Impact of Molnupiravir Treatment on Patient-Reported COVID-19 Symptoms in the Phase 3 MOVe-OUT Trial: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Molnupiravir is an orally administered antiviral authorized for COVID-19 treatment in adults at high risk of progression to severe disease. Here, we report secondary and post hoc analyses of participants' self-reported symptoms in the MOVe-OUT trial, which evaluated molnupiravir initiated within 5 days of symptom onset in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19. METHODS: Eligible participants completed a 15-item symptom diary daily from day 1 (randomization) through day 29, rating symptom severity as "none," "mild," "moderate," or "severe"; loss of smell and loss of taste were rated as "yes" or "no." Time to sustained symptom resolution/improvement was defined as the number of days from randomization to the first of 3 consecutive days of reduced severity, without subsequent relapse. Time to symptom progression was defined as the number of days from randomization to the first of 2 consecutive days of worsening severity. The Kaplan-Meier method was used to estimate event rates at various time points. The Cox proportional hazards model was used to estimate the hazard ratio between molnupiravir and placebo. RESULTS: For most targeted COVID-19 symptoms, sustained resolution/improvement was more likely, and progression was less likely, in the molnupiravir versus placebo group through day 29. When evaluating 5 distinctive symptoms of COVID-19, molnupiravir participants had a shorter median time to first resolution (18 vs 20 d) and first alleviation (13 vs 15 d) of symptoms compared with placebo. CONCLUSIONS: Molnupiravir treatment in at-risk, unvaccinated patients resulted in improved clinical outcomes for most participant-reported COVID-19 symptoms compared with placebo. Clinical Trials Registration. ClinicalTrials.gov: NCT04575597.

Guideline Compliance and Indications for Inferior Vena Cava Filter Placement at a Quaternary Care Medical Center.

PURPOSE: This study investigated physician compliance with indications for inferior vena cava (IVC) filter placement according to the 2012 American College of Chest Physicians (ACCP) and the 2011 Society of Interventional Radiology (SIR) guidelines. MATERIALS AND METHODS: A retrospective medical record review of 231 retrievable IVC filters placed between August 15, 2016, and December 28, 2017, at a large urban academic medical center. Guideline compliance to the 2012 ACCP and the 2011 SIR guidelines, and indications for IVC filter placements were assessed through an adjudication protocol. Filter retrieval and complication rates were also examined. RESULTS: Compliance to guidelines was low (60.2% for ACCP; 74.0% for SIR), especially for non-intensive care unit (ICU) patients (ICU 74.6% vs non-ICU 54.8%, p=0.007 for ACCP; ICU 82.5% vs non-ICU 70.8%, p=0.092 for SIR). After adjudication, 8.2% (19/231) of filters were considered non-indicated but reasonable, 17.7% (41/231) non-indicated and unreasonable, and 13.9% (32/231) SIR-indicated but not ACCP-indicated. The most common indication was venous thromboembolism with contraindication to anticoagulation. The most common reasons for non-compliance were distal deep venous thrombosis with contraindication to anticoagulation (19/60, 31.6%) and clot burden (19/60, 31.6%). One-year filter retrieval and 90-day complication rates were 32.0% (74/231) and 6.1% (14/231), respectively. CONCLUSION: Compliance to established guidelines was low. Reasons for non-compliance included limitations or discrepancies in guidelines, as well as non-evidence-based filter placements. CLINICAL IMPACT: Despite increasing utilization of inferior vena cava (IVC) filters, guideline compliance for IVC filter placement among providers is unclear. The results of this study indicate that physician compliance to established guidelines is poor, especially in non-intensive-care-unit patients. Noncompliance stems from non-evidence-based filter placement as well as differences and limitations in guidelines. Avoiding non-indicated IVC filter placement and consolidation of guidelines may significantly improve guideline compliance. The critical insights gained from this study can help promote judicious use of IVC filters and highlight the role of venous thromboembolism experts in navigating complex cases and nuances of guidelines.

Human antimicrobial peptides and cancer.

