Determinants of Public Opinion Toward Gender-Affirming Surgery in the United States.

Purpose: National polling data indicate that Americans support the right of transgender persons to undergo gender-affirming surgery (GAS). It remains unknown whether public perceptions of GAS differ depending on patient subpopulations, anatomical site, or insurance coverage and whether the public widely believes that transgender people will regret GAS. Methods: We built a Qualtrics™ survey derived from an online validated 2017 Ipsos survey and distributed it to American adults through Amazon Mechanical Turk. Associations of demographic characteristics with perception of GAS were determined using multinomial logistic regression. Results: Respondents (n=312) were predominantly non-Hispanic White (69.2%), held a bachelor's degree (64.7%), and reported an annual income of $25,000 to $74,999 (64.4%). Approximately half of respondents identified as socially liberal (50.3%); 34.0% as socially conservative; and 15.7% as neither. Respondents supported a right to GAS independent of anatomy and insurance. Support for transgender children (62%) was less than for adult transgender men (84%) and women (83%). Despite supporting a right to GAS, respondents agreed that transgender adults (67%) and children (74%) would regret GAS. Education was the strongest predictor of support for GAS rights. Socially conservative respondents were significantly more likely than nonideological or liberal respondents to believe that transgender people would regret GAS. Conclusion: This large online sample of American adults with diverse ideologies demonstrated support for GAS independent of anatomical site and insurance. Support of GAS for transgender children is robust, although lower than support for adults. Despite broad support, most laypersons believe that transgender people would regret GAS.

Trends in Preoperative Outcome Measures From 2013 to 2021 in Patients Undergoing Primary Total Joint Arthroplasty.

INTRODUCTION: The prevalence of total joint arthroplasty (TJA) continues to increase exponentially. Patient-reported outcome measures (PROMs) are used to define clinical and quality-of-life improvement and for reimbursement. Temporal trends of preoperative PROMs and specifically how COVID-19 has affected these PROMs is lacking. This study evaluated preoperative PROMs over time, whether medical factors affected preoperative PROMs, and what correlations the COVID-19 pandemic had with these trends in PROMs. METHODS: A total of 3,014 patients who underwent primary total hip total hip arthroplasty or total knee arthroplasty from 2013 to 2021 were retrospectively reviewed for covariates and preoperative PROMs. Commonly reported preoperative PROMs were evaluated in univariate and multivariate models. RESULTS: Preoperative activity level steadily increased from 2015 to 2021 for THAs and steadily increased from 2015 to 2019 for TKAs, followed by a decrease in 2020. Preoperative KOOS JR scores increased from 2016 to 2019 and then decreased in 2020 and 2021. Preoperative knee pain with level walking and climbing stairs steadily increased from 2013 to 2019, with additional increases in 2020. The COVID-19 era was significantly associated with higher activity levels for THAs, higher levels of pain with level walking, and lower KOOS JR scores. Preoperative PROM scores demonstrated correlations with postoperative PROM scores, which differed from that during the COVID era (rho range 0.105 to 0.391) at a mean of 2.0 years postoperatively. DISCUSSION: Surgical delays because of COVID-19 were associated with increased preoperative disability as evidenced by lower activity levels. Aside from this pandemic era, patient activity levels increased over time, indicating that modern TJA patients are more active preoperatively and likely to demand higher levels of function after surgery. Additional studies should evaluate the clinical effect of these statistically significant findings. Providers should consider the trends in preoperative PROMs over time when counseling patients on expectations after TJA.

Label-free detection and profiling of individual solution-phase molecules.

Most chemistry and biology occurs in solution, in which conformational dynamics and complexation underlie behaviour and function. Single-molecule techniques1 are uniquely suited to resolving molecular diversity and new label-free approaches are reshaping the power of single-molecule measurements. A label-free single-molecule method2-16 capable of revealing details of molecular conformation in solution17,18 would allow a new microscopic perspective of unprecedented detail. Here we use the enhanced light-molecule interactions in high-finesse fibre-based Fabry-Pérot microcavities19-21 to detect individual biomolecules as small as 1.2 kDa, a ten-amino-acid peptide, with signal-to-noise ratios (SNRs) >100, even as the molecules are unlabelled and freely diffusing in solution. Our method delivers 2D intensity and temporal profiles, enabling the distinction of subpopulations in mixed samples. Notably, we observe a linear relationship between passage time and molecular radius, unlocking the potential to gather crucial information about diffusion and solution-phase conformation. Furthermore, mixtures of biomolecule isomers of the same molecular weight and composition but different conformation can also be resolved. Detection is based on the creation of a new molecular velocity filter window and a dynamic thermal priming mechanism that make use of the interplay between optical and thermal dynamics22,23 and Pound-Drever-Hall (PDH) cavity locking24 to reveal molecular motion even while suppressing environmental noise. New in vitro ways of revealing molecular conformation, diversity and dynamics can find broad potential for applications in the life and chemical sciences.

