Keratinocytes and immune cells in the epidermis are key drivers of inflammation in hidradenitis suppurativa providing a rationale for novel topical therapies.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disease characterized by painful nodules, drainage and scarring in skin folds. Injectable adalimumab is the only drug approved by the US Food and Drug Administration for the treatment of HS. Although systemic Janus kinase (JAK) inhibitors show promise, serious side-effects have been reported. There are no highly effective topical treatments for HS; furthermore, the contribution of epidermal keratinocytes to the intense inflammation has largely been unexplored. OBJECTIVES: We investigated the role of keratinocytes and epidermal immune cells in HS inflammation at all Hurley stages of disease severity. We aimed to determine whether ruxolitinib can mitigate inflammation from keratinocytes and to develop a better understanding of how topical therapeutics might benefit patients with HS. METHODS: We used skin samples from 87 patients with HS (Hurley stages I-III) and 39 healthy controls to compare keratinocyte- and immune cell-driven epidermal inflammation, in addition to the response of lesional HS keratinocytes to treatment with interferon (IFN)-γ and ruxolitinib. We used haematoxylin and eosin staining, immunohistochemistry, immunoblotting and quantitative reverse-transcription polymerase chain reaction assessments in whole skin, isolated epidermis, and cultured keratinocytes from healthy controls and both nonlesional and lesional HS skin to identify and define epidermal and keratinocyte-mediated inflammation in HS and how this may be targeted by therapeutics. RESULTS: HS lesional keratinocytes autonomously secreted high levels of chemokines, such as CCL2, CCL3 and CXCL3, which recruited neutrophils, CD8 T cells, and natural killer cells to the epidermis. Keratinocytes were the dominant source of tumour necrosis factor-α and interleukin (IL)-6 in HS lesions with little to no contribution from underlying dermal immune cells. In the presence of IFN-γ, which is dependent on immune cell infiltrate in vivo, keratinocytes expressed increased levels of additional cytokines including IL-1ß, IL-12, IL-23 and IL-36γ. The JAK inhibitor ruxolitinib mitigated the expression of inflammatory cytokines and chemokines in HS lesional keratinocytes, thus providing a rationale for future study as a topical treatment for HS. CONCLUSIONS: This study demonstrates that keratinocytes actively recruit immune cells to HS epidermis and interactions between these cells drive a broad inflammatory profile in HS epidermis. Targeting epidermal inflammation in HS with novel topical formulations may be highly efficacious with reduced systemic side-effects.

Standardized Protocols for Clinical and Histopathological Characterization of Hidradenitis Suppurativa Tissue Specimens.

Methods for describing and reporting the clinical and histological characteristics of cutaneous tissue samples from patients with hidradenitis suppurativa (HS) are not currently standardized, limiting clinicians' and scientists' ability to uniformly record, report, and communicate about the characteristics of tissue used in translational experiments. A recently published consensus statement outlined morphological definitions of typical HS lesions, but no consensus has been reached regarding clinical characterization and examination of HS tissue samples. Here we aimed to establish a protocol for reporting histopathologic and clinical characteristics of HS tissue specimens. This study was conducted from May 2023 to August 2023. Experts in clinical care, dermatopathology, and translational research were recruited, and a modified Delphi technique was used to develop a protocol for histologic reporting and clinical characterization of submitted tissue specimens from HS patients. A total of 27 experts participated (14 dermatologists, 3 fellowship-trained dermatopathologists, 3 plastic surgeons, 3 general surgeons, and 4 research scientists) in creating and reviewing protocols for the clinical and histopathological examination of HS tissue specimens. The protocols were formatted as a synoptic report and will help consistently classify specimens in biobanks based on histological features and more accurately report and select samples used in translational research projects.

Spontaneous retroperitoneal hemorrhage in a dialysis patient.

