Inhibition of integrin alpha v/beta 5 mitigates the protective effect induced by irisin in hemorrhage.

INTRODUCTION: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. Integrin αvß5 was recently identified as a receptor for irisin to elicit its physiologic function. It remains unknown whether integrin αvß5 is required for irisin's function in modulating the physiologic response to hemorrhage. The objective of this study is to examine if integrin αvß5 contributes to the effects of irisin during the hemorrhagic response. METHODS: Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Irisin (0.5  µg/kg) was administrated to assess its pharmacologic effects in hemorrhage. Cilengitide, a cyclic Arg-Gly-Asp peptide (cRGDyK) which is an inhibitor of integrin αvß5, or control RGDS (1 mg/kg) was administered with irisin. In another cohort of mice, the irisin-induced protective effect was examined after knocking down integrin ß5 with nanoparticle delivery of integrin ß5 sgRNA using CRSIPR/Cas-9 gene editing. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization, respectively. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium, skeletal muscles, and lung tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was carried out to assess apoptosis in tissues. RESULTS: Hemorrhage induced reduction of integrin αvß5 in skeletal muscles and repressed recovery of cardiac performance and hemodynamics. Irisin treatment led to significantly improved cardiac function, which was abrogated by treatment with Cilengitide or knockdown of integrin ß5. Furthermore, irisin resulted in a marked suppression of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), muscle edema, and inflammatory cells infiltration in myocardium and skeletal muscles, which was attenuated by Cilengitide or knockdown of integrin ß5. Irisin-induced reduction of apoptosis in the myocardium, skeletal muscles, and lung, which were attenuated by either the inhibition of integrin αvß5, or knockdown of integrin ß5. CONCLUSION: Integrin αvß5 plays an important role for irisin in modulating the protective effect during hemorrhage.

Why Are Family Doctors Still Not Addressing Oral Health?

Oral health dramatically affects overall health and vice versa. Oral health is a key health indicator for Healthy People 2030. Yet family physicians are not addressing this important health issue at the same level they address other essential health problems. Studies show that family medicine training and clinical activities are lacking in the area of oral health. The reasons are multi-factorial including insufficient reimbursement, lack of accreditation emphasis, and poor medical-dental communication. There is hope. Robust oral health curricula for family doctors exist and efforts are being made to create primary care oral health education champions. The tide is turning on accountable care organizations adding oral health services, access, and outcomes to their systems. Like behavioral health, oral health can be fully integrated into the care family physicians offer.

Blood Pressure Challenge Reduces Hematomas in Gender-Affirming Mastectomy: A Retrospective Chart Review of 92 Consecutive Patients.

BACKGROUND: Gender-affirming mastectomy is a common surgery for the treatment of gender incongruence and gender dysphoria and improves quality of life. Hematoma rates for gender-affirming double incision mastectomies are between 2.8% and 8.1%. This study aims to investigate the utility of a blood pressure challenge, whereby the patient's blood pressure is medically increased intraoperatively to reveal bleeding vessels that can be addressed with additional hemostasis before skin closure, to reduce postoperative hematoma. METHODS: A retrospective chart review of patients who underwent gender-affirming double incision mastectomies over a 6-year period by a single surgeon was conducted. Surgeries were separated into a blood pressure challenge experimental group and a non-blood pressure challenge control group. Demographics, surgical characteristics, and postoperative complications were compared between the 2 cohorts using Pearson χ2, Fisher exact, t tests, univariate logistic regression, and multivariable logistical regression. Significance was established at P < 0.05. RESULTS: A total of 92 patients (184 breasts) were included with 32 patients (64 breasts) in the control group and 60 (120 breasts) in the blood pressure challenge group. In the control group, there were 5 hematomas (7.81%) compared with 1 (0.83%) in the blood pressure challenge group (P = 0.02). On univariate logistical regression analysis, blood pressure challenge was the only variable significantly associated with hematoma (odds ratio, 0.1; 95% confidence interval, 0.01-0.63; P = 0.04). On multivariable logistical regression, after controlling for age, body mass index, smoking status, and mass of excised breast tissue, patients who underwent blood pressure challenge demonstrated lower hematoma rates (odds ratio, 0.08; 95% CI, 0.004-0.59; P = 0.04). CONCLUSIONS: Using an intraoperative blood pressure challenge was associated with reduced hematoma rates. Guidelines for blood pressure challenge goals should be established to standardize care and reduce complications in gender-affirming mastectomies.

Introduction to the special section on prevention science: From generic rules to differential adaptations.

Prevention science as an interdisciplinary specialty is addressed in this introduction to the special section of the journal. The six papers that comprise the special section are briefly summarised, especially noting the global regions that are represented, that is, Europe, Middle East, New Zealand and South America. Attention to the importance of differential adaptations of prevention interventions developed in one region, country or locale but implemented in another is emphasised. The Guest Editors reflect on the importance of developing cross-national collaborations to further the advance of prevention science globally.

Case Series Regarding Parastomal Variceal Bleeding: Presentation and Management.

Parastomal variceal bleeding (PVB) is a serious complication occurring in up to 27% of patients with an ostomy and concurrent cirrhosis and portal hypertension. The management of PVB is difficult and there are no clear guidelines on this matter. Transjugular intrahepatic portosystemic shunt (TIPS), sclerotherapy, and /or coil embolization are all therapies that have been shown to successfully manage PVB. We present a case series with five different patients who had a PVB at our institution. The aim of this case series is to report our experience on the management of this infrequently reported but serious condition. We also conducted a systemic literature review focusing on the treatment modalities of 163 patients with parastomal variceal bleeds. In our series, patient 1 had embolization and sclerotherapy without control of bleed and expired on the day of intervention due to hemorrhagic shock. Patient 2 had TIPS in conjunction with embolization and sclerotherapy and had no instance of rebleed 441 days after therapy. Patient 3 did not undergo any intervention due to high risk for morbidity and mortality, the bleed self-resolved and there was no further rebleed, this same patient died of sepsis 73 days later. Patient 4 had embolization and sclerotherapy and had no instance of rebleed 290 days after therapy. Patient 5 had TIPS procedure and was discharged five days post procedure without rebleed, patient has since been lost to follow-up.

Challenges in the Management of and Biologic Use in Incarcerated Patients With Inflammatory Bowel Disease.

Background: Therapy and management of inflammatory bowel disease (IBD) require commitment from both the provider and patient to ensure optimal disease management. Prior studies show vulnerable patient populations with chronic medical conditions and compromised access to health care, such as incarcerated patients, suffer as a result. After an extensive literature review, there are no studies outlining the unique challenges associated with managing prisoners with IBD. Methods: A detailed retrospective chart review of 3 incarcerated patients cared for at a tertiary referral center with an integrated patient-centered IBD medical home (PCMH) and a review of literature was performed. Results: All 3 patients were African American males in their 30s with severe disease phenotypes requiring biologic therapy. All patients had challenges with medication adherence and missed appointments related to inconsistent access to clinic. Two of the 3 cases depicted better patient-reported outcomes through frequent engagement with the PCMH. Conclusions: It is evident there are care gaps and opportunities to optimize care delivery for this vulnerable population. It is important to further study optimal care delivery techniques such as medication selection, though interstate variation in correctional services poses challenges. Efforts can be made to focus on regular and reliable access to medical care, especially for those who are chronically ill.

Establishing Human Observer Criterion in Evaluating Artificial Social Intelligence Agents in a Search and Rescue Task.

Artificial social intelligence (ASI) agents have great potential to aid the success of individuals, human-human teams, and human-artificial intelligence teams. To develop helpful ASI agents, we created an urban search and rescue task environment in Minecraft to evaluate ASI agents' ability to infer participants' knowledge training conditions and predict participants' next victim type to be rescued. We evaluated ASI agents' capabilities in three ways: (a) comparison to ground truth-the actual knowledge training condition and participant actions; (b) comparison among different ASI agents; and (c) comparison to a human observer criterion, whose accuracy served as a reference point. The human observers and the ASI agents used video data and timestamped event messages from the testbed, respectively, to make inferences about the same participants and topic (knowledge training condition) and the same instances of participant actions (rescue of victims). Overall, ASI agents performed better than human observers in inferring knowledge training conditions and predicting actions. Refining the human criterion can guide the design and evaluation of ASI agents for complex task environments and team composition.