Trapdoor endarterectomy for coral reef plaque of the paravisceral aorta in the modern era.

Coral reef atherosclerosis of the paravisceral aorta is a rare disease whose description is confined to before contemporary vascular surgical techniques. This study aims to describe the characteristics and outcomes of patients with coral reef aorta treated with trapdoor endarterectomy at a single high-volume quaternary referral center since 2010. From 2010 to 2022, 14 patients with coral reef aorta were treated with trapdoor endarterectomy. The patient data were obtained via a retrospective medical record review. The patients were predominantly women (79%) with a median age of 65 years (interquartile range [IQR], 60-70 years). The patients universally had a tobacco smoking history and hypertension. More than 85% had previously diagnosed carotid stenosis. Two patients (14%) had undergone prior aortofemoral reconstruction, and one patient (7%) had undergone prior axillobifemoral bypass. The most common presenting symptoms were claudication (71%), chronic mesenteric ischemia (50%), and renovascular hypertension (43%). Of the 14 patients, 8 (57%) underwent isolated endarterectomy and 6 (43%) underwent concomitant aortobifemoral bypass. In addition, 13 patients (93%) required a supraceliac aortic clamp position with a median clamp time of 23 minutes (IQR, 20-30 minutes). The median estimated blood loss was 1650 mL (IQR, 1025-3000 mL). A cell saver was used in 13 procedures (93%), with a median transfusion of 563 mL (IQR, 231-900 mL). The median operative time was 341 minutes (IQR, 315-416 minutes). Eight patients (57%) experienced acute kidney injury in the postoperative period with a peak creatinine of 1.96 mg/dL (IQR, 1.50-2.84 mg/dL). The median length of stay was 11 days (IQR, 6-16 days), with an intensive care unit stay of 4 days (IQR, 2-7 days). One patient (7%) required reoperation in the immediate perioperative period for a retroperitoneal hematoma. The postoperative ankle brachial index increased from a median of 0.58 (right) and 0.57 (left) bilaterally in the preoperative period to 1.09 (right) and 1.10 (left) postoperatively. Eight patients (57%) had follow-up data available for >2 years postoperatively, with five patients (36%) having follow-up data available for >3 years. Two major adverse cardiac events were reported at the last follow-up. One patient reported mild recurrent symptoms of chronic mesenteric ischemia during 3 years of postoperatively, with no concurrent imaging findings or loss of patency found on computed tomography angiography. Symptomatic coral reef atherosclerosis of the paravisceral aorta is a complex disease rarely encountered even at high-volume referral centers. These patients can be expected to experience short-term postoperative morbidity and require intensive care. Despite these challenges, trapdoor endarterectomy is a safe and effective procedure for coral reef aorta, and most patients achieve dramatic symptomatic improvement with durable results.

SOHO State-of-the-Art Updates and Next Questions: Treatment for Newly Diagnosed Peripheral T-Cell Lymphomas.

Although a rare subset of non-Hodgkin lymphomas, peripheral T-cell lymphomas (PTCL) account for a disproportionate proportion of patient mortality. Conventional therapies are derived from experience treating aggressive B-cell lymphomas and center around CHOP-based chemotherapy. However, due to the unique biology and diverse subtypes of PTCL, most patients fail to durably respond to this approach and 5-year survival is only 20% to 30%. There have been multiple attempts to improve outcomes for patients with PTCL. Among the more successful strategies are the use of consolidative autologous stem cell transplant, the augmentation of CHOP with etoposide (CHOEP), and the use of brentuximab vedotin in CD30-positive PTCL. Advances in the understanding of histology-specific biology has cultivated enthusiasm to evaluate hypomethylating agents, histone deacetylate inhibitors, and phosphoinositol-3-kinase inhibitors in the frontline setting. Improvements in monitoring disease response and prognostication including the use of cell-free DNA, mutational profiling, and interim PET/CT imaging are also on the horizon. For patients with acute T-cell leukemia/lymphoma, the use of mogamulizumab-based therapy in the frontline setting may lead to advances in care. The true impact of these new-era therapies will only be elucidated as clinical practices incorporate the rapidly changing evidence.

