Ambulatory Surgery Centers Reduce Patient Out-of-Pocket Expenditures for Isolated Arthroscopic Rotator Cuff Repair, but Patient Out-of-Pocket Expenditures Are Increasing at a Faster Rate Than Total Healthcare Utilization Reimbursement From Payers.

PURPOSE: To categorize and trend annual out-of-pocket expenditures for arthroscopic rotator cuff repair (RCR) patients relative to total healthcare utilization (THU) reimbursement and compare drivers of patient out-of-pocket expenditures (POPE) in a granular fashion via analyses by insurance type and surgical setting. METHODS: Patients who underwent outpatient arthroscopic RCR in the United States from 2013 to 2018 were identified from the IBM MarketScan Database. Primary outcome variables were total POPE and THU reimbursement, which were calculated for all claims in the 9-month perioperative period. Trends in outcome variables over time and differences across insurance types were analyzed. Multivariable analysis was performed to investigate drivers of POPE. RESULTS: A total of 52,330 arthroscopic RCR patients were identified. Between 2013 and 2018, median POPE increased by 47.5% ($917 to $1,353), and median THU increased by 9.3% ($11,964 to $13,076). Patients with high deductible insurance plans paid $1,910 toward their THU, 52.5% more than patients with preferred provider plans ($1,253, P = .001) and 280.5% more than patients with managed care plans ($502, P = .001). All components of POPE increased over the study period, with the largest observed increase being POPE for the immediate procedure (P = .001). On multivariable analysis, out-of-network facility, out-of-network surgeon, and high-deductible insurance most significantly increased POPE. CONCLUSIONS: POPE for arthroscopic RCR increased at a higher rate than THU over the study period, demonstrating that patients are paying an increasing proportion of RCR costs. A large percentage of this increase comes from increasing POPE for the immediate procedure. Out-of-network facility status increased POPE 3 times more than out-of-network surgeon status, and future cost-optimization strategies should focus on facility-specific reimbursements in particular. Last, ambulatory surgery centers (ASCs) significantly reduced POPE, so performing arthroscopic RCRs at ASCs is beneficial to cost-minimization efforts. CLINICAL RELEVANCE: This study highlights that although payers have increased reimbursement for RCR, patient out-of-pocket expenditures have increased at a much higher rate. Furthermore, this study elucidates trends in and drivers of patient out-of-pocket payments for RCR, providing evidence for development of cost-optimization strategies and counseling of patients undergoing RCR.

The Effect of Intraoperative Overdistraction on Subsidence Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to evaluate the effect of overdistraction on interbody cage subsidence. BACKGROUND: Vertebral overdistraction due to the use of large intervertebral cage sizes may increase the risk of postoperative subsidence. METHODS: Patients who underwent anterior cervical discectomy and fusion between 2016 and 2021 were included. All measurements were performed using lateral cervical radiographs at 3 time points - preoperative, immediate postoperative, and final follow-up >6 months postoperatively. Anterior and posterior distraction were calculated by subtracting the preoperative disc height from the immediate postoperative disc height. Cage subsidence was calculated by subtracting the final follow-up postoperative disc height from the immediate postoperative disc height. Associations between anterior and posterior subsidence and distraction were determined using multivariable linear regression models. The analyses controlled for cage type, cervical level, sex, age, smoking status, and osteopenia. RESULTS: Sixty-eight patients and 125 fused levels were included in the study. Of the 68 fusions, 22 were single-level fusions, 35 were 2-level, and 11 were 3-level. The median final follow-up interval was 368 days (range: 181-1257 d). Anterior disc space subsidence was positively associated with anterior distraction (beta = 0.23; 95% CI: 0.08, 0.38; P = 0.004), and posterior disc space subsidence was positively associated with posterior distraction (beta = 0.29; 95% CI: 0.13, 0.45; P < 0.001). No significant associations between anterior distraction and posterior subsidence (beta = 0.07; 95% CI: -0.06, 0.20; P = 0.270) or posterior distraction and anterior subsidence (beta = 0.06; 95% CI: -0.14, 0.27; P = 0.541) were observed. CONCLUSIONS: We found that overdistraction of the disc space was associated with increased postoperative subsidence after anterior cervical discectomy and fusion. Surgeons should consider choosing a smaller cage size to avoid overdistraction and minimize postoperative subsidence.

Performance of a Large Language Model in the Generation of Clinical Guidelines for Antibiotic Prophylaxis in Spine Surgery.

OBJECTIVE: Large language models, such as chat generative pre-trained transformer (ChatGPT), have great potential for streamlining medical processes and assisting physicians in clinical decision-making. This study aimed to assess the potential of ChatGPT's 2 models (GPT-3.5 and GPT-4.0) to support clinical decision-making by comparing its responses for antibiotic prophylaxis in spine surgery to accepted clinical guidelines. METHODS: ChatGPT models were prompted with questions from the North American Spine Society (NASS) Evidence-based Clinical Guidelines for Multidisciplinary Spine Care for Antibiotic Prophylaxis in Spine Surgery (2013). Its responses were then compared and assessed for accuracy. RESULTS: Of the 16 NASS guideline questions concerning antibiotic prophylaxis, 10 responses (62.5%) were accurate in ChatGPT's GPT-3.5 model and 13 (81%) were accurate in GPT-4.0. Twenty-five percent of GPT-3.5 answers were deemed as overly confident while 62.5% of GPT-4.0 answers directly used the NASS guideline as evidence for its response. CONCLUSION: ChatGPT demonstrated an impressive ability to accurately answer clinical questions. GPT-3.5 model's performance was limited by its tendency to give overly confident responses and its inability to identify the most significant elements in its responses. GPT-4.0 model's responses had higher accuracy and cited the NASS guideline as direct evidence many times. While GPT-4.0 is still far from perfect, it has shown an exceptional ability to extract the most relevant research available compared to GPT-3.5. Thus, while ChatGPT has shown far-reaching potential, scrutiny should still be exercised regarding its clinical use at this time.

Sclerotherapy of the Post renal Transplant Lymphoceles: A Meta-Analysis.

PURPOSE: This study evaluated the effectiveness of sclerotherapy in treating lymphoceles after kidney transplantation, focusing on factors such as recurrence rates and procedural success. MATERIALS AND METHODS: Retrospective studies using sclerotherapy as the only form of treatment for postrenal transplant lymphoceles were included. All studies used percutaneous transcatheter sclerotherapy as treatment, and the success rate of the intervention was recorded. Sixty-one references were obtained by manually searching the MEDLINE (n = 20), Embase (n = 41), and Cochrane Library databases (n = 0) for retrospective research studies that included the keywords "sclerotherapy post renal transplant lymphoceles." After removing 3 duplicates, 50 of the remaining articles were excluded after the screening, and the remaining studies were extracted for demographic data and our primary outcome of the success rate of sclerotherapy. RESULTS: A descriptive analysis of the outcomes and complication rates associated with sclerotherapy interventions for lymphoceles is provided. A high degree of variation across the different studies was observed. According to the Kruskal-Wallis test, there was no correlation between the sclerosant used and the sclerotherapy complication rate (P = .472) or the success rate (P = .591). There was also no correlation between the gender of the patient and the success rate; however, there was a significant difference in the complication rate by gender (P < .005). CONCLUSIONS: In conclusion, different sclerosant products have been used for therapy with no consensus on the most efficacious product because the success rate has been variable. In addition, the gender of the patient may influence the complication rates associated with sclerotherapy for lymphoceles in patients post-kidney transplant.

Increased rate of out-of-network surgeon selection for hip arthroscopy compared to more common orthopedic sports procedures.

Background: Demand for hip arthroscopy (HA) has increased, but shortfalls in HA training may create disparities in care access. This analysis aimed to (1) compare out-of-network (OON) surgeon utilization for HA with that of more common orthopedics sports procedures, including rotator cuff repair (RCR), partial meniscectomy (PM), and anterior cruciate ligament reconstruction (ACLR), (2) compare the HA OON surgeon rate with another less commonly performed procedure, meniscus allograft transplant (MAT), and (3) analyze trends and predictors of OON surgeon utilization. Methods: The 2013-2017 IBM MarketScan database identified patients under 65 who underwent HA, RCR, PM, ACLR, or MAT. Demographic differences were determined using standardized differences. Cochran-Armitage tests analyzed trends in OON surgeon utilization. Multivariable logistic regression identified predictors of OON surgeon utilization. Statistical significance was set to p < 0.05 and significant standardized differences were >0.1. Results: 410,487 patients were identified, of which 12,636 patients underwent HA, 87,607 RCR, 233,241 PM, 76,700 ACLR, and 303 MAT. OON surgeon utilization increased for HA, rising from 7.98 % in 2013 to 9.37 % in 2017 (p = 0.026). Compared to RCR, PM, and ACLR, HA was associated with higher likelihood of OON surgeon utilization. Usage of ambulatory surgery centers (ASCs) was predictive of higher OON surgeon rates along with procedure year, insurance plan type, and geographic region. HA performed in an ASC was 13 % less likely to have an OON surgeon (p = 0.047). Conclusion: OON surgeon utilization generally declined but increased for HA. HA was a predictor of OON surgeon status, possibly because HA is a technically complicated procedure with fewer trained in-network providers. Other predictors of OON surgeon status included ASC usage, PPO/EPO plan type, and Northeast geographic region. There is a need to improve access to experienced HA providers-perhaps with prioritization of HA training in residency and fellowship programs-in order to address rising OON surgeon utilization.

CT and chest radiography in evaluation of mechanical circulatory support devices for acute heart failure.

Acute heart failure and cardiogenic shock are a major cause of morbidity and mortality in patients who have had recent cardiac surgery, myocardial infarct or pulmonary hypertension. The use of percutaneous mechanical circulatory support (MCS) devices before organ failure occurs can improve outcomes in these patients. Imaging plays a key role in identifying appropriate positioning of MCS devices for supporting ventricle function. These devices can be used for left ventricle, right ventricle or biventricular support. Fluoroscopy, angiography and echocardiography are used for implanting these devices. Radiographs and CT can identify both intra- and extra-cardiac complications. The cardiothoracic imager will see increasing use of these devices and familiarity with their normal appearance and complications is important. CRITICAL RELEVANCE STATEMENT: Chest radiographs and CT are useful for assessing the position of the mechanical cardiac support device used for treatment of acute heart failure. CT can identify cardiac and extra-cardiac complications associated with these devices. KEY POINTS: IABP upper/distal marker should be 2-3 cm distal to the ostia of the left subclavian artery. Inlet of Impella CP should be 3.5 cm below the aortic valve. The Impella 5.5 does not have a pigtail portion. The inlet should be about 5 cm below the aortic annulus. Impella RP inlet port should be in the right atrium or inferior vena cava, the pigtail portion should be positioned in the main pulmonary artery. Protek Duo inflow is in the right atrium or right ventricle. The outflow is in the main pulmonary artery.

Direct percutaneous puncture versus transarterial embolization for head and neck paragangliomas: A systematic review and meta-analysis.