BACKGROUND: Patients with end-stage renal disease (ESRD) often present to the Emergency Department with a multitude of complaints. Abnormal vital signs and a chief complaint of pain can produce a diagnosis ranging from a cardiac etiology to an infectious source. OBJECTIVES: Our goal is to discuss a case in which an ESRD dialysis patient presented with a rare, life-threatening emergency. CASE REPORT: A 55-year-old man with ESRD presented with acute abdominal pain and hypotension caused by a spontaneous retroperitoneal hemorrhage. CONCLUSION: This case report demonstrates the necessity of having broad differential diagnoses when evaluating patients with ESRD.

Core EPAs in the Acting Internship: Early Outcomes from an Interdepartmental Experience.

INTRODUCTION: The Core Entrustable Professional Activities for Entering Residency (Core EPAs) are clinical activities all interns should be able to perform on the first day of residency with indirect supervision. The acting (sub) internship (AI) rotation provides medical students the opportunity to be assessed on advanced Core EPAs. MATERIALS AND METHODS: All fourth-year AI students were taught Core EPA skills and performed these clinical skills under direct supervision. Formative feedback and direct observation data were provided via required workplace-based assessments (WBAs). Supervising physicians rated learner performance using the Ottawa Clinic Assessment Tool (OCAT). WBA and pre-post student self-assessment data were analyzed to assess student performance and gauge curriculum efficacy. RESULTS: In the 2017-2018 academic year, 167 students completed two AI rotations at our institution. By their last WBA, 91.2% of students achieved a target OCAT supervisory scale rating for both patient handoffs and calling consults. Paired sample t tests of the student pre-post surveys showed statistically significant improvement in self-efficacy on key clinical functions of the EPAs. DISCUSSION: This study demonstrates that the AI rotation can be structured to include a Core EPA curriculum that can assess student performance utilizing WBAs of directly observed clinical skills. CONCLUSIONS: Our clinical outcomes data demonstrates that the majority of fourth-year medical students are capable of performing advanced Core EPAs at a level acceptable for intern year by the conclusion of their AI rotations. WBA data collected can also aid in ad hoc and longitudinal summative Core EPA entrustment decisions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01208-y.

What Makes Wounds Chronic.

Chronic wounds present a unique therapeutic challenge to heal. Chronic wounds are colonized with bacteria and the presence of a biofilm that further inhibits the normal wound healing processes, and are locked into a very damaging proinflammatory response. The treatment of chronic wounds requires a coordinated approach, including debridement of devitalized tissue, minimizing bacteria and biofilm, control of inflammation, and the use of specialized dressings to address the specific aspects of the particular nonhealing ulcer.

Redefining the Acting Internship in the Era of Entrustment: One Institution's Approach to Reforming the Acting Internship.

Creating a Core Entrustable Professional Activities (Core EPA) curriculum requires a longitudinal approach. Current curricular efforts have focused primarily on the pre-clerkship and clerkship phases of training; however, the role of the Acting Internship (AI) has not been explored. The AI experience offers opportunities for students to have enhanced clinical responsibility, demonstrate proficiency, and allows for assessment of Core EPAs that are beyond the focus of clerkships. We share our experience developing an interdepartmental AI experience designed to assess designated Core EPAs and highlight tensions that should be considered when incorporating an AI experience into a longitudinal Core EPA-oriented curriculum.

Management of penetrating intraperitoneal colon injuries: A meta-analysis and practice management guideline from the Eastern Association for the Surgery of Trauma.

BACKGROUND: The management of penetrating colon injuries in civilians has evolved over the last four decades. The objectives of this meta-analysis are to evaluate the current treatment regimens available for penetrating colon injuries and assess the role of anastomosis in damage control surgery to develop a practice management guideline for surgeons. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines section of EAST conducted a systematic review using MEDLINE and EMBASE articles from 1980 through 2017. We developed three relevant problem, intervention, comparison, and outcome (PICO) questions regarding penetrating colon injuries. Outcomes of interest included mortality and infectious abdominal complications. RESULTS: Thirty-seven studies were identified for analysis, of which 16 met criteria for quantitative meta-analysis and included 705 patients considered low-risk in six prospective randomized studies. Seven hundred thirty-eight patients in 10 studies undergoing damage control laparotomy and repair or resection and anastomosis (R&A) were included in a separate meta-analysis. Meta-analysis of high-risk patients undergoing repair or R&A was not feasible due to inadequate data. CONCLUSIONS: In adult civilian patients sustaining penetrating colon injury without signs of shock, significant hemorrhage, severe contamination, or delay to surgical intervention we recommend that colon repair or R&A be performed rather than routine colostomy. In adult high-risk civilian trauma patients sustaining penetrating colon injury, we conditionally recommend that colon repair or R&A be performed rather than routine colostomy. In adult civilian trauma patients sustaining penetrating colon injury who had damage control laparotomy, we conditionally recommend that routine colostomy not be performed; instead, definitive repair or delayed R&A or anastomosis at initial operation should be performed rather than routine colostomy. LEVEL OF EVIDENCE: Systematic review/meta-analysis, level III.

Network proteomics of human dermal wound healing.

OBJECTIVE: The healing of wounds is critical in protecting the human body against environmental factors. The mechanisms involving protein expression during this complex physiological process have not been fully elucidated. APPROACH: Here, we use reverse-phase protein microarrays (RPPA) involving 94 phosphoproteins to study tissue samples from tubes implanted in healing dermal wounds in seven human subjects tracked over two weeks. We compare the proteomic profiles to proteomes of controls obtained from skin biopsies from the same subjects. MAIN RESULTS: Compared to previous proteomic studies of wound healing, our approach focuses on wound tissue instead of wound fluid, and has the sensitivity to go beyond measuring only highly abundant proteins. To study the temporal dynamics of networks involved in wound healing, we applied two network analysis methods that integrate the experimental results with prior knowledge about protein-protein physical and regulatory interactions, as well as higher-level biological processes and associated pathways. SIGNIFICANCE: We uncovered densely connected networks of proteins that are up- or down-regulated during human wound healing, as well as their relationships to microRNAs and to proteins outside of our set of targets that we measured with proteomic microarrays.

Practice Patterns for the Use of Antibiotic Agents in Damage Control Laparotomy and Its Impact on Outcomes.

BACKGROUND: The purpose of this study was to identify practice patterns associated with the use of antimicrobial agents with damage control laparotomy (DCL) and the relationship with post-operative intra-abdominal infection (IAI) rates. PATIENTS AND METHODS: The study was a retrospective review of trauma patients undergoing laparotomy at a Level 1 trauma center in 2010. Patients undergoing DCL versus those primarily closed (PCL) were compared for antimicrobial use (ABX) and its correlation with IAI rates (p < 0.05). Deaths with length of stay <5 days were excluded. RESULTS: A total of 121 patients were identified (28 DCL, 93 PCL). The DCL group was more severely injured (Injury Severity Score [ISS]: 31.4 ± 15 DCL vs. 18 ± 12.7 PCL, p < 0.001) with more small and large bowel injuries (SLBI), although not statistically significant (53.6% DCL vs. 35.5% PCL, p = 0.12). Practice patterns of ABX administration in terms of pre-operative (94.6% PCL vs. 69.2% DCL, p = 0.0012) and post-operative administration (PCL: 50.5% none, 21.5% one day, 28% long term >1 d; DCL: 21.4% none, 25.0% one day, 53.6% long term >1 day, p = 0.0130) were significant. Regression analyses demonstrated that neither ISS nor DCL was an independent predictor of infection, but pre-operative ABX was a negative predictor (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.05-0.91, p = 0.037), while post-operative ABX (OR 6.7, 95%CI 1.33-33.8, p = 0.044) and SLBI (OR 3.45, CI 1.03-11.5, p = 0.02) were positive predictors of infection with an receiver operating characteristic of 0.81. CONCLUSION: Significant variations exist in the use of ABX in DCL and PCL. These variations may lead to deleterious results from both lack of initial pre-operative coverage and prolonged ABX use. The decrease in infection rates with pre-operative ABX yet significant increase with continued post-operative use even in the presence of SLBI suggests the need for a more standardized approach. With the increase in DCL and the open abdomen, more research is needed to clearly establish ABX protocols in this patient population.

