Embryology, anatomy, physiology and pathophysiology of the peritoneum and the peritoneal vasculature.

The peritoneum is a large serous membrane with both epithelial and mesenchymal features, and is essential for maintaining an intra-abdominal homeostatic equilibrium. The peritoneum plays a central role in the pathogenesis of a number of disorders. Pathological processes affecting the peritoneum such as inflammation and carcinomatosis can have serious clinical consequences, but the pathophysiology of these conditions is poorly understood. Understanding peritoneal embryology, anatomy and physiology is crucial to comprehend pathophysiological mechanisms and to devise a new focus for research. The vascular response to pathological processes appears to be of considerable importance, since the peritoneal vasculature plays a pivotal role in most associated diseases. Therefore, this review summarizes currently available literature with special emphasis on the development, anatomy and function of the peritoneal vasculature. Pathological processes are described to illustrate physiological and pathophysiological characteristics of the peritoneum.

Rapid Molecular Tests for Influenza, Respiratory Syncytial Virus, and Other Respiratory Viruses: A Systematic Review of Diagnostic Accuracy and Clinical Impact Studies.

We systematically reviewed available evidence from Embase, Medline, and the Cochrane Library on diagnostic accuracy and clinical impact of commercially available rapid (results <3 hours) molecular diagnostics for respiratory viruses as compared to conventional molecular tests. Quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies criteria for diagnostic test accuracy (DTA) studies, and the Cochrane Risk of Bias Assessment and Risk of Bias in Nonrandomized Studies of Interventions criteria for randomized and observational impact studies, respectively. Sixty-three DTA reports (56 studies) were meta-analyzed with a pooled sensitivity of 90.9% (95% confidence interval [CI], 88.7%-93.1%) and specificity of 96.1% (95% CI, 94.2%-97.9%) for the detection of either influenza virus (n = 29), respiratory syncytial virus (RSV) (n = 1), influenza virus and RSV (n = 19), or a viral panel including influenza virus and RSV (n = 14). The 15 included impact studies (5 randomized) were very heterogeneous and results were therefore inconclusive. However, we suggest that implementation of rapid diagnostics in hospital care settings should be considered.

External validation and update of a prognostic model to predict mortality in hospitalized adults with RSV: A retrospective Dutch cohort study.

Respiratory syncytial virus (RSV) causes significant mortality in hospitalized adults. Prediction of poor outcomes improves targeted management and clinical outcomes. We externally validated and updated existing models to predict poor outcome in hospitalized RSV-infected adults. In this single center, retrospective, observational cohort study, we included hospitalized adults with respiratory tract infections (RTIs) and a positive polymerase chain reaction for RSV (A/B) on respiratory tract samples (2005-2018). We validated existing prediction models and updated the best discriminating model by revision, recalibration, and incremental value testing. We included 192 RSV-infected patients (median age 60.7 years, 57% male, 65% immunocompromised, and 43% with lower RTI). Sixteen patients (8%) died within 30 days. During hospitalization, 16 (8%) died, 30 (16%) were admitted to intensive care unit, 21 (11%) needed invasive mechanical ventilation, and 5 (3%) noninvasive positive pressure ventilation. Existing models performed moderately at external validation, with C-statistics 0.6 to 0.7 and moderate calibration. Updating to a model including lower RTI, chronic pulmonary disease, temperature, confusion and urea, increased the C-statistic to 0.76 (95% confidence interval, 0.61-0.91) to predict in-hospital mortality. In conclusion, existing models to predict poor prognosis among hospitalized RSV-infected adults perform moderately at external validation. A prognostic model may help to identify and treat RSV-infected adults at high-risk of death.

Use of the moving epidemic method (MEM) to assess national surveillance data for respiratory syncytial virus (RSV) in the Netherlands, 2005 to 2017.

