Postoperative thrombotic events following major surgery in patients with a history of COVID-19: a retrospective cohort analysis of commercially insured beneficiaries in the USA.

PURPOSE: We sought to evaluate the synergistic risk of postoperative thrombosis in patients with a history of COVID-19 who undergo major surgery. Major surgery and SARS-CoV-2 infection are independently associated with an increased risk of thrombosis, but the magnitude of additional risk beyond surgery conferred by a COVID-19 history on the development of perioperative thrombotic events has not been clearly elucidated in the literature. METHODS: We conducted a retrospective cohort study among commercially insured adults in the USA from March 2020 to June 2021 using the Optum Labs Data Warehouse (OLDW), a longitudinal, real-world data asset containing deidentified administrative claims and electronic health records. We compared patients with prior COVID-19 who underwent surgery with control individuals who underwent surgery without a COVID-19 history and with control individuals who did not undergo surgery with and without a COVID-19 history. We assessed the interaction of surgery and previous COVID-19 on perioperative thrombotic events (venous thromboembolism and major adverse cardiovascular events) within 90 days using multivariable logistic regression and interaction analysis. RESULTS: Two million and two-hundred thousand eligible patients were identified from the OLDW. Patients in the surgical cohorts were older and more medically complex than nonsurgical population controls. After adjusting for confounders, only surgical exposure-not COVID-19 history-remained associated with perioperative thrombotic events (adjusted odds ratio [aOR], 4.07; 95% confidence interval [CI], 3.81 to 4.36). The multiplicative interaction term (aOR, 1.25; 95% CI, 0.96 to 1.61) and the synergy index (0.76; 95% CI, 0.56 to 1.04) suggest minimal effect modification of prior COVID-19 on surgery with regards to overall thrombotic risk. CONCLUSIONS: We found no evidence of synergistic thrombotic risk from previous COVID-19 in patients who underwent selected major surgery relative to the baseline thrombotic risk from surgery alone.

RéSUMé: OBJECTIF: Nous avons cherché à évaluer le risque synergique de thrombose postopératoire chez les patient·es ayant des antécédents de COVID-19 qui bénéficient d'une intervention chirurgicale majeure. La chirurgie majeure et l'infection par le SRAS-CoV-2 sont indépendamment associées à un risque accru de thrombose, mais l'ampleur du risque supplémentaire d'apparition de complications thrombotiques périopératoires, au-delà de la chirurgie et conféré par des antécédents de COVID-19, n'a pas été clairement élucidée dans la littérature. MéTHODE: Nous avons mené une étude de cohorte rétrospective auprès d'adultes assuré·es commercialement aux États-Unis de mars 2020 à juin 2021 à l'aide de la base de données Optum Labs Data Warehouse (OLDW), un actif de données longitudinales du monde réel contenant des requêtes administratives anonymisées et des dossiers de santé électroniques. Nous avons comparé les patient·es ayant déjà souffert de COVID-19 et ayant bénéficié d'une intervention chirurgicale avec des personnes témoins ayant bénéficié d'une intervention chirurgicale sans antécédents de COVID-19 et avec des personnes témoins n'ayant pas bénéficié de chirurgie, avec et sans antécédents de COVID-19. Nous avons évalué l'interaction de la chirurgie et des antécédents de COVID-19 avec les complications thrombotiques périopératoires (thromboembolie veineuse et événements cardiovasculaires indésirables majeurs) dans les 90 jours à l'aide d'une régression logistique multivariée et d'une analyse des interactions. RéSULTATS: Deux millions deux cent mille personnes admissibles ont été identifiées à partir du registre OLDW. Les patient·es des cohortes chirurgicales étaient plus âgé·es et présentaient une plus grande complexité médicale que les personnes témoins de la population non chirurgicale. Après ajustement pour tenir compte des facteurs de confusion, seule l'exposition chirurgicale ­ et non les antécédents de COVID-19 ­ est restée associée aux complications thrombotiques périopératoires (rapport de cotes ajusté [RCa], 4,07; intervalle de confiance [IC] à 95 %, 3,81 à 4,36). Le terme d'interaction multiplicative (RCa, 1,25; IC 95 %, 0,96 à 1,61) et l'indice de synergie (0,76; IC 95 %, 0,56 à 1,04) suggèrent une modification minimale de l'effet d'un diagnostic antérieur de COVID-19 sur la chirurgie en matière de risque thrombotique global. CONCLUSION: Nous n'avons trouvé aucune preuve de risque thrombotique synergique lié à une COVID-19 antérieure chez les patient·es ayant bénéficié d'une intervention chirurgicale par rapport au risque thrombotique de base lié à la chirurgie seule.