Vascular tumors of the abdominal wall.

BACKGROUND: Vascular tumors of the abdominal wall are rare, benign congenital malformations that may cause pain or cosmetic disfigurement and are of significance for their ability to mimic more clinically aggressive tumors. There have been no previous reports of vascular tumors of the abdominal wall. This investigation reports the clinical presentation, diagnosis, and treatment of three patients with vascular tumors of the abdominal wall. METHODS: Magnetic resonance angiography (MRA) was used to identify feeding and draining vessels and to aid in operative planning for two patients; in a third patient, standard magnetic resonance imaging revealed the feeding vessels. RESULTS: MRA accurately identified the feeding and draining vessels and aided in operative planning, thus facilitating complete tumor resection. To date, patients have not experienced tumor recurrence. CONCLUSIONS: These cases suggest that MRA can be employed as a noninvasive imaging technique and should be the standard preoperative modality to plan the operative approach to vascular tumors of the abdominal wall.

DVT surveillance program in the ICU: analysis of cost-effectiveness.

BACKGROUND: Venous Thrombo-embolism (VTE--Deep venous thrombosis (DVT) and/or pulmonary embolism (PE)--in traumatized patients causes significant morbidity and mortality. The current study evaluates the effectiveness of DVT surveillance in reducing PE, and performs a cost-effectiveness analysis. METHODS: All traumatized patients admitted to the adult ICU underwent twice weekly DVT surveillance by bilateral lower extremity venous Duplex examination (48-month surveillance period--SP). The rates of DVT and PE were recorded and compared to the rates observed in the 36-month pre-surveillance period (PSP). All patients in both periods received mechanical and pharmacologic prophylaxis unless contraindicated. Total costs--diagnostic, therapeutic and surveillance--for both periods were recorded and the incremental cost for each Quality Adjusted Life Year (QALY) gained was calculated. RESULTS: 4234 patients were eligible (PSP--1422 and SP--2812). Rate of DVT in SP (2.8%) was significantly higher than in PSP (1.3%) - p<0.05, and rate of PE in SP (0.7%) was significantly lower than that in PSP (1.5%) - p<0.05. Logistic regression demonstrated that surveillance was an independent predictor of increased DVT detection (OR: 2.53 - CI: 1.462-4.378) and decreased PE incidence (OR: 0.487 - CI: 0.262-0.904). The incremental cost was $509,091/life saved in the base case, translating to $29,102/QALY gained. A sensitivity analysis over four of the parameters used in the model indicated that the incremental cost ranged from $18,661 to $48,821/QALY gained. CONCLUSIONS: Surveillance of traumatized ICU patients increases DVT detection and reduces PE incidence. Costs in terms of QALY gained compares favorably with other interventions accepted by society.

Role of PTPα in the destruction of periodontal connective tissues.