BackgroundTo control respiratory syncytial virus (RSV), which causes acute respiratory infections, data and methods to assess its epidemiology are important.AimWe sought to describe RSV seasonality, affected age groups and RSV-type distribution over 12 consecutive seasons in the Netherlands, as well as to validate the moving epidemic method (MEM) for monitoring RSV epidemics.MethodsWe used 2005-17 laboratory surveillance data and sentinel data. For RSV seasonality evaluation, epidemic thresholds (i) at 1.2% of the cumulative number of RSV-positive patients per season and (ii) at 20 detections per week (for laboratory data) were employed. We also assessed MEM thresholds.ResultsIn laboratory data RSV was reported 25,491 times (no denominator). In sentinel data 5.6% (767/13,577) of specimens tested RSV positive. Over 12 seasons, sentinel data showed percentage increases of RSV positive samples. The average epidemic length was 18.0 weeks (95% confidence intervals (CI): 16.3-19.7) and 16.5 weeks (95% CI: 14.0-18.0) for laboratory and sentinel data, respectively. Epidemics started on average in week 46 (95% CI: 45-48) and 47 (95% CI: 46-49), respectively. The peak was on average in the first week of January in both datasets. MEM showed similar results to the other methods. RSV incidence was highest in youngest (0-1 and >1-2 years) and oldest (>65-75 and > 75 years) age groups, with age distribution remaining stable over time. RSV-type dominance alternated every one or two seasons.ConclusionsOur findings provide baseline information for immunisation advisory groups. The possibility of employing MEM to monitor RSV epidemics allows prospective, nearly real-time use of surveillance data.

Long-term outcome of transvenous pacemaker implantation in infants: a retrospective cohort study.

AIM: Evaluation of long-term outcome of transvenous pacemaker (PM) implantation in infants. METHODS AND RESULTS: A retrospective analysis of all transvenous PM implantations in infants <10 kg between September 1997 and October 2001 was made. Indications for PM implantation, age at implantation, and determinants of long-term outcome including cardiac function, PM function, and PM (system) complications were noted. Seven patients underwent transvenous VVI(R) PM implantation. Median age at implantation was 3 days (range: 1 day to 14 months), median weight 3.5 kg (range: 2.3-8.7 kg), and median follow-up 14 years (range: 12.3-16.3 years). Pacemaker indications were congenital complete atrioventricular block (n = 4), long QT syndrome with heart block (n = 2), and post-operative complete atrioventricular block with sinus node dysfunction (n = 1). No procedural complications were noted. Today all patients are alive and symptom free with good PM and cardiac function. Two patients underwent PM generator relocation for imminent skin necrosis and skin traction. Two patients suffered from asymptomatic left subclavian vein occlusion and developed thrombosis on the PM electrode. Three patients were converted to an epicardial PM system, due to atrial perforation after upgrading procedure (n = 1), syncope with need for implantable cardioverter defibrillator implantation (n = 1), and systolic dysfunction with development of dilated cardiomyopathy, which normalized under cardiac resynchronization therapy pacing (n = 1). Two patients needed atrioventricular (AV) valve repair for severe insufficiency. Two patients underwent repositioning of dysfunctional PM leads. In five patients, transvenous leads were removed. Indications were elective lead replacement (n = 1), atrial perforation (n = 1), and switch to an epicardial system (n = 3). CONCLUSION: Transvenous PM implantation in infants (<10 kg) is associated with a high incidence of vascular occlusion, thrombosis, and severe atrioventricular valve regurgitation during long-term follow-up. We advocate an epicardial approach for PM implantation in small children.

Translational and pharmacological principles of hyperthermic intraperitoneal chemotherapy for ovarian cancer.

