS: Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27-Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. CONCLUSIONS: Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.

Evaluating chief resident readiness for the teaching assistant role: The Teaching Evaluation assessment of the chief resident (TEACh-R) instrument.

BACKGROUND: The American Board of Surgery has mandated chief residents complete 25 cases in the teaching assistant (TA) role. We developed a structured instrument, the Teaching Evaluation and Assessment of the Chief Resident (TEACh-R), to determine readiness and provide feedback for residents in this role. METHODS: Senior (PGY3-5) residents were scored on technical and teaching performance by faculty observers using the TEACh-R instrument in the simulation lab. Residents were provided with their TEACh-R scores and surveyed on their experience. RESULTS: Scores in technical (p < 0.01) and teaching (p < 0.01) domains increased with PGY. Higher technical, but not teaching, scores correlated with attending-rated readiness for operative independence (p 0.02). Autonomy mismatch was inversely correlated with teaching competence (p < 0.01). Residents reported satisfaction with TEACh-R feedback and desire for use of this instrument in operating room settings. CONCLUSION: Our TEACh-R instrument is an effective way to assess technical and teaching performance in the TA role.

Maintaining Effective Senior Resident-Led Intern Education through Virtual Curricular Transition.

OBJECTIVE: The COVID-19 pandemic has resulted in a significant shift to virtual resident education. While novel methods for virtual resident training have been described, many of these demonstrate a substantial change from previous instructional methods and their efficacy cannot be directly compared to in-person teaching. We sought to determine if the conversion of our intern "summer school" from an in-person to online format (a) impacted the knowledge acquisition of interns, and (b) their preferences for senior resident-led didactics. DESIGN: A senior-resident led intern summer curriculum was started in an in-person format with the 2019-2020 academic year. Interns underwent assessments of their knowledge and surveys of changes in subject confidence. After the COVID-19 pandemic, the curriculum was shifted to an online format for the academic year 2020-2021. SETTING: Washington University in St. Louis, an academic medical center located in St. Louis, Missouri PARTICIPANTS: PGY1 general surgery residents during academic year 2019-2020 (n = 13) and 2020-2021 (n = 14). RESULTS: In both years, interns demonstrated significant increases in confidence pre- and post-summer school in all domains (p <0.01). This was no different between the in-person and the virtual administration of the bootcamp (p 0.76). In both virtual and in-person curricula, interns demonstrated increased knowledge as measured by multiple choice, boards-style question quizzes. There were no significant differences between virtual and in-person formats. In both formats, interns reported a preference for senior residents as teachers (81% v. 77%) and increased comfort in asking questions in senior resident-led vs. attending-led didactics (91% v 100%). CONCLUSION: Virtual senior-resident led intern educational sessions are equally as effective as in-person sessions for knowledge acquisition and improving confidence in intern-specific domains. In both virtual and in-person settings, interns prefer senior resident teachers to attendings. Virtual senior resident-led education is an effective and simple method for intern instruction, regardless of the format/approach.

Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma.

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.

SAVE 2.0: Identifying and strengthening resident leadership skills through simulation based team training.

BACKGROUND: The "Surgery for Abdomino-thoracic ViolencE (SAVE)" animate lab engages surgical residents in the management of penetrating injuries in a team setting. Senior residents, representing postgraduate year (PGY) 3-5, assume the role of team leader and facilitate the junior residents, PGY1-2, in operative management of simulated penetrating wounds. Residents completed five scenarios with increasing level of difficulty within set time limits. Senior residents were evaluated on their team's ability to "SAVE" their patient within the time allotted, as well as their communication and leadership skills. METHODS: General, vascular, urology, and plastic surgery residents (n = 79) were divided into 25 teams of three to four residents by "resident scores" (R scores, the sum of the team members' PGY) to create balanced teams with comparable years of clinical experience. Residents completed assessments of their senior resident's leadership ability and style. RESULTS: Evaluation of a resident's desired learning style changed across PGY with junior residents preferring more hands-on guidance compared with senior residents preferring only verbal correction. Resident leadership evaluations demonstrated that team leaders of varied resident years achieved the highest scores. Greater differences in the mismatch between autonomy provided to and desired by junior residents correlated to greater junior resident discomfort in expressing their opinion, confidence, and leadership ratings of senior residents. However, greater autonomy mismatch also correlated to more rapid time to task completion. CONCLUSION: Different from our expectations, clinical experience alone did not define team leader success. Leadership is a powerful influence on the outcome of team performance and may be a skill, which can transcend overall clinical experience. A match between desired and provided resident autonomy and team cohesion may demonstrate a stronger effect on team success in stressful operative situations, such as trauma resuscitation. Enhancement of leadership skills early in residency training may represent an important focus for trauma surgery education.

Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS) training for emergency medicine and general surgery residents.

BACKGROUND: Successful trauma resuscitation relies on multi-disciplinary collaboration. In most academic programs, general surgery (GS) and emergency medicine (EM) residents rarely train together before functioning as a team. METHODS: In our Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS), EM and GS residents completed manikin-based trauma scenarios and were evaluated on resuscitation and communication skills. Residents were surveyed on confidence surrounding training objectives. RESULTS: Residents showed improved confidence running trauma scenarios in multi-disciplinary teams. Residents received lower communication scores from same-discipline vs cross-discipline faculty. EM residents scored higher in evaluation and planning domains; GS residents scored higher in action processes; groups scored equally in team management. Strong correlation existed between team leader communication and resuscitative skill completion. CONCLUSION: MD-TEAMS demonstrated correlation between communication and resuscitation checklist item completion and communication differences by resident specialty. In the future, we plan to evaluate training-related resident behavior changes and specialty-specific communication differences by residents.

Screening for Pancreatic Ductal Adenocarcinoma: Are We Asking the Impossible?

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. Because of this, significant interest and research funding has been devoted to development of a screening test to identify individuals during a prolonged asymptomatic period; however, to date, no such test has been developed. We evaluated current NIH spending and clinical trials to determine the focus of research on pancreatic cancer screening as compared with other cancer subtypes. Using statistical methodology, we determined the effects of population-based pancreatic cancer screening on overall population morbidity and mortality. Population-based pancreatic cancer screening would result in significant harm to non-diseased individuals, even in cases where a near-perfect test was developed. Despite this mathematical improbability, NIH funding for pancreatic cancer demonstrates bias toward screening test development not seen in other cancer subtypes. Focusing research energy on development of pancreatic screening tests is unlikely to result in overall survival benefits. Efforts to increase the number of patients who are candidates for surgery and improving surgical outcomes would result in greater population benefit.Prevention Relevance: For patients with pancreatic cancer, early stage detection offers the greatest survival benefit. However, the incidence of pancreatic cancer and associated mortality of pancreatic resections make development of a screening test a difficult, if not impossible, challenge.

Pancreatic Adenocarcinoma in New Mexico Native Americans: Disparities in Treatment and Survival.

In this study, we examined the treatment and outcomes of pancreatic adenocarcinoma in New Mexico Native Americans (NA). METHODS: A retrospective review of patients treated for pancreatic adenocarcinoma at a university cancer center from 2002-2016 comparing demographic characteristics, disease presentation, treatment, and outcomes among three main ethnic groups in New Mexico. RESULTS: We identified 457 patients: 240 (52.5%) non-Hispanic Whites, 186 (40.7%) Hispanics, and 31 (6.8%) NA. Non-Hispanic Whites (OR 2.41; p=.026) and Hispanics (OR 2.37; p=.032) were more likely to receive or be offered chemotherapy than NA. More NA than non-Hispanic Whites died within one month of diagnosis (25.8% and 7.5%, respectively; p=.004). The NAs demonstrated a 26.2% one-year survival (CI 11.7-43.3), compared with 48.3% in non-Hispanic Whites (CI 40.9-55.2; p=.015). CONCLUSION: Significant disparities exist in the treatment and outcomes of pancreatic adenocarcinoma in New Mexico NA populations.

Viral hepatitis status does not affect survival in patients with hepatocellular carcinoma.

BACKGROUND: There have been few studies on the impact of viral etiology on the prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the clinical characteristics and survival of patients with viral hepatitis-associated HCC (V-HCC), compared to patients with HCC of non-hepatitis B, non-hepatitis C (NBNC-HCC) etiology. METHODS: We performed a retrospective analysis of all patients with HCC treated at our comprehensive cancer center from 2000 through 2014. Patients were divided into two groups according to their viral hepatitis status. Presentation patterns, treatments, and survival data were analyzed. RESULTS: We evaluated 366 patients: 233 patients (63.7%) had V-HCC while 133 (36.3%) patients had NBNC-HCC. V-HCC patients were younger (P<0.0001) and more likely to be male (P=0.001). Decompensated cirrhosis was more prevalent in V-HCC patients (P=0.01). There was no difference in the resectability rate or disease stage. In patients with resectable disease, those with V-HCC were less likely to undergo hepatectomy (23.7% vs. 38%; P=0.04) for more advanced liver disease. The estimated median survival for V-HCC was 13 months compared to 16 months in NBNC-HCC patients (P=0.57). On multivariate analysis, disease stage (P<0.0001) and Child-Pugh class (P<0.0001) were independent factors affecting survival, but viral status was not (P=0.75). CONCLUSION: Despite presenting with more advanced cirrhosis and being less likely to undergo surgery, V-HCC patients had similar survival to patients with NBNC-HCC.