IL-1ß contributes to connective tissue destruction in part by up-regulating stromelysin-1 (MMP-3), which in fibroblasts is a focal adhesion-dependent process. Protein tyrosine phosphatase-α (PTPα) is enriched in and regulates the formation of focal adhesions, but the role of PTPα in connective tissue destruction is not defined. We first examined destruction of periodontal connective tissues in adult PTPα(+/+) and PTPα(-/-) mice subjected to ligature-induced periodontitis, which increases the levels of multiple cytokines, including IL-1ß. Three weeks after ligation, maxillae were processed for morphometry, micro-computed tomography and histomorphometry. Compared with unligated controls, there was ∼1.5-3 times greater bone loss as well as 3-fold reduction of the thickness of the gingival lamina propria and 20-fold reduction of the amount of collagen fibers in WT than PTPα(-/-) mice. Immunohistochemical staining of periodontal tissue showed elevated expression of MMP-3 at ligated sites. Second, to examine mechanisms by which PTPα may regulate matrix degradation, human MMP arrays were used to screen conditioned media from human gingival fibroblasts treated with vehicle, IL-1ß or TNFα. Although MMP-3 was upregulated by both cytokines, only IL-1ß stimulated ERK activation in human gingival fibroblasts plated on fibronectin. TIRF microscopy and immunoblotting analyses of cells depleted of PTPα activity with the use of various mutated constructs or with siRNA or PTPα(KO) and matched wild type fibroblasts were plated on fibronectin to enable focal adhesion formation and stimulated with IL-1ß. These data showed that the catalytic and adaptor functions of PTPα were required for IL-1ß-induced focal adhesion formation, ERK activation and MMP-3 release. We conclude that inflammation-induced connective tissue degradation involving fibroblasts requires functionally active PTPα and in part is mediated by IL-1ß signaling through focal adhesions.

A 3D scanning confocal imaging method measures pit volume and captures the role of Rac in osteoclast function.

Modulation of Rho GTPases Rac1 and Rac2 impacts bone development, remodeling, and disease. In addition, GTPases are considered treatment targets for dysplastic and erosive bone diseases including Neurofibromatosis type 1. While it is important to understand the effects of Rac modulation on osteoclast function, two-dimensional resorption pit area measurements fall short in elucidating the volume aspect of bone resorption activity. Bone marrow from wild-type, Rac1 and Rac2 null mice was isolated from femora. Osteoclastogenesis was induced by adding M-CSF and RANKL in culture plates containing dentin slices and later stained with Picro Sirius Red to image resorption lacunae. Osteoclasts were also plated on glass cover slips and stained with phalloidin and DAPI to measure their surface area and the number of nuclei. Volumetric images were collected on a laser-scanning confocal system. Sirius Red confocal imaging provided an unambiguous, continuous definition of the pit boundary compared to reflected and transmitted light imaging. Rac1- and Rac2-deficient osteoclasts had fewer nuclei in comparison to wild-type counterparts. Rac1-deficient osteoclasts showed reduced resorption pit volume and surface area. Lacunae made by single Rac2 null osteoclasts had reduced volume but surprisingly surface area was unaffected. Surface area measures are deceiving since volume changed independently in resorption pits made by individual Rac2 null osteoclasts. Our innovative confocal imaging technique allows us to derive novel conclusions about Rac1 and Rac2 in osteoclast function. The data and method can be applied to study effects of genes and drugs including Rho GTPase modulators on osteoclast function and to develop pharmacotherapeutics to treat bone lytic disorders.

Prophylactic antibiotic use in penetrating abdominal trauma: an Eastern Association for the Surgery of Trauma practice management guideline.

BACKGROUND: The use of prophylactic antibiotics in penetrating abdominal trauma has resulted in decreased infection rates. The Eastern Association for the Surgery of Trauma (EAST) first published its practice management guidelines (PMGs) for the use of prophylactic antibiotics in penetrating abdominal trauma in 1998. During the next decade, several new prospective studies were published on this topic. In addition, the practice of damage control laparotomy became widely used, and additional questions arose as to the role of prophylactic antibiotics in this setting. Thus, the EAST Practice Management Guidelines Committee set out to update the original PMG. METHODS: A search of the National Library of Medicine and the National Institutes of Health MEDLINE databases was performed using PubMed (www.pubmed.gov) and specific key words. The search retrieved English language articles regarding the use of antibiotics in penetrating abdominal trauma published from 1973 to 2011. The topics investigated were the need for perioperative antibiotics, the duration of antibiotic therapy, the dose of antibiotics in patients presenting in hemorrhagic shock, and the appropriate duration of antibiotic therapy in the setting of damage control laparotomy. RESULTS: Forty-four articles were identified for inclusion in this review. CONCLUSION: There is evidence to support a Level I recommendation that prophylactic antibiotics should only be administered for 24 hours in the presence of a hollow viscus injury. In addition, there are no data to support continuing prophylactic antibiotics longer than 24 hours in damage control laparotomy.

