LiF-MS+, a revised technique for mapping peptide-protein interactions.

Short linear motifs are sequences of amino acids present in unstructured polypeptide regions that function as ligands for specific sites on folded protein domains. These interactions, which often occur with low to modest affinity, modulate dynamic biological processes such as signal transduction and membrane trafficking. We recently described Ligand Footprinting-Mass Spectrometry (LiF-MS), a technique that rapidly and precisely maps sites at which short peptide ligands bind their biologically relevant recognition sites on folded protein domains. This approach marks the binding location of a peptide ligand on a structured protein using a cleavable crosslinker appended to the ligand that leaves behind a stable chemical modification following cleavage. This modification serves as a mass tag detectable by mass spectrometry, pinpointing sites of peptide ligand binding. Here we present LiF-MS+, an improved version of the footprinting technique that replaces the butanol mass tag with 1-butylpyrrolidine, which is positively charged at neutral pH and thus aids in ionization of the crosslinked peptide for analysis by mass spectrometry. We show ligand-mediated butylpyrrolidine footprinting effectively maps the well characterized binding interaction of the p38α mitogen-activated protein kinase (MAPK) with a MKK6 D-motif short linear motif peptide ligand, uncovering additional binding site information not observed in our original experiment. LiF-MS+ is thus a straightforward improvement of our previously published methodology for mapping the binding of short linear motifs to folded protein domains.

2-Year Clinical and Echocardiography Follow-Up of Transcatheter Mitral Valve Replacement With the Transapical Intrepid System.

BACKGROUND: Thirty-day outcomes with the investigational Intrepid transapical (TA) transcatheter mitral valve replacement (TMVR) system have previously demonstrated good technical success, but longer-term outcomes in larger cohorts need to be evaluated. OBJECTIVES: The authors sought to evaluate the 2-year safety and performance of the Intrepid TA-TMVR system in patients with symptomatic, ≥moderate-severe mitral regurgitation (MR) and high surgical risk. METHODS: Patient eligibility was determined by local heart teams and approved by a central screening committee. Clinical events were adjudicated by an independent clinical events committee. Echocardiography was evaluated by an independent core laboratory. RESULTS: The cohort included 252 patients that were enrolled at 58 international sites before February 2021 as part of the global Pilot Study (n = 95) or APOLLO trial (primary cohort noneligible + TA roll-ins, n = 157). Mean age was 74.2 years, mean STS-PROM was 6.3%, 60.3% were male, and 80.6% were in NYHA functional class III/IV. Most presented with secondary MR (70.1%), and nearly all had ≥moderate-severe MR (98.4%). All-cause mortality was 13.1% (30-day), 27.3% (1-year), and 36.2% (2-year). The 30-day ≥major bleeding event rate was 22.3%. Heart failure rehospitalization was 9.6% (30-day) and 36.2% (2-year). At 2 years, >50% of patients were alive with improvement in NYHA functional class (82.1%, class I/II), and all patients with available echocardiograms had ≤mild MR. CONCLUSIONS: This analysis represents the largest reported TA-TMVR experience with the longest follow-up in high-risk ≥moderate-severe MR patients. Early mortality and heart failure rehospitalizations were significant, exacerbated by early TA-related bleeding events; however, meaningful improvements in clinical outcomes and marked reductions in MR severity were observed through 2 years.

Five-Year Follow-Up from the CoreValve Expanded Use Transcatheter Aortic Valve-in-Surgical Aortic Valve Study.