Antimicrobial peptides (AMPs) have long been a topic of interest for entomologists, biologists, immunologists and clinicians because of these agents' intriguing origins in insects, their ubiquitous expression in many life forms, their capacity to kill a wide range of bacteria, fungi and viruses, their role in innate immunity as microbicidal and immunoregulatory agents that orchestrate cross-talk with the adaptive immune system, and, most recently, their association with cancer. We and others have theorized that surveillance through epithelial cell-derived AMPs functions to keep the natural flora of microorganisms in a steady state in different niches such as the skin, the intestines, and the mouth. More recently, findings related to specific activation pathways of some of these AMPs have led investigators to associate them with pro-tumoral activity; i.e., contributing to a tumorigenic microenvironment. This area is still in its infancy as there are intriguing yet contradictory findings demonstrating that while some AMPs have anti-tumoral activity and are under-expressed in solid tumors, others are overexpressed and pro-tumorigenic. This review will introduce a new paradigm in cancer biology as it relates to AMP activity in neoplasia to address the following questions: Is there evidence that AMPs contribute to tumor promoting microenvironments? Can an anti-AMP strategy be of use in cancer therapy? Do AMPs, expressed in and released from tumors, contribute to compositional shifting of bacteria in cancerous lesions? Can specific AMP expression characteristics be used one day as early warning signs for solid tumors?

Inflatable Penile Prosthesis in the Ambulatory Surgical Setting: Outcomes From a Large Urological Group Practice.

BACKGROUND: The definitive treatment for erectile dysfunction is the surgical implantation of a penile prosthesis, of which the most common type is the 3-piece inflatable penile prosthesis (IPP) device. IPP surgery in outpatient freestanding ambulatory surgical centers (ASC) is becoming more prevalent as payers and health systems alike look to reduce healthcare costs. AIM: To evaluate IPP surgical outcomes in an ASC as compared to contemporaneously-performed hospital surgeries. METHODS: A database of all patients undergoing IPP implantation by practitioners in the largest private community urology group practice in the United States, from January 1, 2013 to August 1, 2019, was prospectively compiled and retrospectively reviewed. Cohorts of patients having IPP implantation performed in the hospital vs ASC setting were compared. MAIN OUTCOME MEASURE: The primary outcome measure was to compare surgical data (procedural and surgical times, need for hospital transfer from ASC) and outcomes (risk for device infection, erosion, and need for surgical revision) between ASC and hospital-based surgery groups. RESULTS: A total of 923 patients were included for this analysis, with 674 (73%) having ASC-based surgery and 249 (27%) hospital-based, by a total of 33 surgeons. Median procedural (99.5 vs 120 minutes, P < .001) and surgical (68 vs 75 minutes, P < .001) times were significantly shorter in the ASC. While the risk for device erosion and need for surgical revision were similar between groups, there was no higher risk for prosthetic infection when surgery was performed in the ASC (1.7% vs 4.4% [hospital], P = .02), corroborated by logistic regression analysis (odds ratio 0.39, P = .03). The risk for postoperative transfer of an ASC patient to the hospital was low (0.45%). The primary reason for mandated hospital-based surgery was medical (51.4%), though requirement as a result of insurance directive (39.7%) was substantial. CLINICAL IMPLICATIONS: IPP implantation in the ASC is safe, has similar outcomes compared to hospital-based surgery with a low risk for need for subsequent hospital transfer. STRENGTHS & LIMITATIONS: The strengths of this study include the large patient population in this analysis as well as the real-world nature of our practice. Limitations include the retrospective nature of the review as well as the potential for residual confounding. CONCLUSION: ASC-based IPP implantation is safe, with shorter surgical and procedural times compared to those cases performed in the hospital setting, with similar functional outcomes. These data suggest no added benefit to hospital-based surgery in terms of prosthetic infection risk. Weinberg AC, Siegelbaum MH, Lerner BD, et al. Inflatable Penile Prosthesis in the Ambulatory Surgical Setting: Outcomes From a Large Urological Group Practice. J Sex Med 2020;17:1025-1032.

Portable Ventilation/Perfusion Scanning is Useful for Evaluating Clinically Significant Pulmonary Embolism in the ICU Despite Abnormal Chest Radiography.