The Opioid Risk Tool Correlates With Increased Postsurgical Opioid Use Among Patients With Orthopedic Trauma.

The aim of this study was to determine whether the Opioid Risk Tool (ORT), which has been validated in patients with chronic pain, relates to postoperative opioid consumption. The purpose was to investigate a tool that could help identify patients with orthopedic trauma at high risk for opioid abuse. Patients 18 to 80 years old presenting between May 2018 and August 2018 to UNC Hospitals with isolated orthopedic injuries that required surgical intervention were considered for inclusion. At 2 weeks postoperatively, the ORT was administered. At 6 weeks postoperatively, total morphine milligram equivalents (MME) was determined for each patient. Each patient was also categorized as either low risk (LR) or moderate to high risk (M-HR) based on the cumulative ORT score. Finally, opioid prescriptions provided after 6 weeks postoperatively was recorded. One hundred four patients met the inclusion criteria, and 42 completed the questionnaire. Thirty patients were categorized as LR and 12 patients as M-HR. Patients who were at M-HR consumed a significantly higher MME than LR patients (LR=406 [95% CI, 287-526]; M-HR=824 [95% CI, 591-1057]; P=.001). Linear regression analysis showed that for each additional risk factor, opioid consumption increased by 61 MME, and approximately 58% of the variation in opioid consumption could be explained by the ORT (beta=61, R2=0.58, P=.02). In this study, the ORT predicted which patients would have increased opioid consumption after orthopedic trauma surgery. Each additional risk factor correlated with increased opioid use. The ORT did not predict which patients would continue to receive opioid prescriptions after 6 weeks postoperatively. [Orthopedics. 2023;46(4):e219-e222.].

Adipose Tissue in Lymphedema: A Central Feature of Pathology and Target for Pharmacologic Therapy.

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.

Composition, Emissions, and Air Quality Impacts of Hazardous Air Pollutants in Unburned Natural Gas from Residential Stoves in California.

The presence of hazardous air pollutants (HAPs) entrained in end-use natural gas (NG) is an understudied source of human health risks. We performed trace gas analyses on 185 unburned NG samples collected from 159 unique residential NG stoves across seven geographic regions in California. Our analyses commonly detected 12 HAPs with significant variability across region and gas utility. Mean regional benzene, toluene, ethylbenzene, and total xylenes (BTEX) concentrations in end-use NG ranged from 1.6-25 ppmv─benzene alone was detected in 99% of samples, and mean concentrations ranged from 0.7-12 ppmv (max: 66 ppmv). By applying previously reported NG and methane emission rates throughout California's transmission, storage, and distribution systems, we estimated statewide benzene emissions of 4,200 (95% CI: 1,800-9,700) kg yr-1 that are currently not included in any statewide inventories─equal to the annual benzene emissions from nearly 60,000 light-duty gasoline vehicles. Additionally, we found that NG leakage from stoves and ovens while not in use can result in indoor benzene concentrations that can exceed the California Office of Environmental Health Hazard Assessment 8-h Reference Exposure Level of 0.94 ppbv─benzene concentrations comparable to environmental tobacco smoke. This study supports the need to further improve our understanding of leaked downstream NG as a source of health risk.

SARS-CoV-2 mRNA Vaccination Causes Prolonged Increased Cortical Thickening and Vascularity in Ipsilateral Axillary Lymph Nodes.

OBJECTIVES: To describe the serial grey-scale and color Doppler appearance of ipsilateral axillary lymphadenopathy in response to the Pfizer-BioNTech Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) messenger RNA (mRNA) vaccine over 24 to 28 weeks. METHODS: The data for this study were collected during an observational study to determine whether mRNA vaccination induced a germinal center B cell reaction in blood and draining axillary lymph nodes. The current study evaluated the serial color Doppler and grey-scale sonographic appearance of these lymph nodes. Ten participants who each underwent 6 sonograms and FNAs over 24 to 28 weeks were included in the study. A total of 11 lateral lymph nodes were identified. Cortical thickness was measured and absence or presence of color Doppler flow in the hilum and lymph node cortex was graded (scale: 0-2). RESULTS: Eleven lateral axillary lymph nodes were biopsied over 24 to 28 weeks. Mean thickness varied through time (P < .001) and was greater weeks 2 to 7 compared to weeks 24 to 28 (mean differences of 2.6 to 1.3; P < .006), but weeks 14 to 17 mean thickness was not different from weeks 24 to 28 (0.57; P = .15). Cortical vascularity was increased in all 11 lymph nodes by week 5. Mean vascularity varied through time (P < .001) and was greater weeks 2 to 14 compared to weeks 24 to 28; mean differences ranged from 1.7 to 0.83 (P < .001). CONCLUSIONS: Serial grey-scale and color Doppler appearance of ipsilateral axillary lymph nodes after mRNA vaccination manifest as increased and prolonged cortical thickening and vascularity that diminishes and approaches normal by 24 to 28 weeks.

SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans.

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.

Reduced antibody activity against SARS-CoV-2 B.1.617.2 delta virus in serum of mRNA-vaccinated individuals receiving tumor necrosis factor-α inhibitors.

BACKGROUND: Although vaccines effectively prevent coronavirus disease 2019 (COVID-19) in healthy individuals, they appear to be less immunogenic in individuals with chronic inflammatory disease (CID) or receiving chronic immunosuppression therapy. METHODS: Here we assessed a cohort of 77 individuals with CID treated as monotherapy with chronic immunosuppressive drugs for antibody responses in serum against historical and variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses after immunization with the BNT162b2 mRNA vaccine. FINDINGS: Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with tumor necrosis factor alpha (TNF-α) inhibitors (TNFi), and this pattern appeared to be worse against the B.1.617.2 delta virus. Within 5 months of vaccination, serum neutralizing titers of all TNFi-treated individuals tested fell below the presumed threshold correlate for antibody-mediated protection. However, TNFi-treated individuals receiving a third mRNA vaccine dose boosted their serum neutralizing antibody titers by more than 16-fold. CONCLUSIONS: Vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) will likely be required to prevent SARS-CoV-2 infection in this susceptible population. FUNDING: This study was supported by grants and contracts from the NIH (R01 AI157155, R01AI151178, and HHSN75N93019C00074; NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014; and Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051).

SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.

Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies1-7. Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-28-10. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived11-13. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n = 77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.

Intraoperative Urinary Biomarkers and Acute Kidney Injury After Cardiac Surgery.

OBJECTIVES: To evaluate the association of intraoperative urinary biomarker excretion during cardiac surgery and the subsequent development of acute kidney injury (AKI). DESIGN: Prospective, nonrandomized, observational study. SETTING: Single tertiary-level, university-affiliated hospital. PARTICIPANTS: Ninety patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary samples were collected every 30 minutes intraoperatively and then at four, 12, and 24 hours after CPB. Samples were measured for interleukin 18 (IL-18), kidney injury molecule-1 (KIM1), and creatinine concentrations. Urinary biomarker excretion (raw and indexed to creatinine) for four intraoperative and three postoperative points were compared between patients with and those without subsequent AKI defined by increased serum creatinine concentration ≥0.3 mg/dL within the first 48 hours or ≥1.5 times baseline within seven days. Raw and indexed median IL-18 values were similar between AKI groups at all intraoperative points, but became significantly different at 12 hours after CPB. Raw and indexed median KIM1 values were significantly different between AKI groups at multiple intraoperative points and at four and 12 hours after CPB. During intraoperative and postoperative points, patients in the fourth quartile of KIM1 excretion had greater AKI incidence and longer intensive care and hospital lengths of stay than those in the first quartile. Only postoperatively did the differences in these outcomes between the fourth and first quartile of IL-18 excretion occur. CONCLUSIONS: Intraoperative KIM1 but not IL-18 excretion was associated with postoperative development of AKI.

'What research was carried out on this vaginal mesh?' Health-related concerns in women following mesh-augmented prolapse surgery: a thematic analysis.

