Revised Diagnosis From Histiocytic Neoplasm to Optic Chiasm Glioblastoma After Genetic Analysis.

ABSTRACT: A 46-year-old man presented with left eye blurring. Automated visual field testing showed an incongruous right hemianopia, with sparing of the lower temporal quadrant in the right eye. MRI revealed foci of gadolinium enhancement in the optic chiasm and optic tracts. Serologic testing (including myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies) and cerebrospinal fluid analysis were negative. Whole-body PET/CT scan found no malignancy. Biopsy of the optic chiasm revealed a moderately cellular neoplasm composed of atypical, discohesive cells with enlarged nuclei, prominent eosinophilic nucleoli, and abundant vacuolated cytoplasm. Immunohistochemical stains for CD68 and S100 were positive, whereas those for GFAP, OLIG2, SOX10, and multiple others were negative, supporting a diagnosis of histiocytic neoplasm. Five weeks later, results became available from next-generation sequencing targeting the coding regions of hundreds of malignancy-associated genes and select introns. Alterations associated with histiocytic neoplasms (i.e. BRAF and MAP2K1 mutations) were absent. However, there was a nonsense mutation in the PTEN gene, a hotspot mutation in the TERT gene promotor, and focal amplifications of the CDK4 and MDM2 genes. Additionally, there was chromosome 6q loss, 7 gain, and 10q loss. Based on these findings, the diagnosis was revised to glioblastoma, IDH-wildtype, CNS WHO grade 4. The patient began treatment with temozolomide while continuing radiation therapy. This case illustrates how next-generation sequencing can at times provide more accurate diagnostic information than standard tissue histopathology.

Cartilage-Sparing Otoplasty: An Overview of the Mustardé and Furnas Suture Techniques.

Otoplasty is commonly used to treat prominauris. Cartilage-sparing techniques for otoplasty are well popularized. The most common cartilage-sparing otoplasty techniques include the Mustardé and Furnas techniques. This article discusses the preparation, surgical steps, postoperative care, and associated complications for Mustardé and Furnas otoplasty in detail.

Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

Video-based coaching for surgical residents: a systematic review and meta-analysis.

BACKGROUND: Video-based coaching (VBC) is used to supplement current teaching methods in surgical education and may be useful in competency-based frameworks. Whether VBC can effectively improve surgical skill in surgical residents has yet to be fully elucidated. The objective of this study is to compare surgical residents receiving and not receiving VBC in terms of technical surgical skill. METHODS: The following databases were searched from database inception to October 2021: Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed. Articles were included if they were randomized controlled trials (RCTs) comparing surgical residents receiving and not receiving VBC. The primary outcome, as defined prior to data collection, was change in objective measures of technical surgical skill following implementation of either VBC or control. A pairwise meta-analyses using inverse variance random effects was performed. Standardized mean differences (SMD) were used as the primary outcome measure to account for differences in objective surgical skill evaluation tools. RESULTS: From 2734 citations, 11 RCTs with 157 residents receiving VBC and 141 residents receiving standard surgical teaching without VBC were included. There was no significant difference in post-coaching scores on objective surgical skill evaluation tools between groups (SMD 0.53, 95% CI 0.00 to 1.01, p = 0.05, I2 = 74%). The improvement in scores pre- and post-intervention was significantly greater in residents receiving VBC compared to those not receiving VBC (SMD 1.62, 95% CI 0.62 to 2.63, p = 0.002, I2 = 85%). These results were unchanged with leave-one-out sensitivity analysis and subgroup analysis according to operative setting. CONCLUSION: VBC can improve objective surgical skills in surgical residents of various levels. The benefit may be most substantial for trainees with lower baseline levels of objective skill. Further studies are required to determine the impact of VBC on competency-based frameworks.

The educational value of thyroidectomy YouTube videos for surgical trainees.

OBJECTIVE: To evaluate the usefulness of thyroidectomy videos posted on YouTube for surgical training. METHODS: The following keywords were searched on YouTube: "thyroidectomy", "conventional thyroidectomy", "hemithyroidectomy", and "thyroid lobectomy". The first 30 videos from each search were selected for a total of 120 videos. Included videos were those displaying a conventional approach to thyroidectomy and real, non-animated patient surgery. Two independent reviewers assessed each video using the LAParoscopic surgery Video Educational Guidelines (LAP-VEGaS) and a thyroidectomy-specific grading score (TSS). RESULTS: The search yielded 22 videos that met the selection criteria. The inter-rater agreement was excellent for the grading systems (ICC = 0.910). The average LAP-VEGaS score was of medium quality (8.82 ± 3.56 standard deviation (SD)). The highest average score (11.00 ± 1.68 SD) was assigned to videos published from academic institutions. There was no statistically significant difference in LAP-VEGaS scores when comparing the type of publisher between videos (p = 0.132). The majority of the videos (12/22, 55 %) did not include all hallmarks of thyroidectomy according to the novel TSS score. There was a significant positive correlation between TSS markers and the overall LAP-VEGaS score (r = 0.577, p = 0.005). CONCLUSION: YouTube videos as an educational resource for thyroidectomy instructions vary in quality. Most of the thyroidectomy videos were medium quality according to the LAP-VEGaS score. YouTube sourced thyroidectomy videos should be used to supplement traditional educational methods.