OBJECTIVE: Computed tomography angiography is limited in the intensive care unit (ICU) due to renal insufficiency, hemodynamic instability, and difficulty transporting unstable patients. A portable ventilation/perfusion (V/Q) scan can be used. However, it is commonly believed that an abnormal chest radiograph can result in a nondiagnostic scan. In this retrospective study, we demonstrate that portable V/Q scans can be helpful in ruling in or out clinically significant pulmonary embolism (PE) despite an abnormal chest x-ray in the ICU. DESIGN: Two physicians conducted chart reviews and original V/Q reports. A staff radiologist, with 40 years of experience, rated chest x-ray abnormalities using predetermined criteria. SETTING: The study was conducted in the ICU. PATIENTS: The first 100 consecutive patients with suspected PE who underwent a portable V/Q scan. INTERVENTIONS: Those with a portable V/Q scan. RESULTS: A normal baseline chest radiograph was found in only 6% of patients. Fifty-three percent had moderate, 24% had severe, and 10% had very-severe radiographic abnormalities. Despite the abnormal x-rays, 88% of the V/Q scans were low probability for a PE despite an average abnormal radiograph rating of moderate. A high-probability V/Q for PE was diagnosed in 3% of the population despite chest x-ray ratings of moderate to severe. Six patients had their empiric anticoagulation discontinued after obtaining the results of the V/Q scan, and no anticoagulation was started for PE after a low-probability V/Q scan. CONCLUSION: Despite the large percentage of moderate-to-severe x-ray abnormalities, PE can still be diagnosed (high-probability scan) in the ICU with a portable V/Q scan. Although low-probability scans do not rule out acute PE, it appeared less likely that any patient with a low-probability V/Q scan had severe hypoxemia or hemodynamic instability due to a significant PE, which was useful to clinicians and allowed them to either stop or not start anticoagulation.

Use of the Bedside-Placed Angel Catheter IVC Filter for Venous Thromboembolic Disease in Critically Ill Medical Patients.

Venous thromboembolic disease is a major problem among critically ill patients, with significant associated morbidity and mortality. Many critically ill patients have contraindications to systemic anticoagulation, and inferior vena cava (IVC) filters are an important alternative in preventing pulmonary emboli (PE) in this population. The Angel Catheter (Mermaid, Stenlose, Denmark) is a novel percutaneous and removable IVC filter attached to the end of a triple lumen central venous catheter which has been demonstrated to reduce PE in surgical and trauma patients. This case series describes 18 critically ill medical patients who had an Angel catheter placed either for diagnosed PE or due to high risk for PE; over half had at least submassive PE at the time of Angel catheter placement. None of the patients had a recurrence of PE during Angel catheter use, 29.4% had clot found in the filter via cavogram upon removal, and only one had a minor complication which had no clinical consequence. In 2 patients, the placement of the Angel Catheter resulted in the prevention of PE during catheter-directed thrombolysis of extensive deep vein thrombosis. This case series demonstrates that in a population of critically ill, elderly, and obese medical patients the bedside placement of the Angel IVC filter is feasible, safe, and may be effective for preventing PE.

Innate immune mechanisms to oral pathogens in oral mucosa of HIV-infected individuals.

A crucial aspect of mucosal HIV transmission is the interaction between HIV, the local environmental milieu and immune cells. The oral mucosa comprises many host cell types including epithelial cells, CD4 + T cells, dendritic cells and monocytes/macrophages, as well as a diverse microbiome predominantly comprising bacterial species. While the oral epithelium is one of the first sites exposed to HIV through oral-genital contact and nursing infants, it is largely thought to be resistant to HIV transmission via mechanisms that are still unclear. HIV-1 infection is also associated with predisposition to secondary infections, such as tuberculosis, and other diseases including cancer. This review addresses the following questions that were discussed at the 8th World Workshop on Oral Health and Disease in AIDS held in Bali, Indonesia, 13 September -15 September 2019: (a) How does HIV infection affect epithelial cell signalling? (b) How does HIV infection affect the production of cytokines and other innate antimicrobial factors, (c) How is the mucosal distribution and function of immune cells altered in HIV infection? (d) How do T cells affect HIV (oral) pathogenesis and cancer? (e) How does HIV infection lead to susceptibility to TB infections?

Development and External Validation of a Machine Learning Tool to Rule Out COVID-19 Among Adults in the Emergency Department Using Routine Blood Tests: A Large, Multicenter, Real-World Study.