Intraoperative Use of Albumin in Major Noncardiac Surgery: Incidence, Variability, and Association With Outcomes.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P <0.001), severe AKI (aOR 1.45, 95% CI 1.34-1.56, P <0.001), net-positive fluid balance (aOR 1.18, 95% CI 1.16-1.20, P <0.001), pulmonary complications (aOR 1.56, 95% CI 1.30-1.86, P <0.001), and 30-day all-cause mortality (aOR 1.37, 95% CI 1.26-1.49, P <0.001). CONCLUSIONS: Intravenous albumin is commonly administered among noncardiac surgeries with significant inter-institutional variability in use in the United States. Albumin administration was associated with an increased risk of postoperative complications.

Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting.

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.

Fluids, vasopressors, and acute kidney injury after major abdominal surgery between 2015 and 2019: a multicentre retrospective analysis.

BACKGROUND: Practice patterns related to intraoperative fluid administration and vasopressor use have potentially evolved over recent years. However, the extent of such changes and their association with perioperative outcomes, such as the development of acute kidney injury (AKI), have not been studied. METHODS: We performed a retrospective analysis of major abdominal surgeries in adults across 26 US hospitals between 2015 and 2019. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes definition (KDIGO) using only serum creatinine criteria. Univariable linear predictive additive models were used to describe the dose-dependent risk of AKI given fluid administration or vasopressor use. RESULTS: Over the study period, we observed a decrease in the volume of crystalloid administered, a decrease in the proportion of patients receiving more than 10 ml kg-1 h-1 of crystalloid, an increase in the amount of norepinephrine equivalents administered, and a decreased duration of hypotension. The incidence of AKI increased between 2016 and 2019. An increase of crystalloid administration from 1 to 10 ml kg-1 h-1 was associated with a 58% decreased risk of AKI. CONCLUSIONS: Despite decreased duration of hypotension during the study period, decreased fluid administration and increased vasopressor use were associated with increased incidence of AKI. Crystalloid administration below 10 ml kg-1 h-1 was associated with an increased risk of AKI. Although no causality can be concluded, these data suggest that prevention and treatment of hypotension during abdominal surgery with liberal use of vasopressors at the expense of fluid administration is associated with an increased risk of postoperative AKI.

The Bolognese surgeon Giuseppe Ruggi: how and why the aseptic surgery was introduced in Bologna in the middle half of the XIX century.

BACKGROUND: The first reliable statistic data about perioperatory mortality were published in 1841 by the French Joseph-Francois Malgaigne (1806-1863): he referred to a mean mortality of 60% for amputations and this bad result was to be attributed mainly to hospital acquired diseases. The idea of "hospital acquired disease" although vague, included five infective nosologic entities, which at that time were diagnosed more frequently: erysipelas, tetan, pyemia, septicemia, and gangrene. Nonetheless, the suppuration with pus production was considered from most of the surgeons and doctors of that time as a necessary and unavoidable step in the process of wound healing. During the end of the eighteenth century, hospitals of the main European cities were transforming into aggregations of several wards, where the high concentration of patients created poor sanitary conditions and a consistent increase of perioperatory mortality. In 1865, Lister applied his first antiseptic dressing on the surface of an exposed fracture. These experimental attempts lead to an effective reduction of wound infections respect to the dressing with strings used previously. DISCUSSION: Lister's innovations in the field of wound treatment were based on two brand new concepts: germs causing rot were ubiquitarious and the wound infection was not a normal step in the process of wound healing. The concept of antisepsis was hardly accepted in the European surgical world: "Of all countries, Italy is the most indifferent and uninterested in experimenting this method, which has been so favorably judged from the greatest surgical societies in Germany". This quotation from the young surgeon Giuseppe Ruggi (1844-1925) from Bologna comes from his article where he presented his first experiences on aseptic medications started the previous year in the Surgical Department of Maggiore Hospital in Bologna. In his report, Ruggi described the adopted technique and suggested that the medication should be extended to all the surgical patients of the hospital:"… this is needed to totally remove from the hospital all those elements of infection which grow in the wounds dressed with the old method". The experimentation of this new dressing for the few treated cases was rigorous and concerned both the sterilization of surgical tools with the fenic acid (5%) and the shaving of the skin. Ruggi also observed that there was no correlation between the seriousness of the wound and its extension or way of healing: when "simple" cases that "should heal without complication" showed fever he often realized that "it was often due to a medication performed without following the rules for an accurate disinfection and dressing". Ruggi thought that the fever was connected to "reabsorption of pyrogenic substances, which can be removed cleaning and disinfecting the wound" in cases of wounds not accurately dressed and rarely medicated. Frequent postoperative medications of the wound were able to eliminate the fever within 2 h. Ruggi's attitude toward the fine reasoning lead him to introduce the concept of immunodeficiency related to physical deterioration: "… patients treated for surgical disease may sometimes suffer from complications of medical conditions, which initially escape the most accurate investigations… The surgical operation could, in some cases, hold the balance of power". CONCLUSIONS: The obtained results, published in 1879, appear extremely interesting. As he wrote in 1898, for the presentation of his case record of more than 1000 laparotomies, he had started "… operating as a young surgeon without any tutor, helped only by his mind and what he could deduce from publications existing at the moment …".