Post-operative survival in head and neck cancer patients with elevated troponins.

OBJECTIVES: The strenuous demands of head and neck cancer surgery (HNS) place patients at increased risk of myocardial injury. Troponin positivity (TP) post-operatively is a predictor of increased complications and mortality. The present study is the first to investigate the effects of TP on potential delays in adjuvant treatment and disease-specific survival. DESIGN, SETTING, PARTICIPANTS AND MAIN OUTCOME MEASURES: All patients undergoing HNS from 2014 to 2016 had troponins measured at a single academic centre. Relevant patient data was extracted on retrospective chart review. The main outcome measures were the impact of TP on timing of adjuvant treatment and disease-specific survival. RESULTS: Of 166 patients, 26 (15.6%) developed TP post-operatively. There was no significant difference between cohorts for baseline characteristics except for age. Overall and disease-specific survival for TP patients were respectively 45.9% and 57.4% at 3 years. There was no significant difference between cohorts for overall and disease-specific survival, and time to adjuvant therapy. CONCLUSION: No significant association was found between TP and overall and disease-specific survival, and time to adjuvant therapy.

Fecal microbiome and bile acid metabolome in adult short bowel syndrome.

Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to 2 yr to determine which patients will wean from PN. Here, we examined features of gut microbiota and bile acid (BA) metabolism in determining adaptation and ability to wean from PN. Stool and sera were collected from healthy controls and from patients with SBS (n = 52) with ileostomy, jejunostomy, ileocolonic, and jejunocolonic anastomoses fed with PN plus enteral nutrition or who were exclusively enterally fed. We undertook 16S rRNA gene sequencing, BA profiling, and 7α-hydroxy-4-cholesten-3-one (C4) quantitation with LC-MS/MS and serum amino acid analyses. Patients with SBS exhibited altered gut microbiota with reduced gut microbial diversity compared with healthy controls. We observed differences in the microbiomes of patients with SBS with ileostomy versus jejunostomy, jejunocolonic versus ileocolonic anastomoses, and PN dependence compared with those who weaned from PN. Stool and serum BA composition and C4 concentrations were also altered in patients with SBS, reflecting adaptive changes in enterohepatic BA cycling. Stools from patients who were weaned from PN were enriched in secondary BAs including deoxycholic acid and lithocholic aicd. Shifts in gut microbiota and BA metabolites may generate a favorable luminal environment in select patients with SBS, promoting the ability to wean from PN. Proadaptive microbial species and select BA may provide novel targets for patient-specific therapies for SBS.NEW & NOTEWORTHY Loss of intestinal surface area causes short bowel syndrome, intestinal failure, and parenteral nutrition dependence. We analyzed the gut microbiota and bile acid metabolome of a large cohort of short bowel syndrome adult patients with different postsurgical anatomies. We report a novel analysis of the microbiome of patients with ileostomy and jejunostomy. Enrichment of specific microbial and bile acid species may be associated with the ability to wean from parenteral nutrition.

Nasal Septal Perforation Reconstruction with Polydioxanone Plate: A Systematic Review.

Nasal septal perforation is an uncommon pathology that is difficult to surgically repair and may significantly impact patients' quality of life. Existing treatments have high complication and failure rates. The use of polydioxanone (PDS) plates to repair septal perforations is an innovative approach that has demonstrated superior outcomes to the conventional techniques. This study aimed to review the literature on PDS plates for nasal septal perforation reconstruction. PubMed, OVID Medline, and OVID Embase databases were searched for relevant articles in June 2021. Search terms included nasal septal perforation, polydioxanone, septal perforation, septal repair, nasal septum, and PDS plate. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were adhered to for this systematic review. Database searches yielded 80 articles. Seven articles were included representing 74 patients. All studies reported the use of PDS plates in addition to other materials. They all reported closure rates of at least 80%. The majority of studies reported no postoperative complications. Nasal septal perforation reconstruction with PDS plates is a promising approach that has demonstrated positive outcomes. Further larger studies are required to evaluate the long-term efficacy of using PDS plates on patients with septal perforations.