Middle Cerebral Artery Stroke in a Neonate With a Congenital Hypercoagulable Condition Following Repair of an H-type Tracheoesophageal Fistula.

We report a case of middle cerebral artery stroke with heterozygosity for 2 separate hypercoagulable conditions following repair of an H-type tracheoesophageal fistula (TEF) in an infant. Neonatal stroke is rare, occurring in 1 in 4000 births annually in the United States. Stroke after pediatric surgery occurs in approximately 0.05% of patients. Etiologies of stroke in neonates include cardiac, hematologic, vascular, traumatic, metabolic, pharmacologic, infectious, and hypoxemic insults. Thrombophilia has been described in 42% to 78% of neonates with neonatal stroke. Stroke after repair of an H-type TEF has not been reported as a postoperative complication. Manipulation of the carotid artery during this operation is presumed to have contributed to a thromboembolic event in this infant with a hypercoagulable state. Whereas preoperative workup may not be indicated due to the low prevalence of neonatal stroke, workup for a congenital hypercoaguable condition may be considered in infants with stroke as a postoperative complication. This report provides a concise review of the etiology and treatment of stroke and hypercoagulable states in neonates as well as presents the case of a previously undescribed complication of repair of an H-type TEF.

Impact of Ethanol and Saccharin on Fecal Microbiome in Pregnant and Non-Pregnant Mice.

Research identifying connections between the gastrointestinal flora and human health has developed at a rapid pace. Several studies link the gut microbiome to a variety of biological functions beyond the gastrointestinal tract. Changes in our diets, including the consumption of artificial sweeteners, have profound effects on the composition of the gut microbiome and can, in turn, affect brain function, glucose tolerance, and inflammation. Sweeteners are often used to encourage consumption of agents such as ethanol and nicotine in laboratory studies using rodents. Studies aiming to examine the effects of agents like ethanol on the developing nervous system administer these agents during pregnancy. To date, there have been no studies exploring the impact of the combination of dietary ethanol and saccharin during pregnancy on the gut microbiome in either humans or laboratory animal models. In the study presented, we evaluated the impact of ethanol in either water or saccharin on the fecal microbiome in pregnant and non-pregnant mice using a qPCR approach. We found that the combination of ethanol and saccharin produced different effects than ethanol in water, depending on pregnancy status. Levels of Clostridium were reduced in ethanol-saccharin but not ethanol-water drinking mice, even though the total levels of ethanol consumed were the same for the two groups. Eubacteria were increased in the pregnant, but decreased in the non-pregnant, ethanol-saccharin drinking group. These treatment and pregnancy specific changes could impact the development of the offspring. In developing and quality checking our primer sets for these studies we identified several problems within previous research in the field. The technical drawbacks in previous studies, as well as our own study, are discussed. Despite some progress in the ability to study the gut microbiome, more advances and standardization of practices should be established to improve the reliability and validity of microbiome research.

Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD1 and 11ß-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11ß-HSD1, while 11ß-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11ß-HSD1 and 11ß-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11ß-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of arsenic results in altered fetal programming of the glucocorticoid system.

Common questions about Clostridium difficile infection.

Clostridium difficile infection is a common cause of antibiotic-associated diarrhea. It causes no symptoms in more than one-half of infected patients, but can also cause a wide spectrum of illnesses and death. The incidence and severity have increased in recent years. The most important modifiable risk factor for C. difficile infection is antibiotic exposure; this risk is dose-related and higher with longer courses and combination therapy. C. difficile infection is also associated with older age, recent hospitalization, multiple comorbidities, use of gastric acid blockers, inflammatory bowel disease, and immunosuppression. It has become more common in younger, healthier patients in community settings. The most practical testing options are rapid testing with nucleic acid amplification or enzyme immunoassays to detect toxin, or a two-step strategy. Treatment includes discontinuing the contributing antibiotic, if possible. Mild C. difficile infection should be treated with oral metronidazole; severe infection should be treated with oral vancomycin. Fidaxomicin may be an effective alternative. Recurrences of the infection should be treated based on severity. Tapering and the pulsed-dose method of oral vancomycin therapy for second recurrences are effective. Prevention includes responsible antibiotic prescribing and vigilant handwashing. Probiotics prevent antibiotic-associated diarrhea, but are not recommended specifically for preventing C. difficile infection.