INTRODUCTION: Embolization of head and neck paragangliomas (HNPs) is a well-established treatment strategy and adjunctive therapy. However, the optimal mode of intervention, whether by direct percutaneous puncture (DP) or via transarterial embolization (TAE), remains unclear. METHODS: The aim of this study was to complete a systematic literature review and meta-analysis to compare the safety and efficacy of DP versus TAE for HNP embolization. The Cochrane Library and MEDLINE databases were used to identify studies describing the clinical outcomes of either DP or TAE for HNP embolization. Outcome measures included: complete angiographic devascularization, major complications, and minor complications. Pooled rates were calculated for each variable which were then compared with meta-regression using a random effects model. RESULTS: Thirty-one retrospective studies met inclusion criteria, detailing 394 patients with 411 HNPs. Overall, DP was associated with a higher rate of complete devascularization (91.5%, 95% confidence interval [CI]: 85.6% to 97.4%; I2 = 0%) when compared to TAE technique (40.1%, CI: 27.2% to 58.9%; I2 = 93%). However, there was no difference regarding major complication rates between DP (6%, CI:1.3% to 10.8%; I2 = 0%) and TAE for HNP embolization (3.3%, CI: 1.4% to 5.3%; I2 = 0%) (p = 0.370), nor in minor complications between the techniques (p = 0.211). Subgroup analysis of TAE embolic agents revealed that particle embolics were associated with a significantly lower rate of major complications (2.5%; 0.4% to 4.6%; I2 = 0%) when compared to liquid embolics (10.6%, CI:4% to 17.3%; I2 = 48%; p = 0.022). CONCLUSIONS: A DP approach for HNP embolization results in a higher rate of complete devascularization and with a similar complication profile when compared to TAE. These findings also suggest that particle embolics are associated with fewer major complications compared to liquid embolics when TAE is utilized.

Use of Glycoprotein IIb-IIIa Inhibitors in Patients Undergoing Carotid Artery Stenting in the Vascular Quality Initiative.

BACKGROUND: Antiplatelet therapies with thromboxane inhibitors and adenosine 5'-diphosphate antagonists have been widely used following carotid artery stenting (CAS). However, these therapies may not apply to patients who are intolerant or present acutely. Glycoprotein IIb/IIIa inhibitors (GPI) are a proposed alternative therapy in these patients; however, their use has been limited due to concerns of increased risk for intracranial bleeding. Thus, this study aims to assess the safety profile of GPI in patients undergoing CAS. METHODS: All patients undergoing CAS in the Society of Vascular Surgery - Vascular Quality Initiative database from 2012 to 2021 was included and grouped into GPI versus non-GPI therapy (control). The primary outcome was in-hospital stroke or death, and secondary outcomes included in-hospital stroke/transient ischemic attack (TIA), death, myocardial infarction, and intracranial hemorrhage (ICH)/seizure. Patients were stratified by surgical approach (Transcarotid artery revascularization using flow reversal (TCAR) and transfemoral carotid artery stenting), and stepwise backward logistic regression analysis was conducted to evaluate major primary and secondary outcomes. RESULTS: A total of 50,628 patients underwent carotid revascularization. Of these, 4.4% of the patients received GPI. Mean age was similar between control versus GPI (71.35(9.67) vs. 71.36(10.20) years). Compared to the control group, patients who receive GPI are less likely to be on optimal medical therapy, including aspirin (83.0% vs. 88.1%), P2Y12 inhibitor (73.0% vs. 82.7%), and statin (82.3% vs. 86.0%) (All P < 0.05). In addition, patients in the GPI group were more likely to undergo TCAR for carotid revascularization (52.2% vs. 48.4%) for emergent/urgent (29.4% vs. 16.8%) and symptomatic indications (55.5% vs. 49.7%) (All P < 0.001). After stratifying by surgical approach, if patients underwent TFCAS and received a GPI, they were at increased odds of developing stroke/death (1.77(1.25-2.51)), death (odds ratio (OR) (95% CI): 1.67(1.07-2.61)), stroke/TIA (OR (95% confidence interval (CI)): 1.65(1.09-2.51)), and ICH/seizure (OR (95% CI): 2.13(1.23-3.68)) (All P < 0.05). No difference was seen in outcomes between the 2 groups if undergoing TCAR. CONCLUSIONS: Patients who receive GPI were more likely to be symptomatic at presentation and less likely to be medically optimized before their carotid revascularization. Transfemoral access in patients receiving GPI was associated with increased odds of morbidity and mortality. However, this was not observed if undergoing TCAR. TCAR can be considered for its overall favorable results in high-risk patients who are not medically optimized.

