Outcomes of Implant Exchange and Latissimus Dorsi Flap Replacement After Breast Implant Complications.

BACKGROUND: Immediate action is required to address some complications of implant-based reconstruction after mastectomy to prevent reconstruction failure. Implant exchange may be simple but poses the risk of further complications while autologous flap reconstruction seems more complex but may pose less subsequent risk. Which of these is preferable remains unclear. METHODS: We reviewed thirty-two female breast cancer patients who had serious complications with their breast implants after post-mastectomy reconstruction. Latissimus dorsi flap (LDF) patients underwent explantation and immediate reconstruction with an LDF, while implant exchange (IE) patients underwent immediate implant removal and exchange with an expander followed by delayed reconstruction with silicon or immediately with a smaller size silicone implant. RESULTS: LDF patients underwent a single operation with an average duration of care of 31 days compared to an average 1.8 procedures (p= 0.005) with an average duration of care of 129.9 days (p < 0.001) among IE patients. Seven IE (50%) had serious complications that required subsequent revision while no LDF patients required additional procedures. Patient overall satisfaction and esthetics results were also superior in the LDF group at six months. CONCLUSION: In patients who want to reconstructively rescue and salvage their severely infected or exposed breast implant, the LDF offers an entirely autologous solution. LDF reconstruction in this setting allows patients to avoid an extended duration of care, reduces their risk of complications, and preserves the reconstructive process. LEVEL OF EVIDENCE III: The journal asks authors to assign a level of evidence to each article. For a complete description of Evidence-Based Medicine ratings, see the Table of Contents or the online Instructions for Authors at www.springer.com/00266 .

Vil-Cre specific Slfn3KO mice exhibit sex-specific differences in lung, stomach, cecum, kidney, and proximal colon differentiation markers and Slfn family members expression levels.

The Schlafen (Slfn) family proteins are critical regulators of cell proliferation, induction of immune responses, differentiation, self-restoration, and cell cycle progression. Rodent Slfn3 and human ortholog SLFN12 are critical in the regulation of intestinal epithelial differentiation. Following previous work utilizing Vil-Cre epithelial-specific Slfn3 knockout (VC-Slfn3KO) mice to evaluate Slfn3's role in small intestinal epithelial differentiation, we sought to characterize and distinguish the effects of Slfn3 loss on Slfn family member mRNA expression and differentiation markers for other epithelial cells in the lung, stomach, cecum, and proximal colon. Quantitative PCR analysis of Slfn1, 2, 4, 5, 8, and 9 and multiple differentiation markers were evaluated. We observed gender-specific effects with the loss of Slfn3 on the other Slfn family members and epithelial differentiation markers expression. Lung Slfn4 and 5 were increased only in male VC-Slfn3KO while lung Slfn2 and 8 were decreased only in female VC-Slfn3KO compared to controls. Slfn1, 2, 4, and 9 were increased in the gastric mucosa of male VC-Slfn3KO mice compared to controls. Slfn5 was reduced in female VC-Slfn3KO proximal colonic mucosa compared to controls. Lung AT1 cell differentiation marker Hopx mRNA expression was decreased and Ager was increased in VC-Slfn3KO male mice compared to controls. Lung AT2 differentiation markers and surfactant genes Sftpc and Sftpd were decreased in male VC-Slfn3KO mice. Stomach transcription factors, Lgr5 and Notch1 were increased in male VC-Slfn3KO. Tff1 secretory protein gene was decreased in female VC-Slfn3KO mice. Sucrase isomaltase was greatly increased in male VC-Slfn3KO mice in both cecal and proximal colonic mucosa, but glucose transporter Glut2 was decreased only in the cecum of female VC-Slfn3KO. The changes induced by VC-Slfn3KO in the expression of epithelial differentiation markers and other Schlafen proteins in various target tissues, indicate a complex regulation of gene expression that is sex-dependent.

Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival, yet no treatment is known to upregulate SLFN12 in TNBC. We hypothesized that Interferon-α (IFN-α2) upregulates SLFN12 in TNBC, subsequently reducing cell viability. We utilized short hairpin adenovirus to knockout SLFN12 (AdvShSLFN12) in MDA-MB-231, Hs-578T, and BT-549 TNBC cells. Cells were treated with AdvShSLFN12 and IFN-α2. After treatment, TNBC cell viability, SLFN family mRNA, and protein expression were analyzed. Treating TNBC cells with IFN-α2 increased SLFN12 expression and reduced cell viability. However, when AdvShSLFN12 knocked down SLFN12 during IFN-α2 treatment, TNBC cell viability was still reduced. We, therefore, investigated the potential involvement of other SLFN members IFN-α2 effects on cell viability. IFN-α2 increased SLFN5, SLFN12-Like, and SLFN14 but not SLFN11 or SLFN13. During AdvShSLFN12 + IFN-α2 treatment, the expressions of SLFN5, SLFN12-Like, and SLFN14 further increased. However, when siRNA knocked down SLFN5, SLFN12-Like, and SLFN14, the IFN-α2 reduction in viability was blunted. Although the interpretation of these results may be limited by the potential interactions between different siRNAs, these data suggest a complex regulatory signaling cascade among SLFN family members. Targeting this cascade to manipulate SLFN levels may, in the future, offer the potential to manipulate the chemosensitivity of TNBC tumors.

Effect of COVID-19 and its vaccines on surgical and postsurgical mortality, ICU admission and 90-day readmission for elective surgical procedures in a United States veteran population.

BACKGROUND: We investigated how COVID-19 infection and vaccination impact elective surgical outcomes. METHODS: We retrospectively compared pre-pandemic (P) veterans to those with COVID (C) more than three weeks preoperatively or no COVID (NC) history after carotid endarterectomy, CABG, hip replacement, or colectomy. Subgroup analysis considered vaccination. Age and sex propensity matching, and conditional logistic regression analyzed one-year-mortality, 90-day-readmission, and ICU requirements among 519 â€‹C, 1038 NC, and 2076 â€‹P, culled from 61,641 veterans. RESULTS: NC, C, and P had similar ICU requirements and mortality, although NC required fewer readmissions. However, NC immunized at least once were readmitted and died less commonly than C who received at least one immunization. CONCLUSIONS: SARS-CoV-2 history increased readmission without affecting ICU requirement or mortality. Further studies should evaluate whether the worse outcomes in postoperative patients with histories of both COVID infection and one vaccination reflect the effects of incomplete vaccination or dataset limitations.

A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing.

Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug directly stimulates mucosal wound healing. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, induces epithelial sheet migration. We synthesized and evaluated a water-soluble FAK-activating small molecule, M64HCl, with drug-like properties. Monolayer wound closure and Western blots measured migration and FAK phosphorylation in Caco-2 â€‹cells, in vitro kinase assays established FAK activation, and pharmacologic tests assessed drug-like properties. 30 â€‹mg/kg/day M64HCl was administered in two murine small intestine injury models for 4 days. M64HCl (0.1-1000 â€‹nM) dose-dependently increased Caco-2 FAK-Tyr 397 phosphorylation, without activating Pyk2 and accelerated Caco-2 monolayer wound closure. M64HCl dose-responsively activates the FAK kinase domain vs. the non-salt M64, increasing the Vmax of ATP-binding. Pharmacologic tests suggested M64HCl has drug-like properties and is enterally absorbed. M64HCl 25 â€‹mg/kg/day continuous infusion promoted healing of ischemic jejunal ulcers and indomethacin-induced small intestinal injury in C57Bl/6 mice. M64HCl-treated mice exhibited smaller ulcers 4 days after ischemic ulcer induction or indomethacin injury. Renal histology and plasma creatinine were normal. Mild hepatic inflammatory changes and ALT elevation were similar among M64HCl-treated mice and controls. M64HCl was concentrated in kidney and gastrointestinal mucosa and functional nephrectomy studies suggested predominantly urinary excretion. Little toxicity was observed in vitro or in single-dose mouse toxicity studies until >1000x higher than effective concentrations. M64HCl, a water-soluble FAK activator, promotes epithelial restitution and intestinal mucosal healing and may be useful to treat gut mucosal injury.

Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival.

The Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and performed RNA-seq on xenografts to investigate related SLFN12 pathways. Stable SLFN12 overexpression reduced tumorigenesis, increased tumor latency, and reduced tumor volume. RNA-seq showed that SLFN12 overexpressing xenografts had higher luminal markers levels, suggesting that TNBC cells switched from an undifferentiated basal phenotype to a more differentiated, less aggressive luminal phenotype. SLFN12-overexpressing xenografts increased less aggressive BC markers, HER2 receptors ERBB2 and EGFR expression, which are not detectable by immunostaining in TNBC. Two cancer progression pathways, the NAD signaling pathway and the superpathway of cholesterol biosynthesis, were downregulated with SLFN12 overexpression. RNA-seq identified gene signatures associated with SLFN12 overexpression. Higher gene signature levels indicated good survival when tested on four independent BC datasets. These signatures behaved differently in African Americans than in Caucasian Americans, indicating a possible biological difference between these races that could contribute to the worse survival observed in African Americans with BC. These results suggest an increased SLFN12 expression modulates TNBC aggressiveness through a gene signature that could offer new treatment targets.

Management of Malignant Pleural Effusions in U.S. Veterans: A Retrospective Review.

PURPOSE: To compare malignant pleural effusion (MPE) treatment outcomes and complications among patients receiving indwelling pleural catheter (IPC), talc pleurodesis (TPS), or dual therapy. Outcomes were determined by measuring length of stay (LOS) and post-procedure dyspnea scores. Complications were measured by comparing intervention failures and adverse events. METHODS: The Veterans Affairs' Corporate Data Warehouse was utilized to retrospectively review the charts of 314 MPE subjects. Dyspnea scores were estimated by researchers and LOS was determined by adding the duration of stay for all admissions post procedure. Complications were recorded through chart review. RESULTS: IPC exhibited higher failure rates than the other approaches 1 year post intervention. Pneumonia/chest infection rate and lung entrapment were also more prevalent. There was no significant difference in dyspnea rates. LOS illustrated a significant difference between groups, with talc patients spending a median of 7 days in the hospital immediately post procedure, while IPC and IPC + TPS patients spent a median of 3 and 2 days, respectively. CONCLUSION: Patients receiving IPC or combination treatment spend fewer days in the hospital than TPS patients. However, IPC appears to be associated with more adverse events and higher long-term failure rates than other management strategies.

RNA Sequencing of Intestinal Enterocytes Pre- and Post-Roux-en-Y Gastric Bypass Reveals Alteration in Gene Expression Related to Enterocyte Differentiation, Restitution, and Obesity with Regulation by Schlafen 12.

BACKGROUND: The intestinal lining renews itself in a programmed fashion that can be affected by adaptation to surgical procedures such as gastric bypass. METHODS: To assess adaptive mechanisms in the human intestine after Roux-en-Y gastric bypass (RYGB), we biopsied proximal jejunum at the anastomotic site during surgery to establish a baseline and endoscopically re-biopsied the same area 6-9 months after bypass for comparison. Laser microdissection was performed on pre- and post-RYGB biopsies to isolate enterocytes for RNA sequencing. RESULTS: RNA sequencing suggested significant decreases in gene expression associated with G2/M DNA damage checkpoint regulation of the cell cycle pathway, and significant increases in gene expression associated with the CDP-diacylglycerol biosynthesis pathway TCA cycle II pathway, and pyrimidine ribonucleotide salvage pathway after RYGB. Since Schlafen 12 (SLFN12) is reported to influence enterocytic differentiation, we stained mucosa for SLFN12 and observed increased SLFN12 immunoreactivity. We investigated SLFN12 overexpression in HIEC-6 and FHs 74 Int intestinal epithelial cells and observed similar increased expression of the following genes that were also increased after RYGB: HES2, CARD9, SLC19A2, FBXW7, STXBP4, SPARCL1, and UTS. CONCLUSIONS: Our data suggest that RYGB promotes SLFN12 protein expression, cellular mechanism and replication pathways, and genes associated with differentiation and restitution (HES2, CARD9, SLC19A2), as well as obesity-related genes (FBXW7, STXBP4, SPARCL1, UTS).

Lessons learned in evaluating system interdependencies using qualitative methods.

This article shares lessons learned while evaluating the system interdependencies for a clinical and translational research centre (CTR). It explores the methodological challenge of discussing system concepts (e.g., cascading failures, feedback loops, and reflex arcs) with layperson participants during evaluation interviews. The article discusses the iterative process of moving from structured interview approaches in favor of an open narrative approach for data collection and lessons learned.

ZINC40099027 promotes monolayer circular defect closure by a novel pathway involving cytosolic activation of focal adhesion kinase and downstream paxillin and ERK1/2.