The long-term survival of advanced-stage ovarian cancer patients remains poor, despite extensive cytoreductive surgery, chemotherapy, and the recent addition of poly (ADP-ribose) polymerase inhibitors (PARPi). Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown survival benefit by specifically targeting peritoneal metastases, the primary site of disease recurrence. Different aspects of how HIPEC exerts its effect remain poorly understood. Improved understanding of the effects of hyperthermia on ovarian cancer cells, the synergy of hyperthermia with intraperitoneal chemotherapy, and the pharmacological and pharmacokinetic properties of intraperitoneally administered cisplatin may help identify ways to optimize the efficacy of HIPEC. This review provides an overview of these translational and pharmacological principles of HIPEC and aims to expose knowledge gaps that may direct further research to optimize the HIPEC procedure and ultimately improve survival for women with advanced ovarian cancer.

Poor perfusion of the microvasculature in peritoneal metastases of ovarian cancer.

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment.

More targeted use of oseltamivir and in-hospital isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients.

BACKGROUND: Immunocompromised adults are more vulnerable to a complicated course of viral respiratory tract infections (RTI). OBJECTIVES: Provide evidence on the effect of implementation of rapid molecular diagnostics for viruses on use of in-hospital isolation facilities, oseltamivir and antibiotic usage, and other clinical outcomes in immunocompromised patients. STUDY DESIGN: A before-after study during two consecutive respiratory viral seasons, including immunocompromised adult patients presenting at a tertiary care emergency department with clinical suspicion of RTI. During the first season (2016/2017), respiratory viruses were detected using inhouse real-time PCR. The second season (2017/2018), we implemented a diagnostic flowchart including a rapid molecular test for 15 respiratory viruses (FilmArray®). We assessed the effect of this implementation on need for isolation, antivirals and empirical antibiotics. RESULTS: We included 192 immunocompromised adult patients during the first and 378 during the second season. Respiratory viral testing was performed in 135 patients (70%) during the first and 284 (75%) during the second season (p = 0.218) of which 213 (75%) using the rapid test. After implementation, use of in-hospital isolation facilities was reduced (adjusted odds ratio 0.35, 95%CI 0.19-0.64). Furthermore, adequate use of oseltamivir improved, with fewer prescriptions in influenza negative patients (0.15, 95%CI 0.08-0.28) and more in influenza positive patients (11.13, 95%CI 1.75-70.86). No effect was observed on empirical antibiotic use, hospital admissions, length of hospital stay or safety outcomes. CONCLUSIONS: Implementation of rapid molecular testing for respiratory viruses in adult immunocompromised patients results in more adequate use of oseltamivir and in-hospital isolation facilities without compromising safety.

High epidemic burden of RSV disease coinciding with genetic alterations causing amino acid substitutions in the RSV G-protein during the 2016/2017 season in The Netherlands.

BACKGROUND: We found amino acid substitutions in the Gglycoprotein of respiratory syncytial virus (RSV) A during the 2016/2017 epidemic in The Netherlands. OBJECTIVES: We evaluated whether these alterations led to increased RSV incidence and disease burden. STUDY DESIGN: We sequenced the gene encoding the G-protein of prospectively collected clinical specimens from secondary care adult patients testing positive for RSV during the 2016/2017 and 2017/2018 epidemic RSV season. We evaluated associations between genetic, clinical and epidemiological data. RESULTS: We included 49 RSV strains. In 2016/2017 28 strains were included, 20 community acquired RSV-A, 5 hospital acquired RSV-A and 3 community acquired RSV-B. In 2017/2018 21 strains were included, 8 community acquired RSV-A and 13 community acquired RSV-B. G-proteins of 10 out of the 20 community acquired 2016/2017 RSV-A strains shared a set of eight novel amino acid substitutions of which seven in mucin-like regions 1 and 2 and one in the heparin binding domain. This genetic variant was no longer detected among 2017/2018 RSV-A strains. Among patients carrying the novel RSV-A strain-type, 30% died. CONCLUSIONS: A set of eight amino acid substitutions was found in 50% of the 2016/2017 community acquired RSV-A G-proteins. This combination of substitutions was globally never observed before. The appearance of this new strain-type coincided with an increased RSV peak in The Netherlands and was associated with higher disease severity. The transient character of this epidemic strain-type suggests rapid clearance of this lineage in our study community.