Thromboembolic prophylaxis in spine surgery: an analysis of ChatGPT recommendations.

BACKGROUND CONTEXT: Venous thromboembolism is a negative outcome of elective spine surgery. However, the use of thromboembolic chemoprophylaxis in this patient population is controversial due to the possible increased risk of epidural hematoma. ChatGPT is an artificial intelligence model which may be able to generate recommendations for thromboembolic prophylaxis in spine surgery. PURPOSE: To evaluate the accuracy of ChatGPT recommendations for thromboembolic prophylaxis in spine surgery. STUDY DESIGN/SETTING: Comparative analysis. PATIENT SAMPLE: None. OUTCOME MEASURES: Accuracy, over-conclusiveness, supplemental, and incompleteness of ChatGPT responses compared to the North American Spine Society (NASS) clinical guidelines. METHODS: ChatGPT was prompted with questions from the 2009 NASS clinical guidelines for antithrombotic therapies and evaluated for concordance with the clinical guidelines. ChatGPT-3.5 responses were obtained on March 5, 2023, and ChatGPT-4.0 responses were obtained on April 7, 2023. A ChatGPT response was classified as accurate if it did not contradict the clinical guideline. Three additional categories were created to further evaluate the ChatGPT responses in comparison to the NASS guidelines: over-conclusiveness, supplementary, and incompleteness. ChatGPT was classified as over-conclusive if it made a recommendation where the NASS guideline did not provide one. ChatGPT was classified as supplementary if it included additional relevant information not specified by the NASS guideline. ChatGPT was classified as incomplete if it failed to provide relevant information included in the NASS guideline. RESULTS: Twelve clinical guidelines were evaluated in total. Compared to the NASS clinical guidelines, ChatGPT-3.5 was accurate in 4 (33%) of its responses while ChatGPT-4.0 was accurate in 11 (92%) responses. ChatGPT-3.5 was over-conclusive in 6 (50%) of its responses while ChatGPT-4.0 was over-conclusive in 1 (8%) response. ChatGPT-3.5 provided supplemental information in 8 (67%) of its responses, and ChatGPT-4.0 provided supplemental information in 11 (92%) responses. Four (33%) responses from ChatGPT-3.5 were incomplete, and 4 (33%) responses from ChatGPT-4.0 were incomplete. CONCLUSIONS: ChatGPT was able to provide recommendations for thromboembolic prophylaxis with reasonable accuracy. ChatGPT-3.5 tended to cite nonexistent sources and was more likely to give specific recommendations while ChatGPT-4.0 was more conservative in its answers. As ChatGPT is continuously updated, further validation is needed before it can be used as a guideline for clinical practice.

TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques.

The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.

Microsatellite Instability-High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles.

PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix.

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.

Recurrent MED12 exon 2 mutations in benign breast fibroepithelial lesions in adolescents and young adults.

AIMS: Most benign breast fibroepithelial lesions (FEL) in adults harbour recurrent somatic MED12 exon 2 mutations and rare TERT promoter hotspot mutations. We sought to determine the frequency of MED12 exon 2 and TERT promoter hotspot mutations in fibroadenomas (FA) and benign phyllodes tumours (BePT) in adolescents and young adults. METHODS: DNA from 21 consecutive FAs and eight consecutive BePTs in adolescents and young adults was subjected to Sanger sequencing of the exon 2 of MED12 and the TERT promoter hotspot locus. RESULTS: We identified MED12 exon 2 mutations in 62% and 88% of FAs and BePTs, respectively, and no TERT promoter hotspot mutations. The majority of the MED12 exon 2 mutations identified were in-frame deletions (60%). CONCLUSIONS: As in adults, benign FELs in juvenile patients harbour recurrent MED12 exon 2 mutations.