Transcatheter aortic valve replacement (TAVR) provides an option for extreme-risk patients who underwent reoperation for a failed surgical aortic bioprosthesis. Long-term data on patients who underwent TAVR within a failed surgical aortic valve (TAV-in-SAV) are limited. The CoreValve Expanded Use Study evaluated patients at extreme surgical risk who underwent TAV-in-SAV. Outcomes at 5 years were analyzed by SAV failure mode (stenosis, regurgitation, or combined). Echocardiographic outcomes are site-reported. TAV-in-SAV was attempted in 226 patients with a mean age of 76.7 ± 10.8 years; 63.3% were male, the Society of Thoracic Surgeons predicted risk of mortality score was 9.0 ± 6.7%, and 87.5% had a New York Heart Association classification III or IV symptoms. Most of the failed surgical bioprostheses were stented (81.9%), with an average implant duration of 10.2 ± 4.3 years. The 5-year all-cause mortality or major stroke rate was 47.2% in all patients; 54.4% in the stenosis, 37.6% in the regurgitation, and 38.0% in the combined groups (p = 0.046). At 5 years, all-cause mortality was higher in patients with versus without 30-day severe prosthesis-patient mismatch (51.7% vs 38.3%, p = 0.026). The overall aortic valve reintervention rate was 5.9%; highest in the regurgitation group (12.6%). The mean aortic valve gradient was 14.1 ± 9.8 mm Hg and effective orifice area was 1.57 ± 0.70 at 5 years. Few patients had >mild paravalvular regurgitation at 5 years (5.5% moderate, 0.0% severe). TAV-in-SAV with supra-annular, self-expanding TAVR continues to represent a safe and lasting intermediate option for extreme-risk patients who have appropriate sizing of the preexisting failed surgical valve. Clinical and hemodynamic outcomes were stable through 5 years.

1-Year Outcomes Following Transfemoral Transseptal Transcatheter Mitral Valve Replacement: Intrepid TMVR Early Feasibility Study Results.

BACKGROUND: High surgical risk may preclude mitral valve replacement in many patients. Transcatheter mitral valve replacement (TMVR) using transfemoral transseptal access is a novel technology for the treatment of mitral regurgitation (MR) in high-risk surgical patients. OBJECTIVES: This analysis evaluates 30-day and 1-year outcomes of the Intrepid TMVR Early Feasibility Study in patients with ≥moderate-severe MR. METHODS: The Intrepid TMVR Early Feasibility Study is a multicenter, prospective, single-arm study. Clinical events were adjudicated by a clinical events committee; endpoints were defined according to Mitral Valve Academic Research Consortium criteria. RESULTS: A total of 33 patients, enrolled at 9 U.S. sites between February 2020 and August 2022, were included. The median age was 80 years, 63.6% of patients were men, and mean Society of Thoracic Surgeons Predicted Risk of Mortality for mitral valve replacement was 5.3%. Thirty-one (93.9%) patients were successfully implanted. Median postprocedural hospitalization length of stay was 5 days, and 87.9% of patients were discharged to home. At 30 days, there were no deaths or strokes, 8 (24.2%) patients had major vascular complications and none required surgical intervention, there were 4 cases of venous thromboembolism all successfully treated without sequelae, and 1 patient had mitral valve reintervention for severe left ventricular outflow tract obstruction. At 1 year, the Kaplan-Meier all-cause mortality rate was 6.7%, echocardiography showed ≤mild valvular MR, there was no/trace paravalvular leak in all patients, median mitral valve mean gradient was 4.6 mm Hg (Q1-Q3: 3.9-5.3 mm Hg), and 91.7% of survivors were in NYHA functional class I/II with a median 11.4-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. CONCLUSIONS: The early benefits of the Intrepid transfemoral transseptal TMVR system were maintained up to 1 year with low mortality, low reintervention, and near complete elimination of MR, demonstrating a favorable safety profile and durable valve function.

Intracorporeal Vessel Ligation in Laparoscopic Right Colectomy for Cancer is Associated with Increased Lymph Node Yield.