OBJECTIVE: To understand health-related issues in women following mesh-augmented prolapse surgery. DESIGN: Inductive thematic analysis of free-text comments from participants in a cross-sectional study of laparoscopic mesh sacrohysteropexy. SETTING: Tertiary urogynaecology centres, United Kingdom. POPULATION: Women who underwent laparoscopic mesh sacrohysteropexy by surgeons based at two tertiary urogynaecology centres between 2010 and 2018. METHODS: A total of 1766 potential participants were contacted by post and invited to complete paper, online or telephone questionnaires containing a free-text comments section. Of 1121 participants (response proportion 63.5%), 752 (67.1%) provided such comments. These were analysed with a six-stage inductive thematic analysis, using NVivo 11® software. MAIN OUTCOME MEASURES: Themes developed from free-text comments. RESULTS: Following familiarisation, 29 codes and 189 sub-codes were identified. These defined six themes: pelvic floor symptoms, health status, treatment success, mesh, pain and care received. The majority of comments centred on the first of these six themes. There were concerns about mesh use and a desire for more information. A range of pain symptoms were mentioned, often associated with pelvic floor symptoms, prolapse surgery or mesh. CONCLUSIONS: Despite the mesh controversy, pelvic floor symptoms and their impact on quality of life remain the principle concern of women following mesh-augmented prolapse surgery. There is a need for quality, accessible and evidence-based information sources for those women with concerns, and for those considering such surgery in the future, particularly regarding mesh safety and postoperative recovery. The relationships between pain, prolapse, mesh and pelvic floor surgery require further study. TWEETABLE ABSTRACT: Following mesh-augmented prolapse surgery, pelvic floor symptoms remain women's main focus; pain deserves further research.

Immediate Weightbearing After Operative Treatment of Bimalleolar and Trimalleolar Ankle Fractures: Faster Return to Work for Patients with Nonsedentary Occupations.

The goal of this study was to compare immediate weightbearing (IWB) and traditional weightbearing (TWB) postoperative protocols in unstable ankle fractures, as this has not been compared in prior works. We hypothesize that an immediate weightbearing protocol after ankle fracture fixation will lead to an earlier return to work. An ankle fracture registry was reviewed for operatively treated unstable bimalleolar and trimalleolar ankle fractures at an ambulatory surgery center and followed up at associated outpatient clinics. All fracture cases reviewed occurred from 2009 to 2015. Immediate weightbearing patients were placed into a controlled ankle motion (CAM) boot and allowed to fully bear weight the day of surgery. Traditional weightbearing patients were placed into a CAM boot with 6 weeks of non-weightbearing. Demographics, fixation technique, and injury characteristics were surveyed. Physical job demand was stratified for 69 patients meeting the inclusion criteria (34 IWB and 35 TWB). The main outcome of this study was measured as the time to return to work. Subgroup analysis of patients with nonsedentary jobs demonstrated a significantly earlier return to work for the IWB group (5.7 versus 10.0 weeks, p = .04). Multivariate regression analysis identified a statistically significant 2.25-week (p = .05) earlier return to work for the IWB group after adjustment for occupational physical demand, demographics, fracture characteristics, and participation in a light work period before full work return. In patients with nonsedentary jobs, an IWB protocol after operative management of bimalleolar and trimalleolar ankle fractures resulted in an earlier return to work compared with traditional protocols.

Management of sigmoid volvulus using percutaneous endoscopic colostomy.

INTRODUCTION: The aim of this systematic review was to appraise the current literature on the use of percutaneous endoscopic colostomy (PEC) as an alternative to major surgery and endoscopic decompression alone for treating sigmoid volvulus in frail, comorbid patients. METHODS: A systematic literature search of literature published between April 2000 and January 2017 was carried out using the MEDLINE®, Embase™ and CINAHL® (Cumulative Index to Nursing and Allied Health Literature) databases. The search terms were "percutaneous endoscopic colostomy", "PEC", "sigmoidopexy", "sigmoidostomy" and "sigmoid volvulus". The studies identified were screened and those that did not fulfil the inclusion criteria were excluded. FINDINGS: Seven observational studies and seven case reports (comprising eighty-one patients) were found to match our inclusion criteria. All patients had recurrent sigmoid volvulus and were treated with PEC either with a single PEC tube or with two PEC tubes inserted. Sigmoid volvulus recurred in 10 of the 81 patients; 3 of these individuals developed recurrence with PEC tubes in situ and 7 following tube removal. There were seven deaths after the procedure. The most frequent morbidity associated with PEC tube insertion was site infection (n=6). CONCLUSIONS: Our systematic review highlights the use of PEC as an alternative in managing recurrent sigmoid volvulus in frail, comorbid patients unfit for or refusing surgery, with the best outcomes seen in those patients where two PEC tubes were inserted and remained in situ indefinitely. Further studies are needed to improve the safety and efficacy of the procedure as well as post-procedure care.