Wound healing primer.

Surgeons often care for patients with conditions of abnormal wound healing, which include conditions of excessive wound healing, such as fibrosis, adhesions, and contractures, as well as conditions of inadequate wound healing, such as chronic nonhealing ulcers, recurrent hernias, and wound dehiscences. Despite many recent advances in the field, which have highlighted the importance of adjunct therapies in maximizing the healing potential, conditions of abnormal wound healing continue to cause significant cost, morbidity, and mortality. To understand how conditions of abnormal wound healing can be corrected, it is important to first understand the basic principles of wound healing.

Correlation of manual dexterity with USMLE scores and medical student class rank.

INTRODUCTION: Surgical programs often rely on objective measures of medical school cognitive performance, including United States Medical Licensing Exams (USMLE) scores and class rank, to predict success of an applicant in their training program. Although job applicants in non-medical fields often undergo dexterity testing prior to being hired, this has not been widely used in the selection process for surgical residency applicants. Thus, successful identification of applicants likely to succeed in surgical fields remains elusive. Given this difficulty, we wondered if performance on tests of manual dexterity would correlate with USMLE board scores and medical school class rank. METHODS: Fourth year medical students underwent a clinical study of dexterity testing using the Stromberg Dexterity Test (gross motor), the O'Conner Tweezer Test (fine motor), and the MIST-VR laparoscopic simulator (Mentice Corporation, Gothenberg, Sweden). Performance times were compared with USMLE Step I & II scores and class rank, as well as a self-assessment of manual dexterity. RESULTS: A total of 113 medical students participated. Gross motor dexterity was significantly correlated with class rank (P = 0.04) and USMLE Step I score (P = 0.04). Fine motor dexterity and MIST-VR performance did not correlate with class rank or USMLE scores. Self-assessment of good manual dexterity correlated with faster performance times on the MIST-VR laparoscopic simulator (0.0174). CONCLUSIONS: Gross motor skill is associated with objective measures of medical school cognitive performance, such as class rank and USMLE scores. Furthermore, self-assessment of dexterity may predict baseline laparoscopic abilities. Further research is necessary to determine whether such dexterity testing could be helpful in identifying applicants who possess the ability to develop into competent surgeons.

Differential use of Erk1/2 and transforming growth factor beta pathways by mid- and late-gestational murine fibroblasts.

BACKGROUND: Previously, we demonstrated the rapid closure of mid-gestational excisional murine wounds at 32 hours. In this study, we theorized that mid-gestational wounds would be completely regenerated, whereas late-gestational wounds would heal with scar formation at 48 hours. Furthermore, we theorized that mid- and late-gestational fibroblasts differentially use the transforming growth factor beta and mitogen-activated protein kinase pathways. METHODS: Three-millimeter excisional cutaneous wounds were made on murine mid- (embryonic day 15 [E15]) and late-gestational (E18) fetuses and harvested at 48 hours for histology. Percent wound closure was calculated. E15 and E18 fibroblasts were cultured overnight for in vitro scratch wound assay in the presence of the activin receptor-like kinase 4-5-7, Erk1/2, and p38 inhibitors. RESULTS: E15 wounds healed in a regenerative manner, whereas E18 wounds exhibited scar formation. In vitro scratch closure was similar in the E15 and E18 groups at 8 hours; yet, it increased in E15 compared with E18 groups with activin receptor-like kinase 4-5-7 and Erk1/2 inhibitors. p38 inhibition resulted in reduced scratch closure in both groups. CONCLUSION: The scarless mid-gestational excisional wounds compared with the scar-forming late-gestational wounds provides a model to study scar formation. This study also suggests that variable transforming growth factor beta and Erk1/2 signaling may influence differences in wound closure between mid- and late-gestational wounds.