Role of cytokine agonists and immune checkpoint inhibitors toward HIV remission.

PURPOSE OF REVIEW: The current article describes the current status of the use of cytokines and immune-checkpoint inhibitors as therapeutic strategies toward HIV remission. RECENT FINDINGS: Clinical trials using IL-2 and IL-7 showed increased levels of circulating T cells, although no reduction to the viral reservoir was observed. Studies in nonhuman primates (NHP) demonstrated that experimental IL-15 administration increased proliferation and cytotoxicity of simian immunodeficiency virus (SIV)-specific CD8 T cells, and promoted their localization to the lymph node (LN) B cell follicles. Immune checkpoint modulators targeting programed cell death-1 and cytotoxic T-lymphocyte associated protein 4, successfully used in oncologic diseases, have shown potential to restore HIV-specific function in early stage clinical trials, while also transiently increasing plasma and cell-associated viral RNA. Due to the complexity of the mechanisms regulating HIV persistence, it is very likely that combinatorial approaches, including cytokines with immune checkpoint blockades (ICBs), will be needed to achieve HIV remission. SUMMARY: The present review covers approaches based on cytokine agonists and immune checkpoint inhibitors that have shown promise toward therapeutic pathways for HIV remission. These strategies have been tested preclinically in animal models of HIV infection to determine their safety, activity, and mechanisms of action, with the goal to inform the design of the most synergistic combinatorial strategies. Several of these interventions are included in ongoing or planned clinical trials in HIV infection; these trials will elucidate the clinical efficacy of these innovative immunotherapy approaches toward HIV remission.

Bone Marrow-Derived CD4+ T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir.

The bone marrow (BM) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature T cells. However, very little is known on the phenotype of BM-derived CD4+ T cells, their fate during simian immunodeficiency virus (SIV) infection, and their contribution to viral persistence during antiretroviral therapy (ART). In this study, we characterized the immunologic and virologic status of BM-derived CD4+ T cells in rhesus macaques prior to SIV infection, during the early chronic phase of infection, and during ART. We found that BM memory CD4+ T cells are significantly depleted following SIV infection, at levels that are similar to those measured in the peripheral blood (PB). In addition, BM-derived memory CD4+ T cells include a high frequency of cells that express the coinhibitory receptors CTLA-4 and PD-1, two subsets previously shown to be enriched in the viral reservoir; these cells express Ki-67 at levels similar to or higher than the same cells in PB. Finally, when we analyzed SIV-infected RMs in which viral replication was effectively suppressed by 12 months of ART, we found that BM CD4+ T cells harbor SIV DNA and SIV RNA at levels comparable to those of PB CD4+ T cells, including replication-competent SIV. Thus, BM is a largely understudied anatomic site of the latent reservoir which contributes to viral persistence during ART and needs to be further characterized and targeted when designing therapies for a functional or sterilizing cure to HIV.IMPORTANCE The latent viral reservoir is one of the major obstacles in purging the immune system of HIV. It is paramount that we elucidate which anatomic compartments harbor replication-competent virus, which upon ART interruption results in viral rebound and pathogenesis. In this study, using the rhesus macaque model of SIV infection and ART, we examined the immunologic status of the BM and its role as a potential sanctuary for latent virus. We found that the BM compartment undergoes a similar depletion of memory CD4+ T cells as PB, and during ART treatment the BM-derived memory CD4+ T cells contain high levels of cells expressing CTLA-4 and PD-1, as well as amounts of cell-associated SIV DNA, SIV RNA, and replication-competent virus comparable to those in PB. These results enrich our understanding of which anatomic compartments harbor replication virus and suggest that BM-derived CD4+ T cells need to be targeted by therapeutic strategies aimed at achieving an HIV cure.