An Agonistic Anti-CD137 Antibody Disrupts Lymphoid Follicle Structure and T-Cell-Dependent Antibody Responses.

CD137 is a costimulatory receptor expressed on natural killer cells, T cells, and subsets of dendritic cells. An agonistic monoclonal antibody (mAb) against CD137 has been used to reduce tumor burden or reverse autoimmunity in animal models and clinical trials. Here, we show that mice treated with an agonistic anti-CD137 mAb have reduced numbers of germinal center (GC) B cells and follicular dendritic cells (FDCs) in lymphoid tissues, which impair antibody responses to multiple T-cell-dependent antigens, including infectious virus, viral proteins, and conjugated haptens. These effects are not due to enhanced apoptosis or impaired proliferation of B cells but instead correlate with changes in lymphoid follicle structure and GC B cell dispersal and are mediated by CD137 signaling in CD4+ and CD8+ T cells. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may impair long-term antibody and B cell memory responses.

A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.

Lysophosphatidylcholine acyltransferase 2 (LPCAT2) co-localises with TLR4 and regulates macrophage inflammatory gene expression in response to LPS.

Despite extensive investigations, an effective treatment for sepsis remains elusive and a better understanding of the inflammatory response to infection is required to identify potential new targets for therapy. In this study we have used RNAi technology to show, for the first time, that the inducible lysophosphatidylcholine acyltransferase 2 (LPCAT2) plays a key role in macrophage inflammatory gene expression in response to stimulation with bacterial ligands. Using siRNA- or shRNA-mediated knockdown, we demonstrate that, in contrast to the constitutive LPCAT1, LPCAT2 is required for macrophage cytokine gene expression and release in response to TLR4 and TLR2 ligand stimulation but not for TLR-independent stimuli. In addition, cells transfected to overexpress LPCAT2 exhibited increased expression of inflammatory genes in response to LPS and other bacterial ligands. Furthermore, we have used immunoprecipitation and Western blotting to show that in response to LPS, LPCAT2, but not LPCAT1, rapidly associates with TLR4 and translocates to membrane lipid raft domains. Our data thus suggest a novel mechanism for the regulation of inflammatory gene expression in response to bacterial stimuli and highlight LPCAT2 as a potential therapeutic target for development of anti-inflammatory and anti-sepsis therapies.

Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor as Novel Biomarkers for Poor Outcomes in Children With Severe Sepsis and Septic Shock.

Vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase (sFLT), are biomarkers of endothelial activation. Vascular endothelial growth factor and sFLT have been associated with sepsis severity among adults, but pediatric data are lacking. The goal of this study was to assess VEGF and sFLT as predictors of outcome for children with sepsis. METHODS: Biomarkers measured for each patient at time of presentation to the emergency department were compared in children with septic shock versus children with sepsis without shock. For children with septic shock, the associations between biomarker levels and clinical outcome measures, including intensive care unit and hospital length of stay, vasoactive inotrope score, and measures of organ dysfunction, were assessed. RESULTS: Soluble fms-like tyrosine kinase and VEGF were elevated in children with septic shock (n = 73) compared with those with sepsis (n = 93). Elevated sFLT but not VEGF was associated with longer intensive care unit length of stay (P = 0.003), longer time requiring vasoactive agents (P < 0.001), higher maximum vasoactive inotrope score (P < 0.001), and higher maximum pediatric logistic organ dysfunction score (P < 0.001). CONCLUSIONS: Vascular endothelial growth factor and sFLT measured in the emergency department are elevated in children with septic shock, and elevated sFLT but not VEGF is associated with worse clinical outcomes.