Biopsy Confirmed Doxycycline Induced Gastric Mucosal Injury.

Doxycycline (DOX) is a tetracycline antibiotic that is prescribed for treating a variety of infections involving the skin, respiratory tract, and urogenital system. Adversely, esophageal mucosal injury due to DOX is well described; however, gastric mucosal injury is less commonly reported and may result in severe gastrointestinal hemorrhage and occasionally, perforation. In most reported cases of DOX-induced gastric lesions, patients are symptomatic upon presentation leading to endoscopic evaluation and diagnosis with biopsy. However, severe gastric insults may go unrecognized in rare cases of asymptomatic patients, increasing the risk of mortality.

Clostridioides difficile Induced Rhabdomyolysis Associated With Decompensated Cirrhosis.

Rhabdomyolysis (RBD) occurs secondary to tissue injury, resulting in (muscle) cell lysis and release of intracellular electrolytes and proteins into circulation. An elevation in the muscle enzyme, creatine kinase (CK), is a diagnostic marker and indicates muscle breakdown. Symptoms include dark urine caused by release of myoglobin, myalgias, and acute kidney injury (AKI). RBD is categorized as (1) traumatic, (2) nontraumatic exertional (ie, metabolic myopathies), or (3) non-exertional and non-traumatic. Clostridioides difficile (CD) has been previously reported to cause RBD, but the risk factors, pathogenesis, and recommended treatment regimen remain unclear.

Irisin reduces inflammatory signaling pathways in inflammation-mediated metabolic syndrome.

Irisin is an exercise induced myokine first shown to induce the browning of white adipose tissue (WAT) which increases energy expenditure, improves glucose tolerance, and reduces insulin resistance. Among irisin's involvement in lipid homeostasis, osteoblast proliferation, and muscle growth, it also acts as a mediator of many inflammatory pathways throughout the body. This review aims to describe the role of irisin in inflammatory processes and understand how targeting irisin can alter the inflammatory response in metabolic syndrome (MetS). The mechanisms involved in irisin's anti-inflammatory functions include reducing production of pro-inflammatory cytokines while increasing production of anti-inflammatory cytokines, reducing macrophage proliferation, inducing alternatively activated (M2-type) macrophage polarization, inhibiting pathways of increased vascular permeability, and preventing the formation of inflammasomes. While there are some contradictory results, most studies found reduced levels of irisin in MetS and type II diabetes mellitus (T2DM). Irisin treatment of cells exposed to inflammatory stimuli ameliorates the inflammatory response and promotes cellular viability. Numerous methods have been studied to increase plasma irisin levels including dietary, behavioral, and pharmaceutical. Further investigation is necessary to understand how irisin can be targeted for disease modification.

Impact of medical school responses during the COVID-19 pandemic on student satisfaction: a nationwide survey of US medical students.

PURPOSE: Medical schools have faced various challenges in preparing their clinical students for the frontlines of a pandemic. This study investigated medical students' satisfaction with their institutions during the coronavirus disease 2019 (COVID-19) pandemic with the intention of guiding educators in future public health crises. METHODS: In this cross-sectional study surveying students in clinical rotations, the primary outcome was overall satisfaction regarding medical schools' responses to the pandemic, and the four secondary outcomes were school communication, exposure to COVID-19, availability of personal protective equipment, and access to COVID-19 testing. RESULTS: The survey was distributed to ten medical schools, of which 430 students responded for a response rate of 13.0%. While most students were satisfied (61.9%, n=266) with their schools' response, more than one in five (21.9%, n=94) were dissatisfied. Among the four secondary outcomes, communication with students was most predictive of overall satisfaction. CONCLUSION: In future crises, schools can best improve student satisfaction by prioritizing timely communication.

Highly-automated, high-throughput replication of yeast-based logic circuit design assessments.

We describe an experimental campaign that replicated the performance assessment of logic gates engineered into cells of Saccharomyces cerevisiae by Gander et al. Our experimental campaign used a novel high-throughput experimentation framework developed under Defense Advanced Research Projects Agency's Synergistic Discovery and Design program: a remote robotic lab at Strateos executed a parameterized experimental protocol. Using this protocol and robotic execution, we generated two orders of magnitude more flow cytometry data than the original experiments. We discuss our results, which largely, but not completely, agree with the original report and make some remarks about lessons learned. Graphical Abstract.

Politics of Prevention: Reflections From the COVID-19 Pandemic.

The COVID-19 pandemic from a prevention science perspective, including research topics, is discussed. Political considerations that influence prevention activities, with examples from the pandemic and from more typical prevention initiatives in schools and communities, are presented. The definitions of prevention science and prevention interventions are delineated, and a brief summary of prevention history is given. The relationship between health disparities and COVID-19 is discussed. Two theoretical perspectives that may help to inform effectiveness of COVID-19 prevention measures, health belief model and theory of reasoned action and planned behavior, are summarized. This article emphasizes the importance of adapting prevention applications to the intended recipients, especially ethnic and cultural groups. The need to strengthen prevention training in graduate education and strategies to reform the education to meet accreditation and licensing standards are suggested.

Hepatocellular Carcinoma in a Patient With Hepatic Steatosis.

Hepatocellular carcinoma (HCC) has historically developed in the setting of known risk factors-chronic liver disease from viral hepatitis and cirrhosis. In the absence of a risk factor, the development of HCC was rare. However, the increasing prevalence of nonalcoholic liver disease and nonalcoholic steatohepatitis, the paradigm is shifting. Currently, no HCC screening guidelines exist for these patients. We report a 30-year-old man with a medical history of treated nonseminomatous germ cell testicular cancer who presented with asymptomatic transaminitis. Subsequent workup was notable for a 1.6-cm liver lesion. The patient underwent a left lobe wedge resection with pathology demonstrating a well-differentiated HCC in a background of hepatic steatosis.

Gastrointestinal Stromal Tumor: GIST Another Duodenal Ulcer.

Background: Gastrointestinal stromal tumors (GISTs), although exceedingly rare, are the most common mesenchymal tumors in the gastrointestinal (GI) tract. GISTs are often asymptomatic; approximately 10% are found incidentally on imaging or endoscopy for other indications, although GI bleeding, intestinal obstruction, and perforation can occur. We present a case of upper GI bleeding from a duodenal GIST. Proton-pump inhibitor (PPI) therapy resulted in complete endoscopic ulcer healing, yet a discrete mass lesion was identified on endoscopic ultrasound (EUS). Case Report: A 70-year-old female presented with upper GI bleeding, and a duodenal ulcer was identified with esophagogastroduodenoscopy (EGD). Computed tomography (CT) scan of the abdomen and pelvis showed duodenal bulb thickening without clear mass. The ulcer was treated with 1:10,000 concentration epinephrine, injected in 4 quadrants around the ulcer base. The patient's GI bleeding resolved, and she was discharged with a referral for outpatient EUS follow-up. One month later, EUS showed resolution of the ulcer after PPI therapy but also showed a lesion consistent with GIST that was confirmed by cytologic analysis. The patient was started on imatinib therapy and had no further bleeding. Conclusion: Initial EGD and CT findings could have easily been attributed to duodenal peptic ulcer disease for which follow-up endoscopy is not routinely recommended given the low risk of malignancy. However, because of the high index of suspicion on the part of the referring physicians, duodenal GIST was diagnosed. This case extends the spectrum of the presentation, evaluation, and diagnosis of GISTs and stresses the importance of keeping this rare disease on the provider's differential, even after routine workup shows no findings of tumor.

Correlation of Immunological Markers with Disease and Clinical Outcome Measures in Patients with Autoimmune Retinopathy.

Purpose: To determine if immunological markers (1) are significantly different between autoimmune retinopathy (AIR) patients and controls and (2) correlate with disease progression in AIR patients. Methods: We enrolled patients with a possible AIR diagnosis, as well as control participants without eye disease, autoimmunity, or cancer. Immunological markers were tested in all participants. In addition, AIR patients had up to three blood draws for testing over their disease course. For AIR patients, clinical measures, including visual acuity (VA) and Goldmann visual field (GVF) area, were recorded at each draw. We used the Mann-Whitney U test to compare the immunological markers between AIR patients and controls. We used multilevel mixed-effect regression to investigate the correlation between markers and clinical parameters over time in AIR patients. Results: Seventeen patients with AIR and 14 controls were included. AIR patients had a higher percent of monocytes (Z = 3.076, P = 0.002). An increase in immunoglobulin G against recoverin was correlated with a VA decrease (ß = 0.0044, P < 0.0001). An increase in monocyte proportion was correlated with a decrease in GVF area (ß = -7.27, P = 0.0021). Several markers of B-cell depletion were correlated with GVF improvement. Conclusions: Monocytes may play a role in AIR pathophysiology and be a disease activity marker. B-cell depletion markers correlated with clinical parameter improvement, particularly GVF. Translational Relevance: This work elucidates immunologic markers that may improve the accuracy of diagnosis and treatment of AIR.

Evaluation of blood product transfusion therapies in acute injury care in low- and middle-income countries: a systematic review.

BACKGROUND: Worldwide, injuries account for approximately five million mortalities annually, with 90% occurring in low- and middle-income countries (LMICs). Although guidelines characterizing data for blood product transfusion in injury resuscitation have been established for high-income countries (HICs), no such information on use of blood products in LMICs exists. This systematic review evaluated the available literature on the use and associated outcomes of blood product transfusion therapies in LMICs for acute care of patients with injuries. METHODS: A systematic search of PubMed, EMBASE, Global Health, CINAHL and Cochrane databases through November 2018 was performed by a health sciences medical librarian. Prospective and cross-sectional reports of injured patients from LMICs involving data on blood product transfusion therapies were included. Two reviewers identified eligible records (κ=0.92); quality was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Report elements, patient characteristics, injury information, blood transfusion therapies provided and mortality outcomes were extracted and analyzed. RESULTS: Of 3411 records, 150 full-text reports were reviewed and 17 met inclusion criteria. Identified reports came from the World Health Organization regions of Africa, the Eastern Mediterranean, and South-East Asia. A total of 6535 patients were studied, with the majority from exclusively inpatient hospital settings (52.9%). Data on transfusion therapies demonstrated that packed red blood cells were given to 27.0% of patients, fresh frozen plasma to 13.8%, and unspecified product types to 50.1%. Among patients with blunt and penetrating injuries, 5.8% and 15.7% were treated with blood product transfusions, respectively. Four reports provided data on comparative mortality outcomes, of which two found higher mortality in blood transfusion-treated patients than in untreated patients at 17.4% and 30.4%. The overall quality of evidence was either low (52.9%) or very low (41.2%), with one report of moderate quality by GRADE criteria. CONCLUSION: There is a paucity of high-quality data to inform appropriate use of blood transfusion therapies in LMIC injury care. Studies were geographically limited and did not include sufficient data on types of therapies and specific injury patterns treated. Future research in more diverse LMIC settings with improved data collection methods is needed to inform injury care globally.

Use of frailty to predict survival in elderly patients with early stage non-small-cell lung cancer treated with stereotactic body radiation therapy.

OBJECTIVES: Frailty has been shown to increase morbidity and mortality independent of age, but studies are lacking in radiation oncology. This study evaluates a modified frailty index (mFI) in predicting overall survival (OS) and non-cancer death for Stage I/II [N0M0] Non-Small-Cell Lung Cancer (NSCLC) patients treated with Stereotactic Body Radiation Therapy (SBRT). MATERIALS AND METHODS: Medical records for all patients with Stage I/II NSCLC treated at our institution with SBRT from 2009 to 2014 were reviewed. A validated mFI score, consisting of 11 variables was calculated, classifying patients as non-frail (0-1) or frail (≥2). Primary endpoint (OS) was analyzed using Kaplan-Meier method and log-rank. Secondary endpoint, non-cancer death, was analyzed using Fine-Gray's method, with death from lung cancer as a competing risk. RESULTS: Patient cohort consisted of 38 (27.3%) non-frail and 101 (72.7%) frail [median total mFI score 3.0 (range 0-7)]. Median age and pack-year history was 74 and 46years, respectively. Median follow-up among survivors was 38.5months (range 4.0-74.1months). Frailty was associated with a lower 3-year OS (37.3% vs. 74.7%; p=0.003) and 3-year cumulative incidence of non-cancer death (36.7% vs. 12.5%; p=0.02). Frailty remained significant in the multivariate model [OS HR for mFI ≥2: 2.25 (1.14-4.44); p=0.02]. CONCLUSION: Frailty is associated with lower OS in older patients with early stage NSCLC treated with SBRT, yet frail patients survived a median 2.5years, and were more likely to die of causes unrelated to the primary lung cancer, suggesting SBRT should be considered even in older patients deemed unfit for surgery.