BACKGROUND: Conventional diagnosis of COVID-19 with reverse transcription polymerase chain reaction (RT-PCR) testing (hereafter, PCR) is associated with prolonged time to diagnosis and significant costs to run the test. The SARS-CoV-2 virus might lead to characteristic patterns in the results of widely available, routine blood tests that could be identified with machine learning methodologies. Machine learning modalities integrating findings from these common laboratory test results might accelerate ruling out COVID-19 in emergency department patients. OBJECTIVE: We sought to develop (ie, train and internally validate with cross-validation techniques) and externally validate a machine learning model to rule out COVID 19 using only routine blood tests among adults in emergency departments. METHODS: Using clinical data from emergency departments (EDs) from 66 US hospitals before the pandemic (before the end of December 2019) or during the pandemic (March-July 2020), we included patients aged ≥20 years in the study time frame. We excluded those with missing laboratory results. Model training used 2183 PCR-confirmed cases from 43 hospitals during the pandemic; negative controls were 10,000 prepandemic patients from the same hospitals. External validation used 23 hospitals with 1020 PCR-confirmed cases and 171,734 prepandemic negative controls. The main outcome was COVID 19 status predicted using same-day routine laboratory results. Model performance was assessed with area under the receiver operating characteristic (AUROC) curve as well as sensitivity, specificity, and negative predictive value (NPV). RESULTS: Of 192,779 patients included in the training, external validation, and sensitivity data sets (median age decile 50 [IQR 30-60] years, 40.5% male [78,249/192,779]), AUROC for training and external validation was 0.91 (95% CI 0.90-0.92). Using a risk score cutoff of 1.0 (out of 100) in the external validation data set, the model achieved sensitivity of 95.9% and specificity of 41.7%; with a cutoff of 2.0, sensitivity was 92.6% and specificity was 59.9%. At the cutoff of 2.0, the NPVs at a prevalence of 1%, 10%, and 20% were 99.9%, 98.6%, and 97%, respectively. CONCLUSIONS: A machine learning model developed with multicenter clinical data integrating commonly collected ED laboratory data demonstrated high rule-out accuracy for COVID-19 status, and might inform selective use of PCR-based testing.

Ensemble survival tree models to reveal pairwise interactions of variables with time-to-events outcomes in low-dimensional setting.

Unraveling interactions among variables such as genetic, clinical, demographic and environmental factors is essential to understand the development of common and complex diseases. To increase the power to detect such variables interactions associated with clinical time-to-events outcomes, we borrowed established concepts from random survival forest (RSF) models. We introduce a novel RSF-based pairwise interaction estimator and derive a randomization method with bootstrap confidence intervals for inferring interaction significance. Using various linear and nonlinear time-to-events survival models in simulation studies, we first show the efficiency of our approach: true pairwise interaction-effects between variables are uncovered, while they may not be accompanied with their corresponding main-effects, and may not be detected by standard semi-parametric regression modeling and test statistics used in survival analysis. Moreover, using a RSF-based cross-validation scheme for generating prediction estimators, we show that informative predictors may be inferred. We applied our approach to an HIV cohort study recording key host gene polymorphisms and their association with HIV change of tropism or AIDS progression. Altogether, this shows how linear or nonlinear pairwise statistical interactions of variables may be efficiently detected with a predictive value in observational studies with time-to-event outcomes.

Robotic transanal minimally invasive rectal mucosa harvest.

INTRODUCTION: Buccal mucosal grafts (BMG) are traditionally used in urethral reconstruction. There may be insufficient BMG for applications requiring large grafts, such as urethral stricture after gender-affirming phalloplasty. Rectal mucosa in lieu of BMG avoids oral impairment, while potentially affording less postoperative pain and larger graft dimensions. Transanal minimally invasive surgery (TAMIS) using laparoscopic instruments has been described. Due to technical challenges of harvesting a sizable graft within the rectal lumen, we adopted a new robotic approach. We demonstrate the feasibility and safety of a novel technique of Robotic TAMIS (R-TAMIS) in the harvest of rectal mucosa for the purpose of onlay graft urethroplasty. METHODS: Six patients (ages 28-60) presenting with urethral stricture and one vaginal stricture underwent robotic rectal mucosal harvest. The procedure, which was first studied on an inanimate bovine colon model, was performed under general anesthesia in lithotomy position using the GelPOINTTM Path Transanal Access. Mucosa was harvested robotically after submucosal hydrodissection. Graft size harvested correlated with surface area needed for urethral or vaginal reconstruction. Following specimen retrieval, flexible sigmoidoscopy confirmed hemostasis. The graft was placed as an onlay for urethroplasty. RESULTS: There were no intraoperative or postoperative complications. Mean graft size was 11.4 × 3.0 cm. All reconstructions had excellent graft take. All patients recovered without morbidity or mortality. They reported minimal postoperative pain and all regained bowel function on postoperative day one. Patients with prior BMG harvests subjectively self-reported less postoperative pain and greater quality of life. There have been no long-term complications at a median follow-up of 17 months. CONCLUSIONS: To our knowledge, this is the first use of R-TAMIS for rectal mucosa harvest. Our preliminary series indicates this approach is feasible and safe, constituting a promising minimally invasive technique for urethral reconstruction. Prospective studies evaluating graft outcomes and donor site morbidity with more long-term follow-up are needed.

Impact of Surgeon Case Volume on Reoperation Rates after Inflatable Penile Prosthesis Surgery.

PURPOSE: We investigated the impact of surgeon annual case volume on reoperation rates after inflatable penile prosthesis surgery. MATERIALS AND METHODS: The New York Statewide Planning and Research Cooperative System database was queried for inflatable penile prosthesis cases from 1995 to 2014. Multivariate proportional hazards regression was performed to estimate the impact of surgeon annual case volume on inflatable penile prosthesis reoperation rates. We stratified our analysis by indication for reoperation to determine if surgeon volume had a similar effect on infectious and noninfectious complications. RESULTS: A total of 14,969 men underwent inflatable penile prosthesis insertion. Median followup was 95.1 months (range 0.5 to 226.7) from the time of implant. The rates of overall reoperation, reoperation for infection and reoperation for noninfectious complications were 6.4%, 2.5% and 3.9%, respectively. Implants placed by lower volume implanters were more likely to require reoperation for infection but not for noninfectious complications. Multivariable analysis demonstrated that compared with patients treated by surgeons in the highest quartile of annual case volume (more than 31 cases per year), patients treated by surgeons in the lowest (0 to 2 cases per year), second (3 to 7 cases per year) and third (8 to 31 cases per year) annual case volume quartiles were 2.5 (p <0.001), 2.4 (p <0.001) and 2.1 (p=0.01) times more likely to require reoperation for inflatable penile prosthesis infection, respectively. CONCLUSIONS: Patients treated by higher volume implanters are less likely to require reoperation after inflatable penile prosthesis insertion than those treated by lower volume surgeons. This trend appears to be driven by associations between surgeon volume and the risk of prosthesis infection.

Human ß Defensin-3 Increases CD86 Expression on Monocytes by Activating the ATP-Gated Channel P2X7.

Human ß defensin-3 (hBD-3), an epithelial cell-derived antimicrobial peptide, mediates chemotaxis and activation of myeloid cells. In this study, we provide evidence that hBD-3 induces the costimulatory molecule CD86 on primary human monocytes by a mechanism involving autocrine activation of ionotropic P2X7 receptors (P2X7R) by ATP. Incubation of monocytes with hBD-3 resulted in increased expression of both the CD80 and CD86 costimulatory molecules. Treatment of monocytes with a selective P2X7R antagonist inhibited the ability of hBD-3 to induce expression of CD86 but not CD80. The hBD-3-dependent upregulation of CD86 was also attenuated in monocytes incubated with apyrase, a potent scavenger of extracellular ATP. Finally, direct activation of monocyte P2X7R by exogenous ATP mimicked the ability of hBD-3 to induce CD86 expression. These data suggest that hBD-3 induces monocyte activation by both P2X7-dependent (CD86 upregulation) and P2X7-independent (CD80 upregulation) signaling mechanisms and raise the possibility that activation of P2X7R could play an important role in shaping the inflammatory microenvironment in conditions where hBD-3 is highly expressed, such as psoriasis or oral carcinoma.

