Definitions of hospital-acquired pneumonia in trauma research: a systematic review.

PURPOSE: What are reported definitions of HAP in trauma patient research? METHODS: A systematic review was performed using the PubMed/MEDLINE database. We included all English, Dutch, and German original research papers in adult trauma patients reporting diagnostic criteria for hospital-acquired pneumonia diagnosis. The risk of bias was assessed using the MINORS criteria. RESULTS: Forty-six out of 5749 non-duplicate studies were included. Forty-seven unique criteria were reported and divided into five categories: clinical, laboratory, microbiological, radiologic, and miscellaneous. Eighteen studies used 33 unique guideline criteria; 28 studies used 36 unique non-guideline criteria. CONCLUSION: Clinical criteria for diagnosing HAP-both guideline and non-guideline-are widespread with no clear consensus, leading to restrictions in adequately comparing the available literature on HAP in trauma patients. Studies should at least report how a diagnosis was made, but preferably, they would use pre-defined guideline criteria for pneumonia diagnosis in a research setting. Ideally, one internationally accepted set of criteria is used to diagnose hospital-acquired pneumonia. LEVEL OF EVIDENCE: Level III.

Outcome of severely injured patients in a unique trauma system with 24/7 double trauma surgeon on-call service.

BACKGROUND: The presence of in-house attending trauma surgeons has improved efficiency of processes in the treatment of polytrauma patients. However, literature remains equivocal regarding the influence of the presence of in-house attendings on mortality. In our hospital there is a double trauma surgeon on-call system. In this system an in-house trauma surgeon is 24/7 backed up by a second trauma surgeon to assist with urgent surgery or multiple casualties. The aim of this study was to evaluate outcome in severely injured patients in this unique trauma system. METHODS: From 2014 to 2021, a prospective population-based cohort consisting of consecutive polytrauma patients aged ≥ 15 years requiring both urgent surgery (≤ 24h) and admission to Intensive Care Unit (ICU) was investigated. Demographics, treatment, outcome parameters and pre- and in-hospital transfer times were analyzed. RESULTS: Three hundred thirteen patients with a median age of 44 years (71% male), and median Injury Severity Score (ISS) of 33 were included. Mortality rate was 19% (68% due to traumatic brain injury). All patients stayed ≤ 32 min in ED before transport to either CT or OR. Fifty-one percent of patients who needed damage control surgery (DCS) had a more deranged physiology, needed more blood products, were more quickly in OR with shorter time in OR, than patients with early definitive care (EDC). There was no difference in mortality rate between DCS and EDC patients. Fifty-six percent of patients had surgery during off-hours. There was no difference in outcome between patients who had surgery during daytime and during off-hours. Death could possibly have been prevented in 1 exsanguinating patient (1.7%). CONCLUSION: In this cohort of severely injured patients in need of urgent surgery and ICU support it was demonstrated that surgical decision making was swift and accurate with low preventable death rates. 24/7 Physical presence of a dedicated trauma team has likely contributed to these good outcomes.

Evidence for a feeding related association between melanocortin in the NTS and Neuropeptide-Y in the PVN.

Melanocortin and neuropeptide-Y (NPY) are both involved in feeding and energy regulation, and they have opposite effects in the paraventricular nucleus of the hypothalamus (PVN). The present study examined an interaction between melanocortin in the nucleus of the solitary tract (NTS) and NPY in the PVN. Male Sprague-Dawley rats were implanted with cannulae in the injection sites of interest. In Experiment 1, subjects received either the melanocortin 3/4-receptor (MC3/4) antagonist SHU9119 (0, 10, 50 and 100 pmol/0.5 µl) or the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 µl) into the NTS. Food intake was measured at 1, 2, 4, 6 and 24-h post-injection. Administration of SHU9119 into the NTS significantly and dose-dependently increased food intake at 1, 2, 4, 6 and 6-24-h, and administration of MTII into the NTS significantly and dