United States

Background:
Surgical Aortic Valve Replacement (SAVR) is the current treatment of choice for good surgical candidates with moderate to severe symptomatic. As TAVR showed an improved 1and 2-year all-cause mortality, it has been opted for moderately symptomatic severe AS patients. The purpose of this review was to do a clinical comparison of TAVR vs SAVR and to analyze the Health Index Factor that makes TAVR a treatment of choice in asymptomatic AS patients. 

Methods:
An extensive literature review of PubMed, Cochrane, and Embase databases was performed using the key words “Aortic stenosis”, “SAVR”, “TAVR”, and “Asymptomatic”. A total of 45 prospective randomized clinical trials in English language that were published from year 2000 onwards were included in the final analysis. 

Results:
Strang G et al found that 59.3% of the asymptomatic AS patients are likely to die in the next 5 years without proactive treatment. Multiple studies have proven that early intervention with aortic valve replacement is superior to conservative treatment in severe asymptomatic AS, however, the choice between SAVR and TAVR is not well established. NOTION Trial, SURTAVI Trail, and PARTNER 3 study showed non-inferiority of TAVR over SAVR, within a 1-year follow-up for low surgical risk patients. Evolut Low-risk study is the only prospective study performed to date that enrolled patients with asymptomatic severe AS. The Trial demonstrated that there was no difference in all-cause mortality at 30 days (1.3% vs 4.8%. p=0.23), and 12 days (1.3% vs 6.5%, p=0.11). Additionally, TAVR also decreases the risk of post-procedural atrial fibrillation,acute kidney injury rehospitalization and has shown significant improvement in mean trans-aortic pressure gradient. TAVR also showed marked improvement in 30 day Quality of Life (QOL) index, where SAVR didn’t report any significant change in the QOL index.

Conclusion:
TAVR has consistently shown a statistically non-significant difference in case mortality, risk of stroke, and rehospitalization in patients with high and moderate surgical risk, whereby recent initial trials have shown significant improvement in the QOL index and hemodynamic index for patients with asymptomatic disease. More extensive studies are required to prove the feasibility and long term outcomes of the TAVR in asymptomatic patients.





AMA Research Challenge 2022

Role of Trans-Catheter Aortic Valve Replacement in Asymptomatic Aortic Stenosis- Feasibility Analysis

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Background: Sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) have proven their efficacy in managing patients with heart failure (HF), yet within this broad family identifying an effective single agent is still controversial. Therefore, we conducted a network meta-analysis to investigate which SGLT-2Is is more effective in patients with HF.

Methods: PubMed, Web of Science, Scopus, and Embase, were systematically searched from inception to February 2022. We included randomized controlled trials (RCTs) that investigated the usage of SGLT-2Is versus placebo in heart failure patients. Main outcomes were all-cause, cardiovascular mortality, serious adverse events, and hospitalization due to HF. The random-effects method model and inverse variance statistics were used to calculate the odds ratio (OR) with a 95% confidence interval (CI).

Results: Our study included 12 RCTs with a total number of 69,024 patients (37,923 in the SGLT2 inhibitors group and 31,101 in the placebo group). Five RCTs used Empagliflozin, four used Dapagliflozin, and one used Canagliflozin, Ertugliflozin, and Sotagliflozin, respectively. Our analysis showed that Empagliflozin has a statistically significant lowest odds for both cardiovascular mortality and serious adverse effects (OR: 0.80 with 95% CI [0.67-0.96]) and (OR: 0.84 with 95% CI [0.76-0.93]), respectively compared to other SGLT-2Is. All SGLT-2Is have been associated with the same lower odds without preferences for one over the others in regard to all-cause mortality. Furthermore, the rate of hospitalization due to HF showed a statistically significant decrease with all of our SGLT-2Is except for canagliflozin, which showed insignificant results with (OR: 0.63 with 95% CI [0.39-1.01]).

Conclusion: Empagliflozin had the lowest odds of cardiovascular mortality and serious adverse effects. Canagliflozin was the only SGLT-2Is that was non-superior to placebo for risk of hospitalization for HF. Meanwhile, no differences between the included SGLT-2Is were observed in terms of all-cause mortality.




Sodium-glucose transporter 2 inhibitors in patients with heart failure: a network meta-analysis

Background
Aortic stenosis (AS) etiologies include degenerative calcific change, bicuspid aortic valve, and systolic dysfunction. Left ventricular systolic dysfunction decreases blood flow across the aortic valve. There are limited data on low-flow aortic stenosis (stroke volume index (SVI) < 35 mL/m2) following aortic valve replacement (AVR) in patients with systolic dysfunction (LVEF < 50%). We hypothesized that patients with low-flow aortic stenosis and systolic dysfunction perform poorly after AVR compared to those patients with normal flow (SVI ≥ 35 mL/m2) and systolic dysfunction.

Methods
We reviewed AVR cases at a high-volume structural heart center in western New York from 2012 to 2017. Of the 120 patients, 70 patients had low flow aortic stenosis. Stroke volume index was calculated at the level of the left ventricular outflow tract from the transthoracic echocardiographic examination prior to AVR. We performed Receiver operator characteristics and Cox regression analyses to examine the accuracy of the SVI model in predicting the postoperative outcome of the patients undergoing AVR procedure with existing left ventricular dysfunction.

Results
Both five-year survival and overall mortality following AVR were decreased in patients with low flow aortic stenosis. 63% of patients with low-flow aortic stenosis compared to 30% with normal flow aortic stenosis were deceased five years post-AVR. ROC curve indicated SVI to be a clinical predictor of both 5 year (AUC .732, 95% CI: 0.641 - 0.823, p < 0.001) and overall mortality (AUC .728, 95% CI: 0.633 - 0.823, p < 0.001). A comparison of survivors and non-survivors showed that diabetes with an odds ratio of 3.18 [1.45-6.99]; (p = 0.005) and low-flow stroke volume with an odds ratio of 4.44 (2.05-9.66); (p < 0.001) were significant clinical risk factors for patient mortality. 

Conclusion
Patients with low flow aortic stenosis and systolic dysfunction had decreased 5-year survival rates and increased overall mortality post-AVR. This highlights the importance of monitoring blood flow across the aortic valve prior to AVR. Diabetes and low flow stroke volume were notable risk factors for patient mortality. Additional studies are in progress to assess other clinical predictors like energy loss index for patient mortality following AVR.

Stroke Volume Index Predicts Mortality Following Aortic Valve Replacement

Background
Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition of the follicular epithelium that impacts 1-4% of the population. HS presents clinically as recurrently inflamed nodules and sinus tracts, located in intertriginous areas of the body. The nodules can become infected and inflamed, leading to abscesses, pain, and scarring; all of which can have debilitating consequences on a patient’s quality of life. This study aims to improve HS outcomes by analyzing which pathogens are most frequently cultured based on lesion location and pathogen sensitivity profiles. These findings will allow physicians to tailor empiric antibiotic treatment based on HS lesion location. 

Methods
A retrospective medical chart review of patients who were seen at The University of Texas Medical Branch with a diagnosis of HS from 2006-2021 was conducted. 485 patients were seen over 600 patient visits from 2006-2021.

Results
Of the 485 patients seen with documented HS lesions, 75% were female and cultures were performed 47% of the time. Staphylococcus aureus was the most commonly cultured bacteria in general, and, was the most frequently cultured bacteria in the axilla, buttocks, and groin. Proteus mirabilis was the second most commonly cultured bacteria. P. mirabilis and Enterococcus spp. were the most common bacteria cultured in the inframammary region.

Sensitivity analysis of Staphylococcus aureus showed sensitivity to clindamycin in 70% of the cultures, rifampin in 93%, tetracycline in 89%, and trimethoprim-sulfamethoxazole (TMP/SMX) in 93%. A majority of Staphylococcus aureus was found to be resistant to erythromycin (59%) and oxacillin (55%). For P. mirabilis, ampicillin and levofloxacin were both found to be 100% sensitive. Lastly, Enterococcus spp. were found to be sensitive to ampicillin in 95% of the cultures.

Conclusion
The authors recommend TMP/SMX or tetracyclines as empiric therapy for axillary, buttocks and groin lesions. For only inframammary lesions, use of ampicillin should be strongly considered. For patients with multiple sites including the inframammary area, TMP/SMX should be used to ensure Gram (+) and Gram (–) coverage. Tetracyclines may be used as first line empiric therapy for multiple sites without inframammary involvement. 


An Updated Reference for Empiric Antibiotic Therapy in Hidradenitis Suppurativa

Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare but deadly complication seen in patients after solid organ transplants as well as hematopoietic stem cell transplants. Current research suggests the underlying etiology of disease progression is likely secondary to a viral reactivation in the setting of immunosuppression such as the Epstein-Barr Virus (EBV). Cutaneous findings are rare but can range from ulcerated plaques to focal alopecia, with mycosis fungoides being the most frequent manifestation of the cutaneous T-cell lymphoma category. The objective of this study was to investigate the epidemiology and various clinical features of cutaneous manifestations of PTLD. 
Methods: A systematic review of published literature regarding cutaneous post-transplant lymphoproliferative disorders was conducted with inclusion of papers that reported individual patient characteristics and clinical courses. The prevalence of cutaneous PTLD for each specific transplantation was adjusted using the respective total transplantation rates conducted in the United States of America. 
Results: 82 cutaneous PTLD patients had a mean (SD) age at diagnosis of 50.9 (20.8) years, onset from transplant to disease presentation of 7.5 (5.8) years, and males comprised 74.4% of reported patients. When adjusted for total number of transplantation types, cutaneous manifestations of PTLD were most prevalent in renal transplants (77.9%) followed by HSCT (9.1%), liver (6.6%), and cardiac (5.1%). The most common areas of skin lesions were the lower extremities (33.8%), the trunk (18.8%), and the head and neck (11.3%). 
Conclusion: Renal transplant patients comprised the highest proportion of transplantations that developed cutaneous PTLD, which was surprising given cardiac transplant patients usually undergo more intense immunosuppressive regimens. Males appear to be predominantly affected, and the onset of cutaneous PTLD can range widely from shortly after transplantation to several years afterwards, emphasizing the important role clinicians have in being diligent within this patient population. Careful examination of cutaneous findings in these high-risk patients is especially important for timely diagnosis and therapeutic interventions, and further studies are needed to characterize the specific risk factors in cutaneous PTLD patients.

Clinical Characteristics of Post-Transplant Lymphoproliferative Disorder Involving the Skin

Venous leg ulcers, the most common leg ulcer, occur in patients with chronic venous
insufficiency due to venous hypertension. Evidence supports the conservative treatment with lower extremity compression, ideally within the range of 30-40 mm Hg. Pressures in this range provide enough force to partially collapse lower extremity veins without restricting arterial flow in patients in patients without peripheral arterial disease. There are many options for applying such compression, and those who apply these devices have varying levels of training and backgrounds. In this quality improvement study, a single observer utilized a reusable pressure monitor to compare pressures applied using different devices by individuals in wound clinics with diverse training from specialties of dermatology, podiatry, and general surgery. Average compression was higher in the dermatology wound clinic compared to the general surgery clinic (p=.004), and wraps applied by clinic staff were nearly twice as likely as a self-applied wrap to have pressures greater than 40 mm Hg (p = .03). Pressures were also dependent upon the specific compression device used (p=.008). These results indicate that the device-provided pressure may be dependent on both the compression device and on the background and training of the applicator. We propose that standardization in the training of compression application and increased use of a point of care pressure monitor may improve the consistency of applied compression, thus improving adherence to treatment and outcomes in patients with chronic venous insufficiency.

Consistent application of compression: an under-considered variable in the prevention of venous leg ulcers

HSCAPS-2: updated prediction score to distinguish hidradenitis suppurativa (HS) 
from site-specific cutaneous abscess

Background: Bullous pemphigoid (BP) is an autoimmune blistering skin disease that may cause significant morbidity and decreased quality of life. Current therapeutic options for patients with BP include systemic and topical corticosteroids, IVIG, and systemic immunosuppressants; however, side effects of these medications are often intolerable and there are few therapeutic options for patients with exclusionary comorbidities or recalcitrant BP. Dupilumab, an IL-4 receptor-alpha antagonist, has been identified as a potential therapeutic agent for BP. We aim to evaluate long-term outcomes, including response maintenance, treatment durability, and adverse events (AEs) of BP patients on dupilumab.

Methods: This is a retrospective case series from three academic medical centers that evaluates outcomes of 17 patients with biopsy-proven BP on dupilumab followed for >6 months.

Results: Ten males and seven females with an average age of 74.2 years were included in the study. The average dupilumab treatment duration was 19.6 months. On average, the patients tried and failed four standard therapies prior to starting dupilumab. In all patients, dupilumab was used as mono-systemic therapy and controlled the disease, with no losses of efficacy recorded. Fourteen patients were clear, two were almost clear, and one was significantly improved. There were no dupilumab-related AEs reported. Three of four patients who experienced treatment interruption had resultant flares; flares fully resolved with reinitiating of treatment. 

Conclusion: This study suggests promising long-term response and safety for BP patients on dupilumab, with all patients maintaining a response. Limitations of the study are that it involved a small number of patients, there was limited time patients were on treatment, and this not a controlled trial. More studies are needed to evaluate dupilumab which is a promising treatment for BP.

Long-term treatment outcomes and safety of dupilumab as a therapy for bullous pemphigoid: A multicenter retrospective review

Background

Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. It is associated with aggressive disease and a greater likelihood of poor outcomes. Melanoma-associated genes (MAGEs) are CTAs expressed in various malignancies and have been widely studied as prognostic biomarkers. 

Methods

Total RNA was extracted from FFPE tissue samples and then processed using a custom probe set via the nCounter Analysis System (NanoString Technologies) as per company’s protocol. The raw quantification that resulted from the nCounter System’s barcode analysis was normalized using the nSolver software with relation to housekeeping genes.

Results

Three out of 9 patients with cutaneous squamous cell carcinoma and perineural invasion had poor clinical outcomes. Their tumors expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. The tumors also showed poor differentiation and deep invasion and thus were classified as Brigham and Women’s Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59; 36.83±19.41 vs. 11.59±5.83; 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody showed a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced percentage closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p=0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblot showed overexpressed MAGE-A3 and cyclin E, A, and B in tumors in 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3).

Conclusion

These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion comparing with normal skin tissues (1132.56±882.7 vs. 107.62±183.62; 1118.15±1109.49 vs. 9.5±5; 2603.87±2385.26 vs. 5.29±3; 957.95±627.14 vs. 400.42±967.66; 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of patients with cutaneous squamous cell carcinoma.

MAGE-A3 and Clinical Outcome in Cutaneous Squamous Cell Carcinoma with Perineural Invasion

Background
Mohs micrographic surgery (MMS) may be an effective treatment modality for oral cavity cancers (OCC) due to possibility of more effective visualization of tumor margins, and greater preservation of benign tissue. The objective of this study is to review the existing literature on the use of MMS for the treatment of OCC, and categorize its uses and limitations. 
Methods
Systematic review was conducted in accordance with AMSTAR (Assessing the Methodological Quality of Systematic Reviews) guidelines Database search of English, Spanish, and Portuguese articles in PubMed, Scopus, and Google Scholar from inception of databases to June 2, 2022 was conducted. 
Inclusion criteria: studies that discussed the use of Mohs micrographic surgery in the management of carcinomas within boundaries of the oral cavity. 
Exclusion criteria: studies that discussed malignancies limited to the cutaneous surface of the mouth such as the cutaneous lips, vermillion lips, or perioral region.
Endpoints of interest included: type of study, category of tumors treated with MMS, number of patients or specimens analyzed, and main study outcome. 
Results
Nine studies met inclusion criteria. Seventy-seven patients were treated with MMS for OCC, 74 of which (96%) were treated for squamous cell carcinoma. The tongue was the most common site (n=57). Other cancers treated with MMS include basal cell carcinoma and melanoma. Zero patients treated with MMS had recurrence of their disease during follow-up periods, which ranged from 8-42 months. Mohs technique did not cause statistically significant increase in operating time. 
Conclusion
MMS may be an effective treatment for OCC, especially for squamous cell carcinomas, and tumors involving the tongue. Potential challenges to the use of MMS in oral tumors include: difficulty of appropriate visualization and operation in the oral cavity, the ability of Mohs surgeons to interpret histopathology from oral specimens, and the availability of labs that can process oral tissue for real-time analysis. These challenges may be overcome with stronger interdisciplinary collaboration among oral disease specialists, and the development of additional best-practice recommendations that can facilitate improved education of providers.






Systematic review of benefits and practical challenges for use of Mohs surgery in oral tumors

The authors present the case of a 29-year-old female diagnosed with acute appendicitis who underwent a laparoscopic appendectomy. Three weeks later, she returned to the emergency department with fevers, abdominal pain, chills, and nausea. Laboratory analysis revealed elevated liver enzymes and leukocytosis, and a computed tomography scan of the abdomen revealed a liver abscess. Interventional radiology placed an 8 French drainage catheter in the hepatic abscess and drained 40cc of purulent fluid. A culture of the abscess fluid revealed Streptococcus constellatus, Bacteroides fragilis, and Bacteroides ovatus. We believe appendicitis causes hematogenous spreading of bowel organisms along the portal vein, which is seeded to the liver.

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Sodium-glucose transporter 2 inhibitors in patients with heart failure: a network meta-analysis

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