T.E.A. Study: three-day ertapenem versus three-day Ampicillin-Sulbactam.

BACKGROUND: Intra-abdominal infections are one of the most common infections encountered by a general surgeon. However, despite this prevalence, standardized guidelines outlining the proper use of antibiotic therapy are poorly defined due to a lack of clinical trials investigating the ideal duration of antibiotic treatment. The aim of this study is to compare the efficacy and safety of a three-day treatment regimen of Ampicillin-Sulbactam to that of a three-day regimen of Ertapenem in patients with localized peritonitis ranging from mild to moderate severity. METHODS: This study is a prospective, multi-center, randomized investigation performed in the Department of General, Emergency, and Transplant Surgery of St. Orsola-Malpighi University Hospital in Bologna, Italy. Discrete data were analyzed using the Chi-squared and Fisher exact tests. Differences between the two study groups were considered statistically significant for p-values less than 0.05. RESULTS: 71 patients were treated with Ertapenem and 71 patients were treated with Ampicillin-Sulbactam. The two groups were comparable in terms of age and gender as well as the site of abdominal infection. Post-operative infection was identified in 12 patients: 10 with wound infections and 2 with intra-abdominal infections. In the Ertapenem group, 69 of the 71 patients (97%) were treated successfully, while the therapy failed in 2 cases (3%). Therapy failures were more frequent in the Unasyn group, amounting to 10 of 71 cases (p = 0.03). CONCLUSION: According to these preliminary findings, the authors conclude that a three-day Ertapenem treatment regimen is the most effective antibiotic therapy for patients with localized intra-abdominal infections ranging from mild to moderate severity. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov: NCT00630513.

The ACTIVE (Acute Cholecystitis Trial Invasive Versus Endoscopic) Study: multicenter randomized, double-blind, controlled trial of laparoscopic versus open surgery for acute cholecystitis.

BACKGROUND/AIMS: In some randomized controlled trials laparoscopic cholecystectomy (LC) for acute cholecystitis was associated with a shorter hospital stay when compared with open cholecystectomy (OC). These studies were not double blinded and without intention to treat purpose. METHODOLOGY: The present study project was a prospective, randomized investigation. The study was performed in the Department of General, Emergency and Transplant Surgery St Orsola-Malpighi University Hospital (Bologna, Italy). Subjects were divided in two groups: in the first group the patient was submitted to LC while in the second group was submitted to OC. RESULTS: Of 164 consecutive patients, 20 were excluded from the study. The two groups were similar in demographic and clinical characteristics. Seven (9.7%) patients in the LC group required conversion to OC. There were no deaths or bile duct lesions in either group, and the postoperative complication rate was similar (p=n.s.). The mean postoperative hospital stay was also comparable. CONCLUSIONS: Even though LC for acute and gangrenous cholecystitis is technically demanding, in experienced hands it is safe and effective. It does not increase the mortality and the morbidity rate with a low conversion rate and no difference in hospital stay.

Leveraging observational data to identify targeted patient populations for future randomized trials.

Randomized controlled trials reported in the literature are often affected by poor generalizability, and pragmatic trials have become an increasingly utilized workaround approach to overcome logistical limitations and explore routine interventions demonstrating equipoise in clinical practice. Intravenous albumin, for example, is commonly administered in the perioperative setting despite lacking supportive evidence. Given concerns for cost, safety, and efficacy, randomized trials are needed to explore the clinical equipoise of albumin therapy in this setting, and we therefore present an approach to identifying populations exposed to perioperative albumin to encourage clinical equipoise in patient selection and optimize study design for clinical trials.