BACKGROUND: This study aimed to compare intra- and extracorporeal division of the vascular pedicle in laparoscopic right colectomy regarding pathological outcomes, short-term morbidity, and local recurrence and distant metastases. METHODS: Retrospective analysis of an IRB-approved database of all patients who underwent laparoscopic right colectomy for cancer between 01/2011 and 08/2021. Main outcome measures were number of harvested lymph nodes, length of resected colon, R1 rate, positive lymph node ratio, short-term post-operative morbidity, local recurrence, and distant metastases. RESULTS: Two-hundred seventy-one consecutive patients (136 males) patients underwent laparoscopic right hemicolectomy for cancer during the study period. Vessel ligation was intracorporeal in 171 (63%) and extracorporeal in 100 patients (37%); groups had similar baseline characteristics except for extent of resection as extended right hemicolectomy was significantly more often performed in the intracorporeal group. When the two groups were matched for the extent of resection (standard versus extended right hemicolectomy), the mean number of harvested lymph nodes (28.61 ± 12.04 versus 25.37 ± 10.06, p = 0.04) and median length of the resected colon [26.00 (IQR: 21.00, 32.00) versus 23.00 (IQR: 19.00, 27.00) cm, p = 0.003] were significantly higher in the intracorporeal than in the extracorporeal group. The intracorporeal group required a significantly longer operative time than did the extracorporeal group (168.94 ± 57.9 vs. 139.7 ± 41.3 mins, p = 0.001). No significant differences were noted between the groups in terms of ileus, hemorrhage, surgical site infection, re-operation rates, recurrence, or distant metastases. CONCLUSION: Intracorporeal vessel ligation in laparoscopic right hemicolectomy was associated with increased lymph node yield and longer specimens, although requiring longer operative times. Postoperative clinical outcomes were similar to outcomes in the extracorporeal ligation group.

Poly-4-hydroxybutyrate Mesh for Ventral Hernia Repairs: A Single-Surgeon Experience.

Background: Poly-4-hydroxybutyrate (P4HB) (Phasix) biosynthetic mesh was recently introduced as an alternative to synthetic and biologic meshes for ventral hernia repair (VHR). However, outcomes data are limited. This study aims to analyze outcomes of VHR with P4HB mesh and identify predictors of postoperative outcomes. Methods: We performed a retrospective study of adults who underwent open VHR with P4HB by the senior author from 2014 to 2020 with >12 months' follow-up. Subgroup comparisons and multivariate logistic regression were performed. Results: Inclusion criteria were met by 169 patients with a median of 15 months of follow-up. Overall, 21.9% had surgical site occurrences, 17.8% required reoperation, and 4.7% had recurrences. Patients with prior VHR (47.9%) experienced similar outcomes to those without. Patients with prior mesh infection (18.3%) had higher rates of postoperative mesh infection (6.5% vs 0.7%; P = .029) but did not have higher rates of reoperation. Retrorectus repairs (45.5%) had similar outcomes to onlay repairs (54.5%). Recurrence risk was increased by hypertension (odds ratio [OR] = 13.64; P = .046), immunosuppression (OR = 42.57; P = .004), and history of prior VHR (OR = 20.20; P = .014). Conclusions: This study aimed to analyze outcomes of VHR augmented with P4HB mesh through retrospective review. VHR with P4HB mesh produces acceptable recurrence rates with favorable complication risks compared with biologic and synthetic meshes. Predictors of recurrence include a history of prior hernia repair, hypertension, and immunosuppression. A history of prior mesh infection seems to place patients at risk for developing subsequent infection but did not increase need for reoperation.

TOR complex 1 negatively regulates NDR kinase Cbk1 to control cell separation in budding yeast.