Massive Pulmonary Embolism: Extracorporeal Membrane Oxygenation and Surgical Pulmonary Embolectomy.

Massive pulmonary embolism (PE) refers to large emboli that cause hemodynamic instability, right ventricular failure, and circulatory collapse. According to the 2016 ACCP Antithrombotic Guidelines, therapy for massive PE should include systemic thrombolytic therapy in conjunction with anticoagulation and supportive care. However, in patients with a contraindication to systemic thrombolytics or in those who fail the above interventions, extracorporeal membrane oxygenation (ECMO) and/or surgical embolectomy may be used to improve oxygenation, achieve hemodynamic stability, and successfully treat massive PE. Randomized controlled human trials evaluating ECMO in this context have not been done, and its role has not been well-defined. The European Society of Cardiology 2014 acute PE guidelines briefly mention that ECMO can be used for massive PE as a method for hemodynamic support and as an adjunct to surgical embolectomy. The 2016 CHEST Antithrombotic Therapy for venous thromboembolism Disease guidelines do not mention ECMO in the management of massive PE. However, multiple case reports and small series cited benefit with ECMO for massive PE. Further, ECMO may facilitate stabilization for surgical embolectomy. Unfortunately, ECMO requires full anticoagulation to maintain the functionality of the system; hence, significant bleeding complicates its use in 35% of patients. Contraindications to ECMO include high bleeding risk, recent surgery or hemorrhagic stroke, poor baseline functional status, advanced age, neurologic dysfunction, morbid obesity, unrecoverable condition, renal failure, and prolonged cardiopulmonary resuscitation without adequate perfusion of end organs. In this review, we discuss management of massive PE, with an emphasis on the potential role for ECMO and/or surgical embolectomy.

Assessment of the incidence of squamous cell papilloma of the esophagus and the presence of high-risk human papilloma virus.

BACKGROUND AND AIMS: There has been a recent increase in the incidence of oropharyngeal cancer (OPC) associated with high-risk human papilloma virus (HPV) infection. We investigated the incidence of esophageal papilloma and the presence of high-risk HPV infection. METHODS: This is a cross-sectional study conducted at a County teaching hospital. Patients with esophageal papilloma between January 2000 and December 2013 were identified. Patients with sufficient specimens were tested for the HPV virus. RESULTS: Sixty patients with esophageal papilloma lesions were identified from 2000 to 2013. (31 males, age 51 ± 13 years). The incidence was 0.13% in 2000 and increased to 0.57% in 2013 (P < 0.0001). Twenty-nine patients (48.3%) had a papilloma that was more than 5 mm in size, and 20% had multiple lesions. The papilloma was located in the distal esophagus in 35 (58.3%) patients, mid esophagus in 17 (28.3%) patients, and proximal in 8 (13.3%) patients. Three (5%) patients had associated OPC, and 9 (47.4%) of the 19 patients tested were positive for high-risk HPV serotype 16. CONCLUSIONS: The incidence of esophageal papilloma has increased by fourfolds over the past 14 years. About half of the tested patients demonstrated high risk HPV. This may suggest a potential growing risk for esophageal squamous cell cancer in the future.

FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6.

We previously identified a cell wall-associated protein from Fusobacterium nucleatum, a Gram-negative bacterium of the oral cavity, that induces human beta defensin 2 (hBD-2) in primary human oral epithelial cells (HOECs) and designated it FAD-I (Fusobacterium-associated defensin inducer). Here, we report differential induction of hBD-2 by different strains of F. nucleatum; ATCC 25586 and ATCC 23726 induce significantly more hBD-2 mRNA than ATCC 10953. Heterologous expression of plasmid-borne fadI from the highly hBD-2-inducing strains in a ΔfadI mutant of ATCC 10953 resulted in hBD-2 induction to levels comparable to those of the highly inducing strains, indicating that FAD-I is the principal F. nucleatum agent for hBD-2 induction in HOECs. Moreover, anti-FAD-I antibodies blocked F. nucleatum induction of hBD-2 by more than 80%. Recombinant FAD-I (rFAD-I) expressed in Escherichia coli triggered levels of hBD-2 transcription and peptide release in HOECs similar to those of native FAD-I (nFAD-I) isolated from F. nucleatum ATCC 25586. Tandem mass spectrometry revealed a diacylglycerol modification at the cysteine residue in position 16 for both nFAD-I and rFAD-I. Cysteine-to-alanine substitution abrogated FAD-I's ability to induce hBD-2. Finally, FAD-I activation of hBD-2 expression was mediated via both Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6 heterodimerization. Microbial molecules like FAD-I may be utilized in novel therapeutic ways to bolster the host innate immune response at mucosal surfaces.