Impact of Vasodilator Administration on Survival in Patients with Sepsis: A Systematic Review and Meta-Analysis.

Rationale: Sepsis and septic shock are associated with microcirculatory dysfunction, which is believed to contribute to sepsis-induced organ failure. Vasodilators have been proposed to improve tissue perfusion in sepsis, but the overall survival impact of this strategy is unclear. Objectives: To evaluate the impact of systemic vasodilator administration in patients with sepsis and septic shock on mortality. Methods: We conducted a meta-analysis using a random effects model. Published and unpublished randomized trials in adult patients with sepsis and septic shock were included when comparing the use of systemic vasodilators against no vasodilators. The primary outcome was 28-30-day mortality, and secondary outcomes were organ function and resource use measures. Results: We included eight randomized trials (1,076 patients). In patients randomized to vasodilator arms compared with those randomized to treatment without vasodilators, the 28-30-day mortality risk ratio was 0.74 (95% confidence interval, 0.54-1.01). In a chronological cumulative meta-analysis, the association between vasodilators and survival improved over time. In a prespecified subgroup analysis in 104 patients in two randomized trials, prostacyclin analogues were associated with a decreased rate of 28-30-day mortality among patients with sepsis and septic shock (risk ratio, 0.46; 95% confidence interval, 0.25-0.85). Conclusions: In patients with sepsis and septic shock, administration of vasodilators is not associated with decreased 28-30-day mortality, but the confidence interval suggests potential benefit, and the meta-analysis might lack power. Prostacyclin appears the most promising. The results of this meta-analysis should encourage randomized trials evaluating the impact of vasodilators on mortality in sepsis.

Negativity and Positivity in the ICU: Exploratory Development of Automated Sentiment Capture in the Electronic Health Record.

OBJECTIVES: To develop proof-of-concept algorithms using alternative approaches to capture provider sentiment in ICU notes. DESIGN: Retrospective observational cohort study. SETTING: The Multiparameter Intelligent Monitoring of Intensive Care III (MIMIC-III) and the University of California, San Francisco (UCSF) deidentified notes databases. PATIENTS: Adult (≥18 yr old) patients admitted to the ICU. MEASUREMENTS AND MAIN RESULTS: We developed two sentiment models: 1) a keywords-based approach using a consensus-based clinical sentiment lexicon comprised of 72 positive and 103 negative phrases, including negations and 2) a Decoding-enhanced Bidirectional Encoder Representations from Transformers with disentangled attention-v3-based deep learning model (keywords-independent) trained on clinical sentiment labels. We applied the models to 198,944 notes across 52,997 ICU admissions in the MIMIC-III database. Analyses were replicated on an external sample of patients admitted to a UCSF ICU from 2018 to 2019. We also labeled sentiment in 1,493 note fragments and compared the predictive accuracy of our tools to three popular sentiment classifiers. Clinical sentiment terms were found in 99% of patient visits across 88% of notes. Our two sentiment tools were substantially more predictive (Spearman correlations of 0.62-0.84, p values < 0.00001) of labeled sentiment compared with general language algorithms (0.28-0.46). CONCLUSION: Our exploratory healthcare-specific sentiment models can more accurately detect positivity and negativity in clinical notes compared with general sentiment tools not designed for clinical usage.

Peritoneal cystic mesothelioma: are surgery and HIPEC optimal first-line treatments?

BACKGROUND: Peritoneal cystic mesothelioma (PCM) is an uncommon clinical pathology. Its high rate of recurrence following partial or total resection as well as its spontaneous onset of malignancy have been well documented in a series of case studies. The medical community has yet to define standardized treatment guidelines for PCM. CASE REPORTS: This study reviews the case of 2 patients admitted and treated for PCM. Recent studies have reported improved recurrence and survival rates achieved by means of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), especially when used as first-line treatments. However, whether or not the use of CRS and HIPEC is more effective than a surgical regimen of multiple debulking procedures, is still the subject of debate. CONCLUSION: CRS and HIPEC as first-line treatments have lower morbidity and mortality rates than regimens of multiple back-to-back surgical procedures, and as such, the CRS/HIPEC method appears to be the more successful approach.

Microscopic margins of resection influence primary gastrointestinal stromal tumor survival.