The target of rapamycin (TOR) signalling pathway plays a key role in the coordination between cellular growth and the cell cycle machinery in eukaryotes. The underlying molecular mechanisms by which TOR might regulate events after anaphase remain unknown. We show for the first time that one of the 2 TOR complexes in budding yeast, TORC1, blocks the separation of cells following cytokinesis by phosphorylation of a member of the NDR (nuclear Dbf2-related) protein-kinase family, the protein Cbk1. We observe that TORC1 alters the phosphorylation pattern of Cbk1 and we identify a residue within Cbk1 activation loop, T574, for which a phosphomimetic substitution makes Cbk1 catalytically inactive and, indeed, reproduces TORC1 control over cell separation. In addition, we identify the exocyst component Sec3 as a key substrate of Cbk1, since Sec3 activates the SNARE complex to promote membrane fusion. TORC1 activity ultimately compromises the interaction between Sec3 and a t-SNARE component. Our data indicate that TORC1 negatively regulates cell separation in budding yeast by participating in Cbk1 phosphorylation, which in turn controls the fusion of secretory vesicles transporting hydrolase at the site of division.

A Novel Approach to Reducing Splash Exposure in Pulsatile Lavage.

Pulsatile lavage is utilized to copiously irrigate contaminated wounds; however, the current devices can cause significant splashing and increase the risk of contaminated fluid exposure to healthcare professionals. To create a larger splash guard for the standard pulsatile lavage device, we use heavy scissors to remove the end of a plastic light handle. We then place the nozzle of the lavage device through the open end to create a larger splash guard. This method provides a quick, accessible way to decrease the risk of splash exposure due to pulsatile lavage irrigation.

Prevention and Treatment of Nonfreezing Cold Injuries and Warm Water Immersion Tissue Injuries: Supplement to Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite.

We convened an expert panel to develop evidence-based guidelines for the evaluation, treatment, and prevention of nonfreezing cold injuries (NFCIs; trench foot and immersion foot) and warm water immersion injuries (warm water immersion foot and tropical immersion foot) in prehospital and hospital settings. The panel graded the recommendations based on the quality of supporting evidence and the balance between benefits and risks/burdens according to the criteria published by the American College of Chest Physicians. Treatment is more difficult with NFCIs than with warm water immersion injuries. In contrast to warm water immersion injuries that usually resolve without sequelae, NFCIs may cause prolonged debilitating symptoms, including neuropathic pain and cold sensitivity.

Early Thoracic Endovascular Aortic Repair of Uncomplicated Type B Thoracic Aortic Dissection: An Aorta Team Approach.

BACKGROUND: Although uncomplicated Type B aortic dissection (uTBAD) is traditionally treated with optimal medical therapy (OMT) as per guidelines, recent studies, performed primarily in interventional radiology or surgical operating rooms, suggest superiority of thoracic endovascular aortic repair (TEVAR) over OMT due to recent advancements in endovascular technologies. We report a large, single-center, case control study of TEVAR versus OMT in this population, undertaken solely in a cardiac catheterization laboratory (CCL) with a cardiologist and surgeon. We aimed to determine if TEVAR for uTBAD results in better outcomes compared with OMT. METHODS: This was a retrospective chart review of all patients with uTBAD during the last 13 years, with 46 cases (TEVAR group) and 56 controls (OMT group). RESULTS: In the TEVAR group, the procedure duration of 2.5 hours resulted in 100% procedural success for stent placement, with 63% undergoing protective left subclavian artery bypass, 0% mortality or stroke, and a lower readmission rate (1 vs. 2%; p = 0.04 in early TEVAR cases), but a longer length of stay (12.9 vs. 8.5 days: p = 0.006). The risk of all-cause long-term mortality was markedly reduced in the TEVAR group (RR = 0.38; p = 0.01), irrespective of early (<14 days) versus late intervention. On follow-up computed tomography imaging, the false lumen stabilized or decreased in 85% of cases, irrespective of intervention timing. CONCLUSION: TEVAR performed solely in the CCL is safe and effective, with lower all-cause mortality than OMT. These data, in collaboration with previous data on TEVAR in different settings, call for consideration of an update of practice guidelines.

Does Completeness of the Mesorectal Excision Still Correlate With Local Recurrence?