High Frequency of Polymicrobial Infections After Surgical Resection of Malignant Bone and Soft Tissue Tumors: A Retrospective Cohort Study.

INTRODUCTION: Surgical resection of a malignant bone tumor (BT) or soft tissue tumor (STT), with or without prosthetic replacement, carries a high risk of developing postoperative infections. There is limited knowledge on the bacteriological spectrum of these postsurgical infections that necessitate empirical antibiotic therapy. The aim of this study was to analyze the incidence and microbiological features of site infections following BT or STT resection. METHODS: In this retrospective mono-center study, we analyzed the surgical and bacteriological data of all consecutive patients who developed an infection after surgical resection of a BT or STT between January 2010 and April 2014. RESULTS: Seventy-two consecutive patients who developed an infection on the site of surgical treatment for a BT (n = 42) or SST (n = 30) were included. Polymicrobism was frequently observed, more often associated with STTs (93%) than BTs (71%; P = 0.03). Gram-negative bacteria were more frequently isolated in STTs (55%) than in BTs (26%; P = 0.01) and non-prosthesis-associated infections (54%) than prosthesis-associated infections (29%; P = 0.04), whereas staphylococci were more frequently found in BTs (76%) than in STTs (52%; P = 0.03). Overall, we found gram negatives in 82% of early acute infections, 11% of chronic infections and 7% of late acute infections (P < 0.01). CONCLUSION: Postoperative infections in patients after surgical resection of BTs or STTs were often polymicrobial, especially following STTs. Causative bacteria were often gram negatives in STTs and non-prosthesis-associated infections, whereas staphylococci were predominant in BTs. Based on these findings, we recommend antibiotic coverage of both gram-positive and -negative bacteria with a combination of broad-spectrum antibiotics in STTs and antistaphylococcal antibiotics as first-line therapy in infections following BT surgery.

Serum Concentration of Anti-TNF Antibodies, Adverse Effects and Quality of Life in Patients with Inflammatory Bowel Disease in Remission on Maintenance Treatment.

BACKGROUND AND AIMS: High serum concentrations of infliximab [IFX] and adalimumab [ADA] may be associated with adverse effects in patients with inflammatory bowel disease [IBD]. We aimed to investigate whether high anti-tumour necrosis factor [TNF] trough levels [TLs] were associated with toxicity and impaired quality of life [QoL]. METHODS: We conducted a prospective cohort study in IBD patients in clinical and biochemical remission on IFX or ADA maintenance therapy. Trough serum concentrations and antidrug antibodies were measured in addition to biochemical markers of inflammation in serum and stool to confirm quiescent disease. QoL was assessed using the Inflammatory Bowel Disease Questionnaire and 36-item short form]. Side effects such as fatigue and arthralgia were measured with a visual analogue score [VAS]. Skin toxicity was reported with a European Organization for Research and Treatment of Cancer-derived score. RESULTS: In all, 252 IBD patients on maintenance anti-TNF therapy were screened, of whom 95 [73 with Crohn's disease, 22 with ulcerative colitis; 72 on IFX, 23 on ADA] were in clinical and biochemical remission and were included. Median TLs were 5.5 µg/ml and 6.6 µg/ml for IFX and ADA, respectively. Patients with anti-TNF TLs above median had lower IBDQ scores than patients with lower TLs [IBDQ 176 vs 187, p = 0.02], particularly regarding systemic symptoms and emotional status. A trend towards lower SF-36 and higher fatigue scores was observed in the higher anti-TNF TL group. Skin and arthralgia scores were not significantly different between the groups. CONCLUSIONS: IBD patients with higher anti-TNF serum concentrations had significantly lower disease-specific QoL. Fatigue, arthralgia, and skin lesions do not occur more often in these patients. These data are reassuring that high serum concentrations of anti-TNF antibodies are not toxic.