BACKGROUND: Primary gastrointestinal stromal tumors (GISTs) are stromal tumors that arise from the gastrointestinal tract. Both surgical resection and molecular therapy are crucial in the treatment of these tumors. This study analyzes the outcomes of 151 patients with GIST treated at 3 institutions. These institutions comprise the GISTologist Study Group and provided follow-up data. PATIENTS AND METHODS: 151 patients with primary GIST were admitted and treated at the St. Orsola-Malpighi University Hospital in Bologna, Italy, the Catholic University Hospital in Rome, Italy, and the Modena University Hospital and National Cancer Institute in Naples, Italy, over the past 11 years. Patient data as well as tumor and therapy variables were studied to identify factors predicting survival with a focus on the microscopic margins of resection. RESULTS: All 151 patients had primary disease without metastasis and underwent complete resection of gross disease. The 5-year disease-free survival rate was 77%. Disease-free survival was predicted by tumor size, mitotic count, and margins of resection. Recurrence of disease after resection was predominantly intra-abdominal. CONCLUSIONS: Tumor size, mitotic count, and microscopic margins of resection predict disease-free survival in patients with primary GIST.

A prospective, multi centre, randomized clinical study to compare the efficacy and safety of Ertapenem 3 days versus Ampicillin-Sulbactam 3 days in the treatment of localized community acquired intra-abdominal infection. (T.E.A. Study: Three days Ertapenem vs three days Ampicillin-sulbactam).

BACKGROUND: The recommendations outlined in the latest guidelines published by the Surgical Infection Society (SIS) and the Infectious Disease Society of America (IDSA) regarding the proper duration of antibiotic therapy in patients with intra-abdominal infections are limited and non-specific. This ambiguity is due mainly to the lack of clinical trials on the topic of optimal duration of therapy. It is well known that the overuse of antibiotics has several important consequences such as increased treatment costs, reduced clinical efficacy, and above all, the increased emergence of antibiotic-resistant pathogens. Ampicillin-Sulbactam is a commonly used "first line" antibiotic for intra-abdominal infections. Ertapenem and Ampicillin-sulbactam are recommended as primary treatment agents for localized peritonitis by both the SIS and IDSA guidelines. METHODS/DESIGN: This study is a prospective multi-center randomized investigation. The study will be performed in the Departments of General, Emergency, and Transplant Surgery of Sant'Orsola-Malpighi University Hospital in Bologna, Italy, in the General Surgery Department of the Ospedali Riuniti of Bergamo, Italy, and in the Trauma and Emergency Surgery Department of Maggiore Hospital in Bologna, Italy, and will be conducted by all surgeons willing to participate in the study. The inclusion period of the study will take approximately two years before the planned number of 142 enrolled patients is reached. DISCUSSION: Ertapenem and Ampicillin-sulbactam are recommended both as primary treatment agents for localized peritonitis by both the SIS and IDSA guidelines. As one of the discussed topic is the optimal duration of the antibiotic therapy and this ambiguity is due mainly to the lack of clinical trials on the topic, the present study aims for obtain precise data. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00630513.

Tubercular bowel perforation: what to do?

BACKGROUND: The incidence of abdominal tuberculosis (TB) is increasing in western and developed countries. This pathology has several complications, including free intestinal perforation. The aim of this study was to analytically summarize all the pertinent literature discussing the various treatments for TB-related perforations. METHODS: We reviewed the patient database of the Emergency Surgery Department of the Bologna University Hospital, checking the last 13 years. A retrospective review was conducted of all reported cases of intestinal perforation due to intestinal TB published through 3 March 2009. RESULTS: 119 cases of abdominal TB presenting with intestinal perforation were published. There are no standardized guidelines regarding the surgical treatment. Of the 119 reported cases, 40 (33.6%) were treated with resection and anastomosis, 17 (14.2%) with direct sutures, 4 (3.3%) with a simple drain, and in 57, the treatment was not reported. CONCLUSION: No clinical evidence has been available for analysis to discern the optimal surgical strategy for treating intestinal perforations induced by TB. The direct closure of the perforation typically correlates with poor morbidity and mortality results. The better treatment seems to be the surgical resection of the perforated part with anastomosis. However, pharmacological therapy remains the essential pillar of treatment.

An innovative abdominal wall repair technique for infected prosthesis: the Eskimo technique.

The use of meshes to repair incisional hernias has been shown to reduce the recurrence rate, though it may increase the risk of surgical site infection. This is one of the most feared and devastating complications of surgical abdominal wall repair. The aim of this work is to describe a new surgical technique that was used to treat two patients suffering from chronic prosthesis infection. Additionally, the outcome of this procedure will be analyzed in terms of its safety, subsequent site infection and recurrence prevention. Two case reports are presented. The procedure was based on a wide surgical excision of the infected prosthesis and the surrounding tissues, plus abdominal wall repair with biological prosthesis. Both patients experienced an uneventful postoperative course. Infection of the surgical site resolved following the procedure and, after a mean follow-up of 36 months, no recurrences of the incisional hernia had occurred. This unique surgical technique not only proved to be safe, but it also solved the chronic prosthesis infection through its use of radical excision, without any postoperative complications or recurrence. This technique confirmed that biological prostheses can be used safely and effectively for implantation in sites of infection.

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-ß (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA.

Current regimens for the detection and surveillance of bladder cancer are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage bladder cancer who had urine collected either prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per patient with bladder cancer and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of bladder cancer. We detected utDNA pretreatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96% to 100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, P = 0.02) and cytology and cystoscopy combined (P ≤ 0.006), detecting 100% of bladder cancer cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of bladder cancer. SIGNIFICANCE: This study shows that utDNA can be detected using HTS with high sensitivity and specificity in patients with early-stage bladder cancer and during post-treatment surveillance, significantly outperforming standard diagnostic modalities and facilitating noninvasive detection, genotyping, and monitoring.This article is highlighted in the In This Issue feature, p. 453.

Pediatric Bickerstaff brainstem encephalitis: a systematic review of literature and case series.

OBJECTIVE: To characterize the phenotype of pediatric Bickerstaff's brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures. METHODS: We systematically reviewed PubMed, Web of Science, and SCOPUS databases as well as medical records at the Lucile Packard Children's Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ≤ 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia. RESULTS: We reviewed 682 manuscripts, identifying a total of 47 pediatric BBE cases. We also describe five previously unreported cases. The phenotype of these pediatric patients was similar to previously published literature. Sixty-eight percent of patients demonstrated positive anti-GQ1b antibody titers, yet the presence of these antibodies was not associated with longer times to recovery. Patients with neuroimaging abnormalities featured a longer median time to recovery, but this was not statistically significant (p = 0.124). Overall, patients treated with any form of immunotherapy (intravenous immunoglobulin, steroids, or plasmapheresis) demonstrated shorter median time to resolution of symptoms compared to supportive therapy, although this trend was not statistically significant (p = 0.277). Post-hoc t tests revealed a trend towards use of immunotherapy against supportive care alone (p = 0.174). CONCLUSION: Our study identified clinical, radiologic, and treatment features that may hold prognostic value for children with BBE. The role of immunotherapy remains under investigation but may prove of utility with further, randomized controlled studies in this rare disease.

Blood Pressure Elevation and Risk of Moyamoya Syndrome in Patients With Trisomy 21.

OBJECTIVES: Individuals with Down syndrome (DS) are at risk for the development of moyamoya syndrome (MMS); MMS is often recognized only after a resulting stroke has occurred. Our goal with this study was to determine if elevations in blood pressure (BP) precede acute presentation of MMS in individuals with DS. METHODS: A single-center, retrospective case-control study was performed. Thirty patients with MMS and DS and 116 patients with DS only were identified retrospectively. Three BP recordings were evaluated at set intervals (18-24 months, 12-18 months, and 6-12 months before diagnosis of MMS). These were then compared against control averages from patients with DS only. To assess changes over the time, we used general linear model repeated measures analysis of variance. To identify independent predictors of MMS and DS, we used a multivariable analysis using generalized estimating equations accounting for repeated measures of BP. RESULTS: BP in patients with MMS and DS rose significantly over the 24-month period preceding presentation (34th, 42nd, and 70th percentiles at the 18-24-month, 12-18-month, and 6-12-month periods, respectively). BPs in the patients with both MMS and DS were significantly higher than in the DS-only controls in the 6 to 12 (P < .001) and 12 to 18 months before presentation (P = .016). Higher Suzuki scores, bilateral disease, and posterior circulation involvement were also predictive of BP elevation before presentation. CONCLUSIONS: Elevations in BP may foreshadow presentation of MMS in individuals with DS. This simple, low-cost screening measure may lead to early identification of at-risk patients in the medical home and prevent irreversible neurologic injury.