Preparedness for Residency: Now More Than Ever

Transitions in medical education, particularly the transition to residency training, are increasingly identified as meriting additional thought and care for the appropriate development of the new physician. In this issue of JAMA Surgery, Engelhardt and colleagues aptly demonstrate that a resident’s sense of preparedness for this transition plays a crucial role in their mental health; the identified association between resident preparedness and meaningful on-call experiences as students likely applies to most specialties requiring in-house call

Transcriptome profiling reveals significant changes in the gastric muscularis externa with obesity that partially overlap those that occur with idiopathic gastroparesis

BACKGROUND: Gastric emptying is impaired in patients with gastroparesis whereas it is either unchanged or accelerated in obese individuals. The goal of the current study was to identify changes in gene expression in the stomach muscularis that may be contributing to altered gastric motility in idiopathic gastroparesis and obesity. METHODS: Quantitative real time RT-PCR and whole transcriptome sequencing were used to compare the transcriptomes of lean individuals, obese individuals and either lean or obese individuals with idiopathic gastroparesis. RESULTS: Obesity leads to an increase in mRNAs associated with muscle contractility whereas idiopathic gastroparesis leads to a decrease in mRNAs associated with PDGF BB signaling. Both obesity and idiopathic gastroparesis were also associated with similar alterations in pathways associated with inflammation. CONCLUSIONS: Our findings show that obesity and idiopathic gastroparesis result in overlapping but distinct changes in the gastric muscularis transcriptome. Increased expression of mRNAs encoding smooth muscle contractile proteins may be contributing to the increased gastric motility observed in obese subjects, whereas decreased PDGF BB signaling may be contributing to the impaired motility seen in subjects with idiopathic gastroparesis

Bullous dermatoses secondary to anti-PD-L1 agents: a case report and review of the literature

Immune checkpoint inhibitors are used to treat numerous malignancies but may be associated with severe adverse events. Bullous dermatoses, chiefly bullous pemphigoid (BP), are potentially progressive adverse events that cause blistering skin lesions and may involve a significant body surface area. Herein, we report an 87-year-old man with urothelial cell carcinoma undergoing atezolizumab treatment who presented with an acute-onset blistering eruption. Biopsy revealed a subepidermal bulla, direct immunofluorescence revealed linear IgG and C3 deposits at the dermal-epidermal junction, and serum studies revealed elevated levels of antibodies to BP180 and BP230. Anti-PD-L1-induced BP was diagnosed, immunotherapy was withheld, and he was treated with oral doxycycline with niacinamide and clobetasol ointment. He restarted atezolizumab and has successfully received four cycles (every 3 weeks) while continuing this BP treatment regimen. A literature review revealed eight other cases of anti-PD-L1-induced bullous disorders. The incidence of bullous dermatoses with anti-PD-1/anti-PD-L1 agents combined is 1%, whereas the reported incidence for anti-PD-L1 agents alone ranges from 1.3-5%, raising concerns for a higher overall risk. In addition to our case, only one other case reported successful resumption of immunotherapy. Early control and management of immunotherapy-induced BP may reduce complications and prevent treatment discontinuation

Management of Persistent Pruritus and Lichenoid Reaction Secondary to Nivolumab With Narrowband Ultraviolet B Phototherapy

Immune checkpoint inhibitors targeting the programmed cell death receptor 1 (PD-1) are increasingly used to treat several malignancies, with the most common adverse event being cutaneous toxicity. We report the case of a 68-years-old man with stage IV non-small cell lung cancer treated with nivolumab who developed a pruritic, lichenoid eruption refractory to treatment with topical or systemic steroids, who was started on narrow band ultraviolet B therapy which resolved the reaction

Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells

The promise of PARP-inhibitors(PARPis) in the management of epithelial ovarian cancer(EOC) is tempered by the fact that approximately 50% of patients with homologous recombination (HR)-proficient tumors do not respond well to these agents. Combination of PARPis with agents that inhibit HR may represent an effective strategy to enhance their activity in HR-proficient tumors. Using a bioinformatics approach, we identified that heat shock protein 90 inhibitors(HSP90i) may suppress HR and thus revert HR-proficient to HR-deficient tumors. Analysis of publicly available gene expression data showed that exposure of HR-proficient breast cancer cell lines to HSP90i 17-AAG(17-allylamino-17-demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia pathways. In HR-proficient EOC cells, 17-AAG suppressed HR as assessed using the RAD51 foci formation assay and this was further confirmed using the Direct Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 protein levels, and induced significantly more γH2AX activation in combination with olaparib compared to olaparib alone. Finally, sublethal concentrations of 17-AAG sensitized HR-proficient EOC lines to olaparib and carboplatin but did not affect sensitivity of the HR-deficient OVCAR8 line arguing that the 17-AAG mediated sensitization is dependent on suppression of HR. These results provide a preclinical rationale for using a combination of olaparib/17-AAG in HR-proficient EOC

Postoperative Dysphagia Following Esophagogastric Fundoplication: Does the Timing to First Dilation Matter?

Background Postoperative dysphagia after anti-reflux surgery typically resolves in a few weeks. However, even after the initial swelling has resolved at 6 weeks, dysphagia can persist in 30% of patients necessitating esophageal dilation. The purpose of this study was to investigate the effect of esophageal dilation on postoperative dysphagia, the recurrence of reflux symptoms, and the efficacy of pneumatic dilations on postoperative dysphagia. Methods A prospectively collected database was reviewed for patients who underwent partial/complete fundoplication with/without paraesophageal hernia repair between 2006 and 2014. Patient age, sex, BMI, DeMeester score, procedure type, procedure duration, length of stay, postoperative dysphagia, time to first pneumatic dilation, number of dilations, and the need for reoperations were collected. Results The study included 902 consecutive patients, 71.3% females, with a mean age of 57.8 ± 14.7 years. Postoperative dysphagia was noted in 26.3% of patients, of whom 89% had complete fundoplication (p < 0.01). Endoscopic dilation was performed in 93 patients (10.3%) with 59 (63.4%) demonstrating persistent dysphagia. Recurrent reflux symptoms occurred in 35 (37.6%) patients who underwent endoscopic dilation. Patients who underwent a dilation for symptoms of dysphagia were less likely to require a revisional surgery later than patients who had dysphagia but did not undergo a dilation before revisional surgery (17.2% vs 41.7%, respectively, p < 0.001) in the 4-year follow-up period. The duration of initial dilation from surgery was inversely related to the need for revisional surgery (p = 0.047), while more than one dilation was not associated with additive benefit. Conclusion One attempt at endoscopic dilation of the esophagogastric fundoplication may provide relief in patients with postoperative dysphagia and can be used as a predictive factor for the need of revision. However, there is an increased risk for recurrent reflux symptoms and revisional surgery may ultimately be indicated for control of symptoms

Comparison of Oral Iron Supplement Formulations for Normalization of Iron Status Following Roux-EN-y Gastric Bypass Surgery: a Randomized Trial