Resolution of ascites and hepatic encephalopathy and absence of variceal bleeding in decompensated hepatitis C virus cirrhosis patients.

BACKGROUND AND AIMS: The aims of this study were to examine changes in the proportion of decompensated hepatitis C virus (HCV) cirrhosis patients with ascites, hepatic encephalopathy, and variceal bleeding at pretreatment compared to 3 and 12 months post-sustained virological response (SVR) and to compare pretreatment and post-SVR model of end-stage liver disease and Child-Pugh scores and alpha-fetoprotein levels. METHODS: Electronic medical records of 64 decompensated HCV cirrhosis patients who received direct-acting antivirals were reviewed. The McNemar-Bowker test and the Wilcoxon-Signed Rank test were used to compare patient outcomes. RESULTS: Ascites was resolved in 29% of patients 3 months post-SVR (65% vs 36%, P < 0.01) and in 35% of patients 12 months post-SVR (65% vs 30%, P = 0.07). Hepatic encephalopathy was resolved in 54% of patients 3 months post-SVR (70% vs 16%, P < 0.01) and in 48% of patients 12 months post-SVR (70% vs 22% P = 0.03). Variceal bleeding was absent in 32% of patients 3 months post-SVR (35% vs 3%, P < 0.01) and in 27% of patients 12 months post-SVR (35% vs 8%, P < 0.01). Alpha-fetoprotein levels were significantly reduced post-SVR, but model of end-stage liver disease and Child-Pugh scores were not. CONCLUSIONS: Decompensated HCV cirrhosis patients who achieved SVR with direct-acting antiviral treatment had significant reductions in manifestations of hepatic decompensation sustainable up to 1 year post-SVR.

Rapid Detection and Identification of Uveitis Pathogens by Qualitative Multiplex Real-Time PCR.

Purpose: Infectious uveitis is a serious sight-threatening infection commonly caused by herpesviruses and Toxoplasma gondii. Etiologic diagnosis based on the clinical evaluation is often challenging. We developed and validated a multiplex real-time PCR assay coupled with high-resolution melting (HRM) for rapid detection and identification of herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), and T. gondii. Methods: The assay was designed to target pathogen genome regions that yield products with distinct melting temperatures. Analytical specificity, sensitivity, and precision of HRM identification were determined. Clinical validation was performed by testing 108 intraocular fluids collected from eyes suffering with infectious uveitis (n = 30) and controls (n = 78). Results: A nonoverlapping high-precision profile for each pathogen was generated following HRM (coefficient of variation 0%). The assay was highly sensitive, with a limit of detection of 20 genome copies for herpesviruses and 200 genome copies for T. gondii. The intra- and interassay variability of cycle threshold (Ct) measurement was ≤4% and ≤6%, respectively. Thirteen intraocular specimens collected from suspected cases of infectious uveitis were positive (mean Ct values varied from 19.4 to 27.7). Melting profiles of positive cases were consistent with HSV-2 (n = 5), VZV (n = 5), CMV (n = 2), and T. gondii (n = 1). Amplicon identities were confirmed by sequencing. Control intraocular samples from patients without a clinical diagnosis of infectious uveitis were all negative. Conclusions: This assay allows rapid, sensitive, and reliable detection and identification of the most common known causes of infectious uveitis, making early pathogen information-based intervention possible.