BACKGROUND: Total mesorectal excision is the standard surgical procedure for rectal cancer treatment. Several studies have shown a close correlation between the prognosis of patients with rectal cancer and the completeness of the mesorectal specimen. OBJECTIVE: To assess the correlation between macroscopic assessment of mesorectal excision and long-term oncological outcomes. DESIGN: Retrospective analysis of an Institutional Review Board-approved database. SETTINGS: Tertiary referral center. PATIENTS: Patients with rectal cancer who were operated on between March 2016 and October 2019 were classified into 3 groups based on the mesorectal specimen quality: complete, near complete, and incomplete. Only patients with a follow-up of ≥2 years and without signs of preoperative distant disease were included. MAIN OUTCOME MEASURES: Relationship between total mesorectal excision and local and distant recurrence rates in patients with rectal cancer. RESULTS: A total of 124 patients (35.5% females) were included in the analysis, with a mean age of 58.1 (SD 12) years and a mean BMI of 26.4 (SD 4.59) kg/m². Neoadjuvant chemoradiation was administered to 71% of patients, whereas 13.7% received total neoadjuvant therapy. Restorative procedures were performed in 107 patients (86.3%), whereas 17 patients (13.7%) underwent abdominoperineal resection. The majority of mesorectal excision specimens (87.09%) were complete or near complete. Local recurrence rates were 6.3% (1/16) in the incomplete and 7.4% (8/108) in the complete/near complete group ( p = 0.86). Metachronous distant metastases occurred in 6 patients (37.5%) in the incomplete group and in 24 patients (22.2%) in the complete/near complete group (p = 0.18). Thus, specimen quality did not appear to impact disease-free survival. LIMITATIONS: Retrospective, single-center study with relatively short follow-up. CONCLUSIONS: In the era of a multidisciplinary approach and extensive use of neoadjuvant therapy, macroscopic completeness of total mesorectal excision may not be as valuable a prognosticator as in the past. Larger studies with longer follow-ups are needed to clarify these preliminary findings. See Video Abstract at http://links.lww.com/DCR/C129. LA INTEGRIDAD DE LA ESCISIN MESORRECTAL TODAVA SE CORRELACIONA CON LA RECURRENCIA LOCAL: ANTECEDENTES:La escisión total desl mesorrecto es el estándar de oro para el tratamiento del cáncer de recto. Varios estudios han demostrado una estrecha correlación entre el pronóstico de los pacientes con cáncer de recto y la integridad espécimen mesorrectal.OBJETIVO:Evaluar la correlación entre la evaluación macroscópica de la escisión mesorrectal y los resultados oncológicos a largo plazo en pacientes con cáncer de recto.DISEÑO:Análisis retrospectivo de una base de datos aprobada por el IRB.ENTORNO CLINICO:El estudio se realizó en un centro de referencia terciario de una sola institución.PACIENTES:Todos los pacientes con cáncer de recto operados entre 3/2016-10/2019. Los pacientes se clasificaron en 3 grupos, según la calidad del espécimen mesorrectal: completo, casi completo e incompleto. Solo se incluyeron pacientes con seguimiento >2 años y sin signos de enfermedad a distancia preoperatoria.PRINCIPALES MEDIDAS DE RESULTADO:Identificar la relación entre la escisión mesorrectal total y las tasas de recurrencia local y a distancia en pacientes con cáncer de recto.RESULTADOS:Se incluyeron 124 pacientes (35,5% mujeres) con una edad media de 58,1 años (DE 12) y un índice de masa corporal medio de 26,4 (DE 4,59). Se administró quimiorradiación neoadyuvante al 71% de los pacientes, mientras que el 13,7% recibió terapia neoadyuvante total. Se realizaron procedimientos de restauración en 107 pacientes (86,3%), mientras que 17 pacientes (13,7%) se sometieron a resección abdominoperineal. La mayoría (87,09%) de los especímenes de escisión mesorrectal fueron completas o casi completas. Las tasas de recurrencia local fueron 1/16 (6,3%) en el grupo incompleto y 8/108 (7,4%) en el grupo completo/casi completo ( p = 0,86). Se produjeron metástasis a distancia metacrónicas en 6 pacientes (37,5%) en el grupo incompleto y 24 (22,2%) en el grupo completo/casi completo ( p = 0,18). Por lo tanto, la calidad del espécimen no pareció afectar la supervivencia libre de enfermedad.LIMITACIONES:Estudio retrospectivo de un solo centro con pequeño número de casos y seguimiento relativamente corto.CONCLUSIÓN:En la era de un enfoque multidisciplinario y el uso extensivo de la terapia neoadyuvante, la integridad macroscópica de la escisión total del mesorrecto, puede no ser un pronóstico tan valioso como en el pasado. Se necesitan estudios más amplios con períodos de seguimiento más prolongados para aclarar estos hallazgos preliminares. Consulte Video Resumen en http://links.lww.com/DCR/C129 . (Traducción-Dr. Fidel Ruiz Healy ).

Understanding public perception of bra size.

BACKGROUND: Breast cup size is often used in conversations between patients and their surgeons to communicate about goals and expectations for postoperative results. Cup size, however, is a poorly defined concept. The goal of this study was to assess whether the perception of breast cup size is consistent in a general population of survey respondents. METHODS: A survey consisting of a demographic questionnaire, personal bra use questionnaire, and 27 de-identified preoperative images of patient's breasts was administered to 500 respondents using the Amazon MTurk platform. Survey respondents were asked to guess the cup size for each of 27 patients. RESULTS: On average, respondents correctly identified the patient's reported cup size 43.32% of the time. Male and female respondents chose the same cup size for most breast images. Survey respondents who had professional fittings were significantly less likely to accurately identify cup size (38.75% vs. 42.67%, p = 0.02). Those who had a personal history of breast surgery were also less likely to choose correctly (36.92% vs. 43.86%, p < 0.01). CONCLUSION: The results of this study suggest that the perception of cup size is broadly similar across a general population sample. However, subgroups who would be expected to have more knowledge about and experience with breast sizing-including women who have had professional bra fittings and women who have had breast surgery-differ significantly in their perception of cup size. This suggests that cup size language should be used with caution in preoperative discussions between patients and their surgeons.

30-Day Outcomes Following Transfemoral Transseptal Transcatheter Mitral Valve Replacement: Intrepid TMVR Early Feasibility Study Results.

OBJECTIVES: The aim of this study was to evaluate outcomes of transcatheter mitral valve replacement (TMVR) with transfemoral access in patients at prohibitive or high surgical risk. BACKGROUND: Prohibitive surgical risk may preclude mitral valve replacement surgery in some patients. The investigational Intrepid TMVR system has previously been evaluated using transapical access for delivery of a self-expanding bioprosthetic valve. METHODS: This prospective, multicenter, nonrandomized early feasibility study evaluated the safety and performance of the Intrepid valve using transfemoral access enabling transseptal delivery in patients with moderate to severe or severe symptomatic mitral regurgitation at high surgical risk. Candidacy was determined by heart teams, with approval by a central screening committee. Echocardiographic data were evaluated by an independent core laboratory. Clinical events were adjudicated by a clinical events committee. RESULTS: Fifteen patients were enrolled at 6 sites from February 2020 to May 2021. The median age was 80 years, and median Society of Thoracic Surgeons Predicted Risk of Mortality was 4.7%; 87% of patients were men, and 53% had undergone prior sternotomy. Fourteen implants were successful. One patient was converted to surgery during the index procedure. Patients stayed a median of 5 days postprocedure. There were 6 access site bleeds (40%) and 11 iatrogenic atrial septal defect closures (73%). At 30 days, there were no deaths, strokes, or reinterventions. All patients undergoing implantation had trace or no valvular or paravalvular mitral regurgitation, and the mean gradient was 4.7 mm Hg (IQR: 3.0-6.7 mm Hg). CONCLUSIONS: Thirty-day results from the Intrepid transfemoral TMVR early feasibility study demonstrate excellent valve function and no mortality or stroke. Additional patients and longer follow-up are needed to confirm these findings. ([The Early Feasibility Study of the Intrepid™ TMVR Transseptal System]; NCT02322840).

A Case of Transcatheter Aortic Valve Implantation in a Centenarian Patient.

Calcified aortic stenosis has become the most common form of acquired valvular heart disease in very old patients. Despite this fact, a majority of these patients were turned down by surgery owing to a risk of mortality > 10% in patients older than 90 years. In recent years, transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic option for severe aortic stenosis. However, there is a paucity of data regarding the outcomes of TAVI in patients older than 100 years. We present the oldest patient who has undergone successful TAVI reported in the current literature.

Use of Absorbable Dermal Stapler in Reduction Mammoplasty: Assessing Technical, Quality-of-Life, and Aesthetics Outcomes.

INTRODUCTION: Reduction mammaplasty is a mainstay in the treatment of symptomatic macromastia, with a well-described positive impact on patient quality-of-life (QoL). Absorbable dermal staplers have the potential to improve the efficiency of skin closure in reduction mammoplasties, but a more comprehensive assessment of its impact on key outcomes has not been fully elucidated. METHODS: A retrospective review of patients undergoing reduction mammoplasty between November 2018 and December 2020 was conducted. Patients were included if they had undergone a wise-pattern reduction with a superomedial pedicle and completed 3 months of follow-up. Patient demographics, operative information, clinical and aesthetic outcomes, and QoL were compared between patients that had INSORB stapler-assisted and suture-only closures. RESULTS: Seventy-five patients met the inclusion criteria, with 34 patients (45%) in the stapler cohort. Total procedure time was significantly reduced with the use of the dermal stapler (stapler: 154 vs. suture: 170 minutes; p = 0.003). The incidence of major complications was similar between cohorts (stapler: 8.8% vs. suture: 12%; p = 0.64), as was the incidence of minor complications (stapler: 44% vs. suture: 41%; p = 0.82). Regardless of closure technique, patients demonstrated significant increases in all QoL domains (p <0.001). Lastly, 10 independent raters found no difference in the cosmetic appearance of breasts from either cohort, when judging overall breast appearance, shape, scars, volume and the nipple-areolar complex (all p > 0.05). CONCLUSIONS: The dermal stapler improves efficiency of closure during reduction mammoplasty without increasing the incidence of wound healing complications. Additionally, cosmetic outcomes are not affected, and patients demonstrate similar post-operative satisfaction with the result regardless of closure technique.

Breast Reconstruction in Inflammatory Breast Cancer: An Analysis of Predictors, Trends, and Survival from the National Cancer Database.

INTRODUCTION: Survival for women diagnosed with inflammatory breast cancer (IBC) has improved with advances in multimodal therapy. This study was performed to evaluate trends, predictors, and survival for reconstruction in IBC patients in the United States. METHODS: Women who underwent mastectomy with or without reconstruction for IBC between 2004 and 2016 were included from the National Cancer Database. Predictors for undergoing reconstruction and association with overall survival were determined. RESULTS: Of 12,544 patients with IBC who underwent mastectomy, 1307 underwent reconstruction. Predictors of reconstruction included younger age, private insurance, higher income, performance of contralateral prophylactic mastectomy, and location within a metropolitan area (P < 0.001). The proportion of women having reconstruction for IBC increased from 7.3% to 12.3% from 2004 to 2016. Median unadjusted overall survival was higher in the reconstructive group l [93.7 months, 95% confidence interval (CI) 75.2-117.5] than the nonreconstructive group (68.1 months, 95% CI 65.5-71.7, hazard ratio = 0.79 95% CI 0.72-0.88, P < 0.001). With adjustment for covariates, differences in overall mortality were not significant, with hazard ratio of 0.95 (95% CI 0.85-1.06, P = 0.37). CONCLUSIONS: Reconstruction rates for IBC are increasing. Women with IBC who undergo reconstruction tend to be younger and are not at the increased risk of all-cause mortality compared to those not having reconstruction. The National Cancer Database does not differentiate immediate from delayed reconstruction. However, the outcomes of immediate reconstruction in carefully selected patients with IBC should be further studied to evaluate its safety. This could impact current guidelines, which are based largely on an expert opinion.

Adapting virus filtration to enable intensified and continuous monoclonal antibody processing.

Ongoing efforts in the biopharmaceutical industry to enhance productivity and reduce manufacturing costs include development of intensified, linked, and/or continuous processes. One approach to improve productivity and process economics of the polishing step (i.e., anion exchange chromatography) is to preconcentrate the product intermediate using a single-pass tangential flow filtration step before loading on the resin. This intensification of the polishing step consequently leads to changes in product intermediate concentration for subsequent virus filtration operations, potentially impacting filter performance and methods for evaluating viral clearance. The filtrate flux performance of a virus filtration operation was evaluated with monoclonal antibody (mAb) solutions of varying concentrations. These data were used to evaluate the effect on filter sizing for a hypothetical mAb perfusion process. The optimum mAb concentration to minimize the area of the virus filter was a function of the filtration step duration and reflected the competing effects of increasing concentration and decreasing volumetric flux on the membrane productivity. mAb solutions at high and low concentrations were used to evaluate viral clearance with extended filtration times (e.g., 24-72 h) simulating continuous processing conditions. Modifications to more traditional filtration viral clearance study methods were required to avoid experimental artifacts associated with the extended filtration time. No virus passage through the filter was observed under these conditions, similar to previous results for batch processes. These data demonstrate the feasibility of obtaining effective virus removal even when mAb concentration and filtrations times are increased by up to an order of magnitude from current common practices.

Effect of complement C1-esterase inhibitor on brain edema and inflammation after mild traumatic brain injury in an animal model.

OBJECTIVE: Traumatic brain injury (TBI) is characterized by damage to the blood-brain barrier, inflammation, and edema formation. In this pilot study, we aimed to investigate the effects of a complement inhibitor, C1-esterase inhibitor (C1 INH), on brain edema and inflammation in a rat model of mild TBI. METHODS: Thirty-six male Sprague Dawley rats were randomly assigned to control, TBI, or TBI plus C1 INH groups. TBI and TBI plus C1 INH rats received an injection of saline or 25 IU/kg C1 INH, respectively, with TBI using a weight drop model. Control rats received saline only. Rats were subsequently euthanized and their brain tissue harvested for analysis. The primary outcome was the extent of edema as assessed by the brain's water content. Secondary outcomes included enzyme-linked immunosorbent assays to determine levels of pro-inflammatory mediators. RESULTS: Tumor necrosis factor-α levels were significantly greater in TBI rats than control rats, indicating that inflammation was generated by the weight drop impact. Brain water content following TBI was significantly different between TBI rats treated with C1-INH (78.7%±0.12), untreated TBI rats (79.3%±0.12), and control rats (78.6%±0.15, P=0.001). There was a significant decrease in C3a and interleukin 2 levels among C1 INH-treated rats compared with untreated TBI rats, but no change in levels of tumor necrosis factor-α and S100ß. CONCLUSION: C1-INH inhibited the complement pathway, suggesting that C1-INH may have a therapeutic benefit in TBI. Further studies are needed to investigate the effect of C1-INH on clinical outcomes.

Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation.

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1-/- mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1-/- mice, albeit with minimal mortality. Like Prf1-/- mice, immunopathology was largely rescued by CD8 depletion or interferon-γ (IFNg) blockade. Unlike Prf1-/- mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18-driven subclass of hyperinflammation.