ZINC40099027 (ZN27) is a specific focal adhesion kinase (FAK) activator that promotes murine mucosal wound closure after ischemic or NSAID-induced injury. Diverse motogenic pathways involve FAK, but the direct consequences of pure FAK activation have not been studied, and how ZN27-induced FAK activation stimulates wound closure remained unclear. We investigated signaling and focal adhesion (FA) turnover after FAK activation by ZN27 in Caco-2 cells, confirming key results in CCD841 cells. ZN27 increased Caco-2 FAK-Y-397, FAK-Y-576/7, paxillin-Y-118, and ERK 1/2 phosphorylation and decreased FAK-Y-925 phosphorylation, without altering FAK-Y-861, p38, Jnk, or Akt phosphorylation. ZN27 increased FAK-paxillin interaction while decreasing FAK-Grb2 association. ZN27 increased membrane-associated FAK-Y-397 and FAK-Y-576/7 phosphorylation and paxillin-Y-118 and ERK 1/2 phosphorylation but decreased FAK-Y-925 phosphorylation without altering Src or Grb2. Moreover, ZN27 increased the fluorescence intensity of GFP-FAK and pFAK-Y397 in FAs and increased the total number of FAs but reduced their size in GFP-FAK-transfected Caco-2 cells, consistent with increased FA turnover. In contrast, FAK-Y397F transfection prevented ZN27 effects on FAK size and number and FAK and pFAK fluorescent intensity in FAs. We confirmed the proposed FAK/paxillin/ERK pathway using PP2 and U0126 to block Src and MEK1/2 in Caco-2 and CCD841 cells. These results suggest that ZN27 promotes intestinal epithelial monolayer defect closure by stimulating autophosphorylation of FAK in the cytosol, distinct from classical models of FAK activation in the FA. Phosphorylated FAK translocates to the membrane, where its downstream substrates paxillin and ERK are phosphorylated, leading to FA turnover and human intestinal epithelial cell migration.

Evaluation Utility Metrics (EUMs) in Reflective Practice.

The article proposes three evaluation utility metrics to assist evaluators in evaluating the quality of their evaluation. After an overview of reflective practice in evaluation, the different ways in which evaluators can hold themselves accountable are discussed. It is argued that reflective practice requires evaluators to go beyond evaluation quality (i.e., technical quality and methodological rigor) when assessing evaluation practice to include an evaluation of evaluation utility (i.e., specific actions taken in response to evaluation recommendations). Three Evaluation Utility Metrics (EUMs) are proposed to evaluate utility: whether recommendations are considered (EUMc), adopted (EUMa), and (if adopted) level of influence of recommendations (EUMli). The authors then reflect on their experience in using the EUMs, noting the importance of managing expectations through negotiation to ensure EUM data is collected and the need to consider contextual nuances (e.g., adoption and influence of recommendations are influenced by multiple factors beyond the control of the evaluators). Recommendations for increasing EUM rates by paying attention to the frequency and timing of recommendations are also shared. Results of implementing these EUMs in a real-world evaluation provide evidence of their potential value: practice tips led to an EUMc = 100% and EUMa > 80%. Methods for considering and applying all three EUMs together to facilitate practice improvement are also discussed.

Integrated secure messaging to enhance medical education: a mixed methods study.

BACKGROUND: Instant messaging applications and texting are useful for educating and communicating with medical students; however, they present patient privacy concerns and do not address the challenge of student inclusion in patient care communication. EMR-integrated secure messaging offers an opportunity to include students on team communication, enhance their medical education, and ensure patient privacy. METHODS: Between July 2019 through March 2020, we performed a mixed method study to evaluate use of EPIC® Secure Chat as a means of enhancing student education and team communication. We promoted use of secure messaging in orientation, performed a pre- and post-rotation survey to assess perceptions of Secure Chat effect on communication, and directly reviewed and categorized messages. RESULTS: Twenty-four 3rd and 4th year students completed the pre-rotation survey, and 22 completed the post-rotation survey. Twelve (50%) students reported the quality of communication with faculty was either good or very good prior to internal medicine rotation, while 20 (91%) reported this post-rotation (p-value 0.001). There was a similar improvement in communication with ancillary staff. Nineteen (86%) students felt that secure messaging improved their communication with faculty. On message review, threads were frequently logistical, but also often included discussions of patient management. CONCLUSIONS: Students viewed Secure Chat as having a favorable effect on their communication with team members and reported communication on internal medicine to be improved compared to prior rotations. Messages included students on important patient care conversations. Secure messaging offers a novel medium to improve team communication, enhance student education, and maintain patient privacy.

Day-to-day blood pressure variability predicts poor outcomes following percutaneous coronary intervention: A retrospective study.

BACKGROUND: For patients with cardiovascular disease, blood pressure variability (BPV), distinct from hypertension, is an important determinant of adverse cardiac events. Whether pre-operative BPV adversely affects outcomes after percutaneous coronary intervention (PCI) is to this point unclear. AIM: To investigate the relationship between blood pressure variability and outcomes for patients post-PCI. METHODS: Patients undergoing PCI in a single state in 2017 were studied (n = 647). Systolic and diastolic BPV, defined as both the largest change and standard deviation for the 3-60 mo prior to PCI was calculated and patients with more than ten blood pressure measurements in that time were included for analysis (n = 471). Adverse outcomes were identified up to a year following the procedure, including major adverse cardiac events (MACE), myocardial infarction, cerebrovascular accident, death, and all-cause hospitalization. RESULTS: Visit-to-visit systolic BPV, as measured by both standard deviation and largest change, was higher in patients who had myocardial infarction, were readmitted, or died within one year following PCI. Systolic BPV, as measured by largest change or standard deviation, was higher in patients who had MACE, or readmissions (P < 0.05). Diastolic BPV, as measured by largest change, was higher in patients with MACE and readmissions (P < 0.05). CONCLUSION: As BPV is easily measured and captured in the electronic medical record, these findings describe a novel method of identifying at-risk patients who undergo PCI. Aggressive risk modification for patients with elevated BPV and known coronary artery disease is indicated.

Gut homeostasis, injury, and healing: New therapeutic targets.

The integrity of the gastrointestinal mucosa plays a crucial role in gut homeostasis, which depends upon the balance between mucosal injury by destructive factors and healing via protective factors. The persistence of noxious agents such as acid, pepsin, nonsteroidal anti-inflammatory drugs, or Helicobacter pylori breaks down the mucosal barrier and injury occurs. Depending upon the size and site of the wound, it is healed by complex and overlapping processes involving membrane resealing, cell spreading, purse-string contraction, restitution, differentiation, angiogenesis, and vasculogenesis, each modulated by extracellular regulators. Unfortunately, the gut does not always heal, leading to such pathology as peptic ulcers or inflammatory bowel disease. Currently available therapeutics such as proton pump inhibitors, histamine-2 receptor antagonists, sucralfate, 5-aminosalicylate, antibiotics, corticosteroids, and immunosuppressants all attempt to minimize or reduce injury to the gastrointestinal tract. More recent studies have focused on improving mucosal defense or directly promoting mucosal repair. Many investigations have sought to enhance mucosal defense by stimulating mucus secretion, mucosal blood flow, or tight junction function. Conversely, new attempts to directly promote mucosal repair target proteins that modulate cytoskeleton dynamics such as tubulin, talin, Ehm2, filamin-a, gelsolin, and flightless I or that proteins regulate focal adhesions dynamics such as focal adhesion kinase. This article summarizes the pathobiology of gastrointestinal mucosal healing and reviews potential new therapeutic targets.

SLFN12 Over-expression Sensitizes Triple Negative Breast Cancer Cells to Chemotherapy Drugs and Radiotherapy.

BACKGROUND/AIM: Schlafen 12 (SLFN12) expression correlates with survival in triple negative breast cancer (TNBC). SLFN12 slows TNBC proliferation and induces TNBC differentiation, but whether SLFN12 affects the tumoral response to chemotherapy or radiation is unknown. MATERIALS AND METHODS: We over-expressed SLFN12 in MDA-MB-231 cells using two different lentiviral vectors. We assessed viable cell numbers via crystal violet assay after treatment with carboplatin, paclitaxel, olaparib, zoledronic acid, camptothecin, or cesium irradiation. CHK1 and CHK2 phosphorylation was assessed by western blot and the effects of inhibiting CHK1/CHK2 by AZD7762 were examined. Key findings were confirmed in Hs578t and BT549 TNBC cells after adenoviral SLFN12 over-expression. RESULTS: SLFN12 over-expression increased TNBC sensitivity to radiation, carboplatin, paclitaxel, zoledronic acid, and camptothecin, but not to olaparib. SLFN12 over-expression decreased CHK1 and CHK2 phosphorylation after treatment with the DNA damaging agent camptothecin (CPT). The CHK1/CHK2 inhibitor diminished the significant cytotoxicity difference between over-expression and baseline SLFN12 levels in response to carboplatin. CONCLUSION: SLFN12 increases TNBC sensitivity to DNA-damaging agents at least in part by reducing CHK1/2 phosphorylation. This may contribute to improved survival in patients whose TNBC over-expresses SLFN12. Therefore, SLFN12 levels may be used to customize or predict radiotherapy and chemotherapy effects in TNBC.

Design and implementation of a core EPA-based acting internship curriculum.

PURPOSE: The Association of American Medical Colleges published Core Entrustable Professional Activities (Core EPAs), expected independent clinical skills for first-day interns. We sought to determine whether a required acting internship (AI) in the fourth-year curriculum could be used for summative assessment of students' mastery of Core EPAs to a predefined level that would readily generalize across disciplines and campuses. METHODS: The University of North Dakota School of Medicine and Health Sciences MD Program created a standardized, required Core EPA-based AI curriculum for multiple specialties at multiple geographic sites providing a final entrustability assessment for 10 EPAs in a single course. RESULTS: The course was successfully designed and launched for all students in a single class. During the AI, students functioned at the level of an acting intern, rated the courses as superior, and performed at satisfactory exit-level competence for 10 Core EPAs. CONCLUSIONS: A standardized, EPA-based AI curriculum can provide an opportunity for exit level EPA assessment in the medical curriculum. This model functions well within multiple specialties and at diverse community-based, volunteer faculty teaching sites.

Using the Homeland Security Exercise and Evaluation Program (HSEEP) Building Block Approach to Implement System Evaluation Theory (SET).

This article shares lessons learned in applying system evaluation theory (SET) to evaluate a Clinical and Translational Research Center (CTR) funded by the National Institutes of Health. After describing how CTR support cores are intended to work interdependently as a system, the case is made for SET as the best fit for evaluating this evaluand. The article then details how the evaluation was also challenged to facilitate a CTR culture shift, helping support cores to move from working autonomously to working together and understanding how the cores' individual operating processes impact each other. This was achieved by incorporating the Homeland Security Exercise and Evaluation Program (HSEEP) building block approach to implement SET. Each of the seven HSEEP building blocks is examined for alignment with each of SET's three steps and the ability to systematically support the goal of moving CTR cores toward working interdependently. The implications of using HSEEP to support SET implementation for future evaluations are discussed.

Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FUNDING: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411.

Vil-Cre specific Schlafen 3 knockout mice exhibit sex-specific differences in intestinal differentiation markers and Schlafen family members expression levels.

The intestinal epithelium requires self-renewal and differentiation in order to function and adapt to pathological diseases such as inflammatory bowel disease, short gut syndrome, and ulcers. The rodent Slfn3 protein and the human Slfn12 analog are known to regulate intestinal epithelial differentiation. Previous work utilizing a pan-Slfn3 knockout (KO) mouse model revealed sex-dependent gene expression disturbances in intestinal differentiation markers, metabolic pathways, Slfn family member mRNA expression, adaptive immune cell proliferation/functioning genes, and phenotypically less weight gain and sex-dependent changes in villus length and crypt depth. We have now created a Vil-Cre specific Slfn3KO (VC-Slfn3KO) mouse to further evaluate its role in intestinal differentiation. There were increases in Slfn1, Slfn2, Slfn4, and Slfn8 and decreases in Slfn5 and Slfn9 mRNA expression that were intestinal region and sex-specific. Differentiation markers, sucrase isomaltase (SI), villin 1, and dipeptidyl peptidase 4 and glucose transporters, glucose transporter 1 (Glut1), Glut2, and sodium glucose transporter 1 (SGLT1), were increased in expression in VC-Slfn3KO mice based on intestinal region and were also highly female sex-biased, except for SI in the ileum was also increased for male VC-Slfn3KO mice and SGLT1 was decreased for both sexes. Overall, the variations that we observed in these VC-Slfn3KO mice indicate a complex regulation of intestinal gene expression that is sex-dependent.

Schlafens: Emerging Proteins in Cancer Cell Biology.

Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.