Operating Room Noise and Team Communication during Facial Plastic and Reconstructive Surgery: A Multicenter Study.

Operating room (OR) noise contributes to team miscommunication. In facial plastic and reconstructive surgery (FPRS), many cases are completed under sedation. This creates a unique environment wherein patients are aware of OR noise. The objectives of this study were to quantify noise and evaluate team members' perspectives on communication inside of FPRS ORs. This study was completed across three surgical institutions. Objective noise measurements were recorded with SoundMeter X. A communication questionnaire was delivered to OR team members following each case. Four hundred and twenty-three noise measurements were recorded during facelift/neck, eye/brow, rhinoplasty, and fat transfer/lip surgeries. The mean and maximum noise levels were 66.1 dB (dB) and 87.6 dB, respectively. Measurements during cases with general anesthetic (221/423, 52.2%) had higher noise measurements (70.3 dB) compared with those with sedation (202/423, 47.8%) (69.7 dB) (p = 0.04). The OR was louder with suction on (72.3 dB) versus off (69.3 dB) (p <0.00). Suction (34.5%) and music (22.4%) were the largest noise contributors according to questionnaire replies. Intraoperative noise, awake patients, and suctions/music may negatively impact FPRS OR communication. Innovation to improve FPRS intraoperative communication should be considered for effective patient care.

Increased Adiposity and Reduced Lean Body Mass in Patients with Short Bowel Syndrome.

BACKGROUND: Few studies have examined the metabolic consequences of short bowel syndrome (SBS) and its effects on body composition in adults. We hypothesized that body composition of SBS patients is altered compared to a normal age-, race-, and sex-matched population, regardless of parenteral nutrition (PN) dependence. AIM: To compare the body composition of adult patients with SBS to age-, sex-, and race-matched healthy controls. METHODS: Twenty patients with SBS underwent body composition analysis using the GE Lunar iDXA scanner. Patients were age-, sex-, and race-matched to controls from the National Health and Nutrition Examination Survey (1999-2004). Mean differences in body mass index, fat-free mass, fat mass, percent body fat, visceral adipose tissue mass and volume, and bone mineral density were measured. Statistical analysis was performed using SAS 9.4 software. RESULTS: Fifty-five percent of subjects had a history of PN use, and 30% were current PN users. Mean percent body fat for SBS patients was 35.1% compared to 30.9% for healthy controls (p = 0.043). Fat-free mass was reduced in SBS (p = 0.007). Patients with reduced bone mass had a trend toward significantly more years of PN exposure compared to those with normal bone mass (p = 0.094), and a trend toward older age (p = 0.075). CONCLUSIONS: SBS is associated with increased percent body fat and reduced fat-free mass, suggesting that improved dietary and therapeutic interventions are needed to restore normal metabolic indices and avoid risk of metabolic syndrome in SBS patients.

Patient Satisfaction following Structural versus Preservation Rhinoplasty: A Systematic Review.

Recently, dorsal preservation rhinoplasty has been gained acceptance among facial plastic surgeons. Despite this, there is limited literature on patient satisfaction following preservation rhinoplasty. This systematic review aims to evaluate all studies quantifying patient satisfaction and to compare results between structural and dorsal preservation rhinoplasty. OVID Medline, EMBASE, and PubMed databases were searched. All studies from the years 2010 to 2020 evaluating satisfaction in patients receiving either structural or dorsal preservation rhinoplasty were included. Data regarding study demographics as well as patient satisfaction results were extracted from included studies. Descriptive results and analysis were calculated. A total of 2,172 articles were initially identified, of which 29 articles were included in the final analysis. Of the 29 articles, 25 were focused on structural rhinoplasty and 4 were focused on preservation rhinoplasty. Of the 25 structural rhinoplasty articles, 17 used the Rhinoplasty Outcome Evaluation (ROE) questionnaire to evaluate patient satisfaction and 5 used the FACE-Q scale. Among the 25 structural rhinoplasty studies, 14 (56%) reported statistically significant improvements in patient satisfaction evaluation scores after rhinoplasty. Among the four preservation rhinoplasty studies, one (25%) study reported significant improvements in satisfaction scores after rhinoplasty. Despite this, most studies included a statement that satisfaction improved in patients following rhinoplasty. Literature in this review supports both structural and preservation rhinoplasty, resulting in high satisfactory results for patients following surgery. More research must be conducted to further quantify satisfaction following preservation rhinoplasty and prospectively compare satisfaction between the two rhinoplasty techniques.