Sub-Coronal Inflatable Penile Prosthesis Placement With Modified No-Touch Technique: A Step-by-Step Approach With Outcomes.

INTRODUCTION: The surgical treatment of disorders of male sexual function requires specific exposure to correct the underlying problem safely and efficiently. Currently, sub-coronal exposure is used for treatment of phimosis, Peyronie's disease plaque (PDP), and semirigid penile prosthesis insertion. Infra-pubic and scrotal incisions are used for inflatable penile prosthesis (IPP) placement. However, men who present with several disorders might require multiple procedures and surgical incisions. AIM: To report a prospective review of our surgical experience and outcomes with a single sub-coronal incision for IPP placement with a modified no-touch technique. This approach allows for access to the entire corporal body for multiple reconstructive procedures. METHODS: Two hundred men had IPPs placed through a sub-coronal incision using our modified no-touch technique. The penis was degloved to the level of the penoscrotal junction and the dartos muscle was everted and secured to the drapes. This allowed exclusion of the scrotal and penile skin from the operative field. After artificial erection, the patient's corpora were inspected for PDP and other abnormalities. Penoscrotal IPP models were placed in all cases with insertion proximal to the penoscrotal junction. After placement of the IPP, the abnormalities were repaired. MAIN OUTCOME MEASURES: Feasibility of the procedure, operative times, complication rate, utilization of accessory, reconstructive procedures, and post-operative penile length. RESULTS: Of the 200 men who had IPP placement, 92 had PDP that was treated, 106 (53%) consented to circumcision, 24 (12%) had their reservoir placed ectopically, and 31 (16%) had a prosthesis exchanged through the sub-coronal technique. Mean operative time was 73 minutes (39-161 minutes). CONCLUSION: Specialists in the surgical treatment of disorders of male sexual function can perform multiple procedures safely and easily through a modified no-touch single sub-coronal incision. This approach allows access to the entire corporal body, providing excellent visibility and allowing the surgeon to perform multiple penile reconstructive surgeries through a single incision.

Clot Extraction With the FlowTriever Device in Acute Massive Pulmonary Embolism.

Clinical guidelines support the use of systemic thrombolytic therapy for acute massive pulmonary embolism (PE). When anticoagulation and thrombolysis fail or are contraindicated, options become limited. We report an acute PE case in which treatment options were limited, and a novel device, the FlowTriever (Inari Medical, Irvine, California), was successfully used. This is the first case report of the use of this device that we are aware of.

Short-chain fatty acids from periodontal pathogens suppress histone deacetylases, EZH2, and SUV39H1 to promote Kaposi's sarcoma-associated herpesvirus replication.

UNLABELLED: Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE: About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

HBD-3 induces NK cell activation, IFN-γ secretion and mDC dependent cytolytic function.

We previously showed that human beta defensin-3 (hBD-3) activates mDC via TLR1/2. Here we investigated the effects of hBD-3 on NK cell activation state and effector functions. We observed that hBD-3 activates PBMC to secrete IFN-γ and kill K562 and HUH hepatoma target cells in an NK dependent fashion, and both TLR1/2 and CCR2 are involved. TLR1, TLR2 and CCR2 were expressed on NK cells, and in purified NK culture experiments we observed hBD-3 to directly act on NK cells, resulting in CD69 upregulation and IFNγ secretion. We also observed mDC-hBD-3 enhanced NK cytolytic activity and IFNγ production. These results implicate hBD-3 in its ability to directly activate NK cells and increase NK cell effector function, as well as promote mDC-dependent NK activity. HBD-3 may therefore act as a mediator of innate cell interactions that result in bridging of innate and adaptive immunity.