Background The evidence behind recommendations for treatment of iron deficiency (ID) following roux-en-y gastric bypass surgery (RYGB) lacks high quality studies. Setting Academic, United States Objective The objective of the study is to compare the effectiveness of oral iron supplementation using non-heme versus heme iron for treatment of iron deficiency in RYGB patients. Methods In a randomized, single-blind study, women post-RYGB and iron deficient received non-heme iron (FeSO4, 195 mg/day) or heme iron (heme-iron-polypeptide, HIP, 31.5 to 94.5 mg/day) for 8 weeks. Measures of iron status, including blood concentrations of ferritin, soluble transferrin receptor (sTfR), and hemoglobin, were assessed. Results At baseline, the mean ± standard deviation for age, BMI, and years since surgery of the sample was 41.5 ± 6.8 years, 34.4 ± 5.9 kg/m2, and 6.9 ± 3.1 years, respectively; and there were no differences between FeSO4 (N = 6) or HIP (N = 8) groups. Compliance was greater than 94%. The study was stopped early due to statistical and clinical differences between groups. Values before and after FeSO4 supplementation, expressed as least square means (95% CI) were hemoglobin, 10.8 (9.8, 11.9) to 13.0 (11.9, 14.0) g/dL; sTfR, 2111 (1556, 2864) to 1270 (934, 1737) μg/L; ferritin, 4.9 (3.4, 7.2) to 15.5 (10.6, 22.6) μg/L; and sTfR:ferritin ratio, 542 (273, 1086) to 103 (51, 204); all p 0.05). Conclusions In accordance with recommendations, oral supplementation using FeSO4, but not HIP, was efficacious for treatment of iron deficiency after RYGB

Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa

BACKGROUND: The molecular changes that occur in the stomach that are associated with idiopathic gastroparesis are poorly described. The aim of this study was to use quantitative analysis of mRNA expression to identify changes in mRNAs encoding proteins required for the normal motility functions of the stomach. METHODS: Full-thickness stomach biopsy samples were collected from non-diabetic control subjects who exhibited no symptoms of gastroparesis and from patients with idiopathic gastroparesis. mRNA was isolated from the muscularis externa and mRNA expression levels were determined by quantitative reverse transcriptase (RT)-PCR. KEY RESULTS: Smooth muscle tissue from idiopathic gastroparesis patients had decreased expression of mRNAs encoding several contractile proteins, such as MYH11 and MYLK1. Conversely, there was no significant change in mRNAs characteristic of interstitial cells of Cajal (ICCs) such as KIT or ANO1. There was also a significant decrease in mRNA-encoding platelet-derived growth factor receptor α (PDGFRα) and its ligand PDGFB and in Heme oxygenase 1 in idiopathic gastroparesis subjects. In contrast, there was a small increase in mRNA characteristic of neurons. Although there was not an overall change in KIT expression in gastroparesis patients, KIT expression showed a significant correlation with gastric emptying whereas changes in MYLK1, ANO1 and PDGFRα showed weak correlations to the fullness/satiety subscore of patient assessment of upper gastrointestinal disorder-symptom severity index scores. CONCLUSIONS AND INFERENCES: Our findings suggest that idiopathic gastroparesis is associated with altered smooth muscle cell contractile protein expression and loss of PDGFRα+ cells without a significant change in ICCs

A Generalizable Multimodal Scrub Training Curriculum in Surgical Sterile Technique

Introduction: Recent endeavors from governing bodies such as the AAMC have formally recognized the importance of aseptic technique. AAMC guidelines include activities that all graduating physicians should be able to perform with minimum indirect supervision and were developed to recognize these needs. For example, the skills necessary for aseptic technique include daily safety habits and general physician procedures. Methods: We developed a scrub training curriculum and evaluated the program through a quasi-experimental study with a pre- and posttest design. Questions were developed to examine students' perceived knowledge and skills as related to the objectives of the course and to their anxieties, concerns, and future training needs. Results: Between February 2020 and March 2020, 44 students completed the curriculum. Students indicated that self-efficacy significantly increased in all aspects of the curricular goals following curriculum completion. Students identified understanding OR etiquette as the most anxiety-provoking element associated with scrub training. They felt that more time could be spent elucidating this etiquette. On the other hand, tasks such as surgical hand hygiene were the least anxiety-inducing. Discussion: We share this multimodal scrub training curriculum, mapped to the AAMC's guidelines, to reduce variability in teaching strategies and skills acquisition through a standardized curriculum. Also, we effectively imparted these skills and instilled a sense of confidence in learners as they worked to provide their best in patient care and safety

Breed-Specific Hematological Phenotypes in the Dog: A Natural Resource for the Genetic Dissection of Hematological Parameters in a Mammalian Species

Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition