Search

Competing Interests: Disclosure: Kellie Mathis has performed consulting for Tsumura and Becton Dickinson (safety oversight of clinical trials for ileus prevention and hernia prevention).

Background: The incidence of rectal cancer has decreased overall, but the incidence of early-onset rectal cancer (eoRC) has increased. Early-onset rectal cancer and late-onset rectal cancer (loRC) differ due to phenotypical, genetic characteristics, and higher stage presentations in eoRC. Thus, eoRC patients undergo more aggressive neoadjuvant treatments. This paper was designed to evaluate the impact of age on the pathological complete response rates in sporadic locally advanced rectal cancer., Methods: All patients with stage II-III rectal cancer who underwent neoadjuvant therapy and curative rectal resection between January 2018 and December 2023 were included and allocated to eoRC (<50 years) and loRC (≥50 years) groups based on their age at diagnosis., Results: A total of 381 patients were included (93 eoRC and 288 loRC). Preoperative radiological imaging revealed higher clinical nodal staging in the eoRC group (p = 0.002). A higher proportion of eoRC resulted in a pathological complete response compared with loRC (29% vs. 18.8%, p = 0.035). The rate of pathological complete response in eoRC and loRC did not differ between patients treated by total neoadjuvant therapy (TNT) and those treated by standard chemoradiotherapy (29.2% vs. 28.6%, p = 0.95 in eoRC and 21.7% vs. 25.9%, p = 0.097 in loRC). Multivariable analysis resulted in young age of onset (odds ratio 2.68; 95% confidence interval 1.11-6.51; p = 0.029) and KRAS wildtype (odds ratio 3.37; 95% confidence interval 1.25-9.07; p = 0.016) as being independent predictors of pathological complete response., Conclusions: Sporadic eoRC and KRAS wildtype tumors are predictive factors for pathological complete response in stage II-III rectal cancer., Competing Interests: Disclosure: Kellie Mathis—Consulting for Tsumura and Becton Dickinson (safety oversight if clinical trials for ileus prevention and hernia prevention), (© 2025. Society of Surgical Oncology.)

Anal Melanoma (AM) is a rare and aggressive disease lacking standardized treatment protocols. Despite advancements in medical oncology, the 5-year overall survival (OS) remains at 20%. Local surgery (LS) has gained popularity over radical surgery (RS) due to its comparable OS when negative margins are achieved. Neoadjuvant chemotherapy and radiotherapy do not improve margins status, while neoadjuvant immunotherapy (Neo-IT) has not been studied on AM margins status. Patients diagnosed with AM in the National Cancer Database (2011-2021) who received Neo-IT were retrospectively identified and divided into two cohorts based on the surgical approach (LS or RS). In each cohort, patients were matched in a 1:1 ratio to those who did not receive Neo-IT based on age and tumor size. Univariate analyses were performed to compare Neo-IT influence on surgical margins in both cohorts. Thirty patients were included in the LS cohort, with 56.7% of positive margins. Univariate analysis revealed that Neo-IT did not improve surgical margins in LS in AM (p value = 0.713). However, the 22 RS (31.8% positive margins) patient cohort's univariate analysis revealed that Neo-IT significantly improved surgical margins in AM (p value = 0.022). Achieving negative margins is crucial to increase OS in anal melanoma. Neo-IT appears to improve negative surgical margin status in RS for anal melanoma. However, Neo-IT did not improve margins in LS. This opportunity to improve margin suggests a potential to increase the 5-year OS of 20%. Future work is needed to determine the impact to OS and confirm the IT role in LS., Competing Interests: Declarations. Conflict interest: The authors have no relevant financial or non-financial interests to disclose. The authors have nothing to disclose. Ethical approval: This study was approved by the institutional review board. Research involving human participants and animal: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent for this type of study is not required., (© 2024. Italian Society of Surgery (SIC).)

Background: Ulcerative colitis, total colectomy, and tofacitinib have all been associated with an increased risk of venous thromboembolism., Objective: To determine whether preoperative tofacitinib exposure increases venous thromboembolism or other postoperative complications among patients with ulcerative colitis undergoing subtotal colectomy, total colectomy, or total proctocolectomy., Design: Retrospective, case-controlled study at a single institution., Settings: A tertiary referral center., Patients: Adult patients with ulcerative colitis undergoing subtotal colectomy, total colectomy, or total proctocolectomy after 2018 who were taking tofacitinib within 30 days of surgery (n = 56) were compared to age- and sex-matched patients with ulcerative colitis undergoing the same surgeries but who were not exposed to tofacitinib (n = 56)., Main Outcome Measure: The primary outcome was differences in the incidence of venous thromboembolism within 90 days of surgery based on tofacitinib exposure. Secondary outcomes were 90-day postoperative complications., Results: Groups were well matched for age (non-tofacitinib: mean 35.2 years [SD 12.0], tofacitinib: 35.9 [SD 12.1], p = 0.36) and sex (41% women in each group, p = 1.00). Medical characteristics were similar between groups except for biological medication exposure 30 days before surgery (non-tofacitinib: 66%, tofacitinib: 36%, p = 0.004). Surgical characteristics did not differ between groups. Most patients were discharged on extended venous thromboembolism prophylaxis (non-tofacitinib: 80% and tofacitinib: 77%). Adjusted for biological exposure, there were no statistically significant differences in venous thromboembolism (non-tofacitinib exposed: 14%, tofacitinib exposed: 4%, p = 0.09) or other postoperative outcomes., Limitation: Retrospective, single institutional study., Conclusions: Among patients with ulcerative colitis undergoing total colectomy or proctocolectomy, exposure to tofacitinib was not associated with an increased risk of venous thromboembolism or other postoperative complications. See Video Abstract ., La Exposicin a Tofacitinib No Aumenta Las Complicaciones Posoperatorias Entre Pacientes Con Colitis Ulcerosa Sometidos a Colectoma Total Un Estudio Retrospectivo De Casos Y Controles: ANTECEDENTES:La colitis ulcerosa, la colectomía total y el tofacitinib han sido asociados con un mayor riesgo de tromboembolismo venoso.OBJETIVO:Determinar si la exposición preoperatoria a tofacitinib aumenta la tromboembolia venosa u otras complicaciones posoperatorias entre pacientes con colitis ulcerosa sometidos a colectomía subtotal, colectomía total o proctocolectomía total.DISEÑO:Estudio retrospectivo de casos y controles en una sola institución.AJUSTES:Un centro de referencia terciario.PACIENTES:Los pacientes adultos con colitis ulcerosa sometidos a colectomía subtotal, colectomía total o proctocolectomía total después del año 2018 que se encontraron consumiendo tofacitinib dentro de los 30 días posteriores a la cirugía (n = 56) fueron comparados con pacientes con colitis ulcerosa de la misma edad y sexo sometidos a las mismas cirugías pero que no estuvieron expuestos a tofacitinib (n = 56).MEDIDA DE RESULTADO PRINCIPAL:El resultado primario fueron las diferencias en las incidencias de tromboembolismo venoso dentro de los 90 días posteriores a la cirugía según la exposición a tofacitinib. Los resultados secundarios fueron las complicaciones posoperatorias a los 90 días.RESULTADOS:Los grupos se encontraban bien emparejados por edad (sin tofacitinib: media 35,2 años [DE 12,0], tofacitinib: 35,9 [DE 12,1], p = 0,36) y sexo (41% mujeres en cada grupo, p = 1,00). Las características médicas fueron similares entre los grupos, excepto por la exposición a medicamentos biológicos 30 días antes de la cirugía (sin tofacitinib: 66 %, tofacitinib: 36 %, p = 0,004). Las características quirúrgicas no difirieron entre los grupos. La mayoría de los pacientes fueron dados de alta con profilaxis extendida para tromboembolismo venoso (sin tofacitinib: 80% y tofacitinib: 77%). Ajustado a la exposición biológica, no hubo diferencias estadísticamente significativas en el tromboembolismo venoso (no expuestos a tofacitinib: 14%, expuestos a tofacitinib: 4%, p = 0,09) u otros resultados posoperatorios.LIMITACIÓN:Estudio institucional único, retrospectivo.CONCLUSIÓN:Entre los pacientes con colitis ulcerosa sometidos a colectomía total o proctocolectomía, la exposición a tofacitinib no se asoció con un mayor riesgo de tromboembolismo venoso u otras complicaciones posoperatorias. (Traducción-Dr Osvaldo Gauto )., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Introduction: Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized. Leptin is overexpressed in the placentas from preeclamptic (PE) pregnancies. PE can result from the impaired invasion of fetal placental cells, cytotrophoblasts (CTBs), into the maternal decidua. We hypothesized that elevated leptin levels would impair human CTB invasion., Methods: The effects of leptin on the invasion of human CTBs were evaluated in three cell models, HTR-8/SVneo cells, primary CTBs, and placental villous explants using invasion assays. Further, leptin receptor expression was characterized in all three cell models using RT-PCR. Further phosphokinase assays were performed in HTR-8/SVneo cells to determine signaling pathways involved in CTB invasion in response to differential leptin doses., Results: We found that, prior to 8 weeks gestation, leptin promoted CTB invasion in the explant model. After 11 weeks gestation in explants, primary CTBs and in HTR-8/SVneo cells, leptin promoted invasion at moderate but not at high concentrations. Further, leptin receptor characterization revealed that leptin receptor expression did not vary over gestation, however, STAT, PI3K and MAPK pathways showed different signaling in response to varied leptin doses., Discussion: These data suggest that the excess placental leptin observed in PE may cause impaired CTB invasion as a second-trimester defect. Leptin's differential effect on trophoblast invasion may explain the role of hyperleptinemia in preeclampsia pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rumer, Sehgal, Kramer, Bogart and Winn.)

Background: The evolution of enhanced recovery pathways (ERPs) in colon and rectal surgery has led to the development of same-day discharge (SDD) procedures for selected patients. Early discharge after diverting loop ileostomy (DLI) closure was first described in 2003. However, its widespread adoption remains limited, with SDD accounting for only 3.2% of all DLI closures in 2005-2006, according to the American College of Surgeons National Surgical Quality Improvement Program database, and rising to just 4.1% by 2016. This study aimed to compare the outcomes of SDD DLI closure with those of DLI closure after the standard ERP., Methods: A retrospective case-matched study compared 125 patients undergoing SDD DLI closure with 250 patients undergoing DLI closure after the standard ERP based on age (±1 year), sex, American Society of Anesthesiologists score, body mass index, surgery date (±2 months), underlying disease, and hospital site. The primary outcome was comparative 30-day complication rates., Results: Patients in the traditional ERP group received more intraoperative fluids (1221.1 ± 416.6 vs 1039.0 ± 368.3 mL, P < .001) but had similar estimated blood loss. Ten patients (8%) in the SDD-ERP group failed SDD. The 30-day postoperative complication rate was significantly lower in the SDD group (14.8%) than the standard ERP group (25.7%, P = .025). This difference was primarily driven by a lower incidence of ileus in the SDD group (9.6% vs 14.8%, P = .034). There were no significant differences in readmission rate (9.6% of SDD-ERP vs 9.2% of standard ERP, P = .900) and reoperation rates (3.2% of SDD-ERP vs 2.4% of standard ERP, P = .650)., Conclusion: SDD ileostomy closure is a safe, feasible, and effective procedure associated with fewer complications than the present study's standard ERP. This could represent a new standard of care. Further prospective trials are required to confirm the findings of this study., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Implementing perioperative interventions such as enhanced recovery pathways (ERPs) has improved short-term outcomes and minimized length of stay. Preliminary evidence suggests that adherence to the enhanced recovery after surgery protocol may also enhance 5-year cancer-specific survival (CSS) in colorectal cancer surgery. This retrospective study presents long-term survival outcomes and disease recurrence from a high-volume, single-center practice., Methods: All patients over 18 years of age diagnosed with rectal adenocarcinoma and undergoing elective minimally invasive surgery (MIS) were retrospectively reviewed between February 2005 and April 2018. Relevant data were extracted from Mayo electronic records and securely stored in a database. Short-term morbidity and long-term oncological outcomes were compared between patients enrolled in ERP and those who received non-enhanced care., Results: Overall, 600 rectal cancer patients underwent MIS, of whom 320 (53.3%) were treated according to the ERP and 280 (46.7%) received non-enhanced care. ERP was associated with a decrease in length of stay (3 vs. 5 days; p < 0.001) and less overall complications (34.7 vs. 54.3%; p < 0.001). The ERP group did not show an improvement in overall survival (OS) or disease-free survival (DFS) compared with non-enhanced care on multivariable (non-ERP vs. ERP OS: hazard ratio [HR] 1.268, 95% confidence interval [CI] 0.852-1.887; DFS: HR 1.050, 95% CI 0.674-1.635) analysis., Conclusion: ERP was found to be associated with a reduction in short-term morbidity, with no impact on long-term oncological outcomes, such as OS, CSS, and DFS., (© 2024. Society of Surgical Oncology.)

Background: Although laparoscopic Ileal pouch-anal anastomosis (IPAA) has become the gold standard in restorative proctocolectomy, surgical techniques have experienced minimal changes. In contrast, substantial shifts in perioperative care, marked by the enhanced recovery program (ERP), modifications in steroid use, and a shift to a 3-staged approach, have taken center stage., Methods: Data extracted from our prospective IPAA database focused on the first 100 laparoscopic IPAA cases (historic group) and the latest 100 cases (modern group), aiming to measure the effect of these evolutions on postoperative outcomes., Results: The historic IPAA group had more 2-staged procedures (92% proctocolectomy), whereas the modern group had a higher number of 3-staged procedures (86% proctectomy) (P < .001). Compared with patients in the modern group, patients in the historic group were more likely to be on steroids (5% vs 67%, respectively; P < .001) or immunomodulators (0% vs 31%, respectively; P < .001) at surgery. Compared with the historic group, the modern group had a shorter operative time (335.5 ± 78.4 vs 233.8 ± 81.6, respectively; P < .001) and length of stay (LOS; 5.4 ± 3.1 vs 4.2 ± 1.6 days, respectively; P < .001). Compared with the modern group, the historic group exhibited a higher 30-day morbidity rate (20% vs 33%, respectively; P = .04) and an elevated 30-day readmission rate (9% vs 21%, respectively; P = .02). Preoperative steroids use increased complications (odds ratio [OR], 3.4; P = .01), whereas 3-staged IPAA reduced complications (OR, 0.3; P = .03). ERP was identified as a factor that predicted shorter stays., Conclusion: Although ERP effectively reduced the LOS in IPAA surgery, it failed to reduce complications. Conversely, adopting a 3-staged IPAA approach proved beneficial in reducing morbidity, whereas preoperative steroid use increased complications., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Ganglioneuromas (GN) are benign neuroblastic tumors that arise from neural crest cells. Since they present with nonspecific symptoms, diagnosis is often incidental. We are reporting a case of an adult appendiceal GN incidentally found during rectal cancer surgery. A 42-year-old male was diagnosed with recurrent rectal cancer after experiencing urinary difficulties and buttock pain. A multiple-stage pelvic exenteration was carried out after neoadjuvant chemotherapy and chemoradiation. Prophylactic appendectomy was done during the course of surgery, and pathology reported an appendix with GN at the distal tip. GN are often found incidentally and rarely cause appendicitis. Depending on their location and size, they might become symptomatic. While there is some controversy on whether surgery is the treatment of choice for all GN, diagnosis is rarely apparent preoperatively, and all appendiceal masses should be resected., Competing Interests: The authors did not have financial interest nor receive any financial support of the products or devices mentioned in this article. All other authors declare that they have no conflicts of interest., (© Published by Oxford University Press and JSCR Publishing Ltd 2024.)

Introduction: Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare type of chronic colonic ischemia. Patients commonly present with progressive abdominal pain, bloody diarrhea, and weight loss. IMHMV is a common mimicker of inflammatory bowel disease. However, medical management does not have a primary role and curative treatment is surgical resection., Presentation of Case: We report two cases of IMHMV with atypical presentation. The first is an 82-year-old male who had refractory, painless, explosive, and non-bloody diarrhea initially treated with antidiarrheal medications and dietary changes to no effect. Colonoscopy was not clarifying. However, CT scan had characteristic findings of IMHMV. He underwent partial colectomy and recovered well. The second case is a 59-year-old male who had recurrent episodes of sudden, massive diarrhea. He was initially treated for diverticulitis based on colonoscopy findings but did not experience relief. Eventually, MRI of the abdomen was suggestive of IMHMV. He underwent surgical resection, which confirmed the diagnosis of IMHMV. He was treated for Clostridioides difficile diarrhea five months after surgery and pulmonary embolism seven months after surgery. With over a year of follow up, neither has had disease recurrence., Discussion: Diagnosis and treatment of rare disorders like IMHMV is challenging, especially when they mimic common entities or present in atypical ways., Conclusion: We present two cases to highlight IMHMV as part of the differential for colitis-like symptoms. These cases demonstrate the importance of diagnostic imaging in diagnosis. Diagnostic uncertainty can lead to exposure to ineffective medical treatments and delay in curative surgery., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. All procedures were performed in studies involving human participants followed the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declare and its later amendments or compared ethical strands., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Preeclampsia is a pregnancy-specific disorder involving placental abnormalities. Elevated placental Sialic acid immunoglobulin-like lectin (Siglec)-6 expression has been correlated with preeclampsia. Siglec-6 is a transmembrane receptor, expressed predominantly by the trophoblast cells in the human placenta. It interacts with sialyl glycans such as sialyl-TN glycans as well as binds leptin. Siglec-6 overexpression has been shown to influence proliferation, apoptosis, and invasion in the trophoblast (BeWo) cell model. However, there is no direct evidence that Siglec-6 plays a role in preeclampsia pathogenesis and its signaling potential is still largely unexplored. Siglec-6 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif in its cytoplasmic tail suggesting a signaling function. Site-directed mutagenesis and transfection were employed to create a series of Siglec-6 expressing HTR-8/SVneo trophoblastic cell lines with mutations in specific functional residues to explore the signaling potential of Siglec-6. Co-immunoprecipitation and inhibitory assays were utilized to investigate the association of Src-kinases and SH-2 domain-containing phosphatases with Siglec-6. In this study, we show that Siglec-6 is phosphorylated at ITIM and ITIM-like domains by Src family kinases. Phosphorylation of both ITIM and ITIM-like motifs is essential for the recruitment of phosphatases like Src homology region 2 containing protein tyrosine phosphatase 2 (SHP-2), which has downstream signaling capabilities. These findings suggest Siglec-6 as a signaling molecule in human trophoblasts. Further investigation is warranted to determine which signaling pathways are activated downstream to SHP-2 recruitment and how overexpression of Siglec-6 in preeclamptic placentas impacts pathogenesis.

The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC] training  = 0.799, p = 4.2e-6; multi-class AUC validation  = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression., Competing Interests: Declaration of interests S.D.B. has consulted for Regeneron, Sanofi, Novartis, and Janssen on topics unrelated to this study and owns stocks in AbCellera Biologics. The other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine whether single-cell and plasma proteomic elements of the host's immune response to surgery accurately identify patients who develop a surgical site complication (SSC) after major abdominal surgery., Summary Background Data: SSCs may occur in up to 25% of patients undergoing bowel resection, resulting in significant morbidity and economic burden. However, the accurate prediction of SSCs remains clinically challenging. Leveraging high-content proteomic technologies to comprehensively profile patients' immune response to surgery is a promising approach to identify predictive biological factors of SSCs., Methods: Forty-one patients undergoing non-cancer bowel resection were prospectively enrolled. Blood samples collected before surgery and on postoperative day one (POD1) were analyzed using a combination of single-cell mass cytometry and plasma proteomics. The primary outcome was the occurrence of an SSC, including surgical site infection, anastomotic leak, or wound dehiscence within 30 days of surgery., Results: A multiomic model integrating the single-cell and plasma proteomic data collected on POD1 accurately differentiated patients with (n = 11) and without (n = 30) an SSC [area under the curve (AUC) = 0.86]. Model features included coregulated proinflammatory (eg, IL-6- and MyD88- signaling responses in myeloid cells) and immunosuppressive (eg, JAK/STAT signaling responses in M-MDSCs and Tregs) events preceding an SSC. Importantly, analysis of the immunological data obtained before surgery also yielded a model accurately predicting SSCs (AUC = 0.82)., Conclusions: The multiomic analysis of patients' immune response after surgery and immune state before surgery revealed systemic immune signatures preceding the development of SSCs. Our results suggest that integrating immunological data in perioperative risk assessment paradigms is a plausible strategy to guide individualized clinical care., Competing Interests: Conflicts of Interest and Source of Funding: This work was supported by the Stanford Department of Anesthesiology, Pain and Perioperative Medicine, the Stanford Department of Surgery, the national institute of health (NIH) R35GM137936 (BG), R35GM138353 (NA), NS114926 (MSA), AG065744 (MSA), the Fluegel Research Fund (KR), and the Center for Human Systems Immunology (BG). A provisional patent application that covers aspects of the subject matter of the article has been filed (S31-07151.PRO, title: systems and methods to generate a surgical risk score and uses thereof, co-inventors: B.G., J.H., K.R., N.A., M.S.A.). The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [ R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10 -40 , N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10 -7 , N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression.

Background: Existing studies on the effects of biological medications on surgical complications among patients with ulcerative colitis have mixed results. Because biologicals may hinder response to infections and wound healing, preoperative exposure may increase postoperative complications., Objective: The purpose of this study was to evaluate associations between biological exposure within 6 months preceding colectomy or proctocolectomy and postoperative complications among patients with ulcerative colitis., Design: This was a retrospective cohort study with multivariate regression analysis after coarsened exact matching., Settings: A large commercial insurance claims database (2003-2016) was used., Patients: A total of 1794 patients with ulcerative colitis underwent total abdominal colectomy with end ileostomy, total proctocolectomy with end ileostomy, or total proctocolectomy with IPAA. Twenty-two percent were exposed to biologicals in the 6 months preceding surgery., Main Outcomes Measures: Healthcare use (length of stay, unplanned reoperation/procedure, emergency department visit, or readmission) and complications (infectious, hernia or wound disruption, thromboembolic, or cardiopulmonary) within 30 postoperative days were measured., Results: Exposure to biological medications was associated with shorter surgical hospitalization (7 vs 8 d; p <0.001) but otherwise was not associated with differences in healthcare use or postoperative complications., Patients: who underwent total proctocolectomy with IPAA had higher odds of infectious complications compared with those who underwent total abdominal colectomy with end ileostomy (adjusted OR = 2.2 (95% CI, 1.5-3.0); p < 0.001) but had lower odds of cardiopulmonary complications (adjusted OR = 0.4 (95% CI, 0.3-0.6); p < 0.001)., Limitations: Analysis of private insurance database claims data may not represent uninsured or government-insured patients and may be limited by coding accuracy. Matched cohorts differed in age and Charlson Comorbidity Index, which could be influential even after multivariate adjustments., Conclusions: Biological exposure among patients with ulcerative colitis is not associated with higher odds of postoperative complications or healthcare resource use. These data, in combination with clinical judgment and patient preferences, may aid in complex decision-making regarding operative timing, operation type, and perioperative medication management. See Video Abstract at http://links.lww.com/DCR/B370. EL USO DE MEDICAMENTOS BIOLÓGICOS NO AUMENTA LAS COMPLICACIONES POSTOPERATORIAS ENTRE PACIENTES CON COLITIS ULCERATIVA SOMETIDOS A UNA COLECTOMÍA: UN ANÁLISIS DE COHORTE RETROSPECTIVO DE PACIENTES CON SEGURO PRIVADO: Estudios existentes sobre los efectos de medicamentos biológicos, en complicaciones quirúrgicas, en pacientes con colitis ulcerativa, presentan resultados mixtos. Debido a que los productos biológicos pueden retrasar la respuesta a las infecciones y curación de heridas, su exposición preoperatoria pueden aumentar las complicaciones postoperatorias.Evaluar las asociaciones entre la exposición biológica dentro de los seis meses anteriores a la colectomía o proctocolectomía y las complicaciones postoperatorias entre los pacientes con colitis ulcerativa.Estudio de cohorte retrospectivo con análisis de regresión multivariante después de una coincidencia exacta aproximada.Una gran base de datos de reclamaciones de seguros comerciales (2003-2016).Un total de 1.794 pacientes con colitis ulcerativa, se sometieron a colectomía abdominal total con ileostomía terminal, proctocolectomía total con ileostomía terminal o proctocolectomía total con anastomosis anal y bolsa ileal. 22% estuvieron expuestos a productos biológicos, seis meses antes de la cirugía.Utilización de la atención médica (duración de la estadía, reoperación o procedimiento no planificado, visita al servicio de urgencias o reingreso) y complicaciones (infecciosas, hernias o dehiscencias de heridas, tromboembólicas o cardiopulmonares) dentro de los 30 días postoperatorios.La exposición a medicamentos biológicos se asoció con una hospitalización quirúrgica más corta (7 frente a 8 días, p <0,001), pero por lo demás, no se asoció con diferencias en la utilización de la atención médica o complicaciones postoperatorias. Los pacientes que se sometieron a proctocolectomía total con anastomosis anal y bolsa ileal, tuvieron mayores probabilidades de complicaciones infecciosas, en comparación con aquellos que se sometieron a colectomía abdominal total con ileostomía final (aOR 2.2, IC 95% [1.5-3.0], p <0.001) pero tuvieron menores probabilidades de complicaciones cardiopulmonares (aOR 0.4, IC 95% [0.3-0.6], p <0.001).El análisis de los datos de reclamaciones, de la base de datos de los seguros privados, puede no representar a pacientes no asegurados o asegurados por el gobierno, y puede estar limitado por la precisión de la codificación. Las cohortes emparejadas diferían en la edad y el índice de comorbilidad de Charlson, lo que podría influir incluso después de ajustes multivariados.La exposición biológica entre los pacientes con colitis ulcerativa, no se asocia con mayores probabilidades de complicaciones postoperatorias, o a la utilización de recursos sanitarios. Estos datos, en combinación con el juicio clínico y las preferencias del paciente, pueden ayudar en la toma de decisiones complejas con respecto al momento quirúrgico, el tipo de operación y el manejo de la medicación perioperatoria. Consulte Video Resumen en http://links.lww.com/DCR/B370. (Traducción-Dr Fidel Ruiz Healy).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC = 0.92, p-value = 3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs' effects on clinical outcomes likely dependent on functional adaptive immune responses.

Purpose of Review: Frailty is the concept of accumulating physiologic declines that make people less able to deal with stressors, including surgery. Prehabilitation is intervention to enhance functional capacity before surgery. Frailty and prehabilitation among transplant populations and the role of wearable fitness tracking devices (WFTs) in delivering fitness-based interventions will be discussed., Recent Findings: Frailty is associated with increased complications, longer length of hospital stay and increased mortality after surgery. Frail kidney transplant patients have increased delayed graft function, mortality and early hospital readmission. Frail lung or liver transplant patients are more likely to delist or die on the waitlist. Prehabilitation can mitigate frailty and has resulted in decreased length of hospital stay and fewer postsurgical complications among a variety of surgical populations. Increasingly, WFTs are used to monitor patient activity and improve patient health. Interventions using WFTs have resulted in improved activity, weight loss and blood pressure., Summary: Frailty is a measurable parameter that identifies patients at risk for worse health outcomes and can be mitigated through intervention. Prehabilitation to reduce frailty has been shown to improve postsurgical outcomes in a variety of populations. WFTs are being integrated in healthcare delivery for monitoring and changing health behavior with promising results.

Problem: We sought to determine whether alternative complement activation fragment Bb (Bb) levels are elevated in the maternal, fetal, and placental blood in cases of severe preeclampsia (PE) compared with normotensive controls., Method of Study: This was a cross-sectional study of women admitted at ≥24 weeks gestation with or without severe PE. Maternal plasma was collected at the time of enrollment. Umbilical venous cord and intervillous space blood were collected at delivery. Plasma Bb levels were assessed using ELISA. Bb levels were compared between cases and controls., Results: Median Bb levels were higher in the maternal plasma of severe PE subjects (n = 24) than in controls (n = 20), 1.45 ± 1.03 versus 0.65 ± 0.23 μg/mL, P < 0.001. In umbilical venous plasma, Bb levels were higher in severe PE subjects (n = 15) compared with controls (n = 15), 2.48 ± 1.40 versus 1.01 ± 0.57 μg/mL, P = 0.01., Conclusion: Activation fragment Bb is increased in the maternal and umbilical venous blood of cases of severe PE when compared with normotensive controls. These data provide support for alternative complement pathway involvement in the pathogenesis of severe PE and demonstrate that alternative complement activation occurs not only in the maternal but also in the fetal compartment., (© 2013 John Wiley & Sons Ltd.)

Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds sialyl-TN glycans and leptin. Among eutherian mammals, only human placentas express Siglec-6. Previous work has implicated Siglec-6 in preeclampsia (PE). Preeclampsia, a leading cause of maternal and perinatal morbidity and mortality, is characterized by placental abnormalities. This study provides a comprehensive analysis of Siglec-6 protein expression during human pregnancy by disease state (PE), biologic compartment (basal plate, chorionic villi, or maternal plasma), gestational age (24-41 weeks), and labor status. Siglec-6 protein was increased in both the basal plate and chorionic villi of preterm PE placentas (P < .05). However, expression did not differ at term by disease state, compartment, or labor status. Siglec-6 was not detectable in maternal serum. Overexpression of Siglec-6 protein in preterm PE placentas may contribute to or represent a response to PE pathogenesis and suggests that preterm PE pathogenesis is distinct from term PE.

Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds leptin. Leptin is an obesity-associated peptide hormone overexpressed in gestational trophoblastic disease (GTD). GTD encompasses several placental abnormalities that range from benign to malignant. Among GTD, molar placentas are characterized by excess proliferation, whereas gestational trophoblastic neoplasias (GTN) have characteristically aggressive invasion. We hypothesized that in GTD, Siglec-6 expression would increase with disease severity and that Siglec-6 and leptin would promote proliferation, inhibit apoptosis and/or promote invasion. Siglec-6 expression patterns were evaluated with particular attention to the diagnostic utility of Siglec-6 in GTD (controls: normal placentas (n=32), hydropic abortus placentas (n=7), non-GTD reproductive tract cancers (n=2); GTD: partial moles (PM; n=11), complete moles (n=24), GTN (n=6)). In normal placentas, Siglec-6 expression dramatically decreased after 8 weeks gestation. Complete molar placentas had significantly higher Siglec-6 expression than controls, but expression was not significantly different from PM. In GTN, Siglec-6 expression was low. These data suggest that Siglec-6 may have diagnostic utility for distinguishing complete moles from normal and hydropic abortus placentas. Functional studies in choriocarcinoma-derived BeWO cells demonstrated a complex interplay between Siglec-6 expression and leptin exposure. In cells lacking Siglec-6, leptin treatment promoted invasion, likely through interaction with LepR leptin receptor, without affecting proliferation or apoptosis. Siglec-6 expression promoted proliferation in a leptin-dependent manner, but protected cells from apoptosis and promoted invasion in a leptin-independent manner. We propose that Siglec-6 and leptin play a role in the aberrant properties characteristic of GTD, namely excess proliferation and invasion.

OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. METHODS: Cohorts of zymosan-treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. CONCLUSIONS: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration.

Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.

The mammary gland microenvironment during postlactational involution shares similarities with inflammation, including high matrix metalloproteinase activity, fibrillar collagen deposition, and release of bioactive fragments of fibronectin and laminin. Because inflammation can promote tumorigenesis, we evaluated whether the tissue microenvironment of the involuting gland is also promotional. Extracellular matrix was isolated from mammary glands of nulliparous rats or rats with mammary glands undergoing weaning-induced involution. Using these matrices as substratum, nulliparous matrix was found to promote ductal organization of normal mammary epithelial MCF-12A cells in three-dimensional culture and to suppress invasion of mammary tumor MDA-MB-231 cells in transwell filter assays. Conversely, involution matrix failed to support ductal development in normal cells and promoted invasiveness in tumor cells. To evaluate the effects of these matrices on metastasis in vivo, MDA-MB-231 cells, premixed with Matrigel, nulliparous matrix, or involution matrix, were injected into mammary fat pads of nude mice. Metastases to lung, liver, and kidney were increased in the involution matrix group, and correlated with a twofold increase in tumor vascular endothelial growth factor expression and increased angiogenesis. These data suggest that the mammary gland microenvironment becomes promotional for tumor cell dissemination during involution, thus providing a plausible mechanism to explain the high rate of metastases that occur with pregnancy-associated breast cancer.