Comorbidities associated with eosinophilic chronic rhinosinusitis: A systematic review and meta-analysis.

OBJECTIVE: Eosinophilic chronic rhinosinusitis (ECRS) is a histological subtype of CRS that is generally recognised as being more difficult to manage. Patients with ECRS tend to have greater disease severity and poorer treatment outcomes after sinus surgery when compared with non-ECRS patients. The histopathology and biomarker assessments of ECRS are often unavailable prior to surgery and may be impractical and costly to analyse. Thus, the primary objective of this study was to understand clinical comorbidities associated with ECRS. DESIGN/SETTING: We searched three independent databases for articles that reported clinical CRS comorbidities associated with tissue eosinophilia. Data from studies with the same reported comorbidities were pooled, and a forest plot analysis was used to assess potential associations with four different conditions including allergic rhinitis, ASA sensitivity, asthma and atopy. The association between the phenotype of nasal polyps and ECRS was also quantified as a secondary objective. ECRS cut-off levels were as defined by papers included. MAIN OUTCOME/RESULTS: Eighteen articles were identified. The presence of nasal polyps (the first numbers in brackets represent odds ratios) (5.85, 95% CI [3.61, 9.49], P < .00001), ASA sensitivity (5.63, 95% CI [3.43, 9.23], P < .00001), allergic rhinitis (1.84, 95% CI [1.27, 2.67], P = .001) and asthma (3.15, 95% CI [2.61, 3.82], P < .00001) were found to be significantly associated with tissue eosinophilia. Atopy, however, was not significantly associated with tissue eosinophilia (1.71, 95% CI [0.59, 4.95], P = .32). CONCLUSION: Certain clinical disease characteristics such as ASA sensitivity, allergic rhinitis and asthma are more associated with CRS patients with eosinophilia when compared to those without eosinophilia. The phenotype of nasal polyps was also associated with ECRS. It is important for surgeons to recognise these comorbidities to ensure correct diagnoses, management and follow-up are implemented.

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

BACKGROUND: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.

Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4.

Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4-/-) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I-Ab-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4-/- mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4-/-, but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.

Perspectives of Facial Plastic Surgeons on Opioid Dependence in Rhinoplasty Patients.

Understanding the perspectives and opinions of facial plastic surgeons on opioid dependence is critical in a national epidemic of opioid overuse. Findings may encourage surgeon education so that facial plastic surgeons may be able to judiciously prescribe opioids, improving patient outcomes and reducing healthcare opioid-related spending. The objective of this study is to understand facial plastic surgeons' perspectives on opioid dependence in rhinoplasty patients. A key secondary objective was to quantify facial plastic surgeons' opioid prescribing patterns. This was a prospective survey study. A nine-question survey was sent to all members of the American Academy of Facial Plastic and Reconstructive Surgery in July of 2018, and analysis of the data was completed in August of 2018. The primary study outcome measurement was surgeon perspectives on opioid dependence. This was measured by an online survey. A total of 164 facial plastic surgeons responded to the survey (response rate: 6.6%). The majority were experienced surgeons in practice for more than 10 years (61.96%) who perform less than five rhinoplasties per week (84.15%). Of the facial plastic surgeons, 89.51% prescribe some variation of opioids following rhinoplasty. Most surgeons believe that opioid dependence is not a problem in rhinoplasty patients (86.96%), but that it is a problem among surgical patients in general (61.11%). The majority (52.45%) of surgeons prescribe between 11 and 25 tablets of opioids following rhinoplasty, with 25.17% of surgeons prescribing > 25 tablets of opioids. Facial plastic surgeons do not believe opioid dependence to be a problem among rhinoplasty patients. Resultantly, many facial plastic surgeons can prescribe more than 25 tables of opioids following rhinoplasty. The findings suggest that facial plastic surgeons may require further education and complete more research regarding opioid dependence among the rhinoplasty population. Additionally, the findings are important for health policy in that they encourage the creation of rhinoplasty specific opioid prescription guidelines.

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment.

Stem cell therapy is a potential therapeutic approach for disorders characterized by intestinal injury or loss of functional surface area. Stem cell function and proliferation are mediated by the stem cell niche. Stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are important but poorly studied components of the stem cell niche. To examine the role of ISEMFs, we have previously generated mice with deletion of epimorphin ( Epim), an ISEMF protein and member of the syntaxin family of intracellular vesicle docking proteins that regulate cell secretion. Herein we explore the mechanisms for previous observations that Epim deletion increases gut crypt cell proliferation, crypt fission, and small bowel length in vivo. Stem cell-derived crypt culture techniques were used to explore the interaction between enteroids and myofibroblasts from Epim-/- and WT mice. Enteroids cocultured with ISEMFS had increased growth and crypt-like budding compared with enteroids cultured without stromal support. Epim deletion in ISEMFs resulted in increased enteroid budding and surface area compared with cocultures with wild-type (WT) ISEMFs. In primary crypt cultures, Epim-/- enteroids had significantly increased surface area and budding compared with WTs. However, stem cell assays comparing the number of Epim-/- vs. WT colony-forming units after first passage showed no differences in the absence of ISEMF support. Epim-/- vs. WT ISEMFs had increased Wnt4 expression, and addition of Wnt4 to WT cocultures enhanced budding. We conclude that ISEMFs play an important role in the stem cell niche. Epim regulates stem cell proliferation and differentiation via stromal contributions to the niche microenvironment. NEW & NOTEWORTHY The role of subepithelial intestinal myofibroblasts (ISEMFs) in the gut stem cell niche is controversial. We provide novel evidence supporting ISEMFs as important niche contributors. We show that the in vivo intestinal effects of deletion of myofibroblast Epim can be recapitulated in crypt stem cell cultures in vitro. ISEMFs support cocultured stem cell proliferation and enteroid growth, and these effects are augmented by deletion of Epim, a syntaxin that regulates myofibroblast cell secretion.

Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

Dry eye disorders, including Sjögren's syndrome, constitute a common problem in the aging population, with limited effective therapeutic options available. The cAMP-activated Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) is a major prosecretory channel at the ocular surface. We investigated whether compounds that target CFTR can correct the abnormal tear film in dry eye. Small-molecule activators of human wild-type CFTR identified by high-throughput screening were evaluated in cell culture and in vivo assays, to select compounds that stimulate Cl(-)-driven fluid secretion across the ocular surface in mice. An aminophenyl-1,3,5-triazine, CFTRact-K089, fully activated CFTR in cell cultures with EC50 ∼250 nM and produced an ∼8.5 mV hyperpolarization in ocular surface potential difference. When delivered topically, CFTRact-K089 doubled basal tear volume for 4 h and had no effect in CF mice. CFTRact-K089 showed sustained tear film bioavailability without detectable systemic absorption. In a mouse model of aqueous-deficient dry eye produced by lacrimal ablation, topical administration of 0.1 nmol CFTRact-K089 3 times daily restored tear volume to basal levels, preventing corneal epithelial disruption when initiated at the time of surgery and reversing it when started after development of dry eye. Our results support the potential utility of CFTR-targeted activators as a novel prosecretory treatment for dry eye.-Flores, A. M., Casey, S. D., Felix, C. M., Phuan, P. W., Verkman, A. S., Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

Evidence-based recommendations for the management of acne fulminans and its variants.

BACKGROUND: Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence-based information and no clear guidelines concerning the classification and treatment of AF. OBJECTIVE: To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. METHODS: A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. RESULTS: Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. LIMITATIONS: Limited evidenced-based data and prospective studies in the literature concerning the treatment of AF is available. CONCLUSION: These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants.

Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival.

BACKGROUND: Colon cancer (CRC) is the third most common cancer worldwide. CRC develops through combinations of genetic and epigenetic changes. However, there is marked heterogeneity in the "driver gene" mutational profiles within and among colon cancers from individual patients, and these are not sufficient to explain differences in colon cancer behavior and treatment response. Global modulation of the tumor landscape may play a role in cancer behavior. Interferon-related developmental regulator 1 (IFRD1) is a transcriptional co-regulator that modulates expression of large gene cassettes and plays a role in gut epithelial proliferation following massive intestinal resection. AIMS: We address the hypothesis that increased IFRD1 expression in colon cancers is associated with poorer patient survival. METHODS: Tumor and normal tissue from colon cancer patient cohorts from the USA, Spain, and China were used for this study. Cancers were scored for the intensity of IFRD1 immunostaining. The primary clinical outcome was overall survival defined as time from diagnosis to death due to cancer. Kaplan-Meier method and log-rank analysis were used to assess the association between IFRD1 expression and survival. RESULTS: Almost all (98.7%) colon cancers showed readily detectable IFRD1 expression, with immunoreactivity primarily in the tumor cytoplasm. High IFRD1 colon cancer expression was significantly associated with decreased 5-year patient survival. Patients in the American cohort with high IFRD1 expression had a poorer prognosis. CONCLUSIONS: We have demonstrated that high IFRD1 protein expression in colon cancer is associated with poorer patient prognosis, suggesting a potential role for IFRD1 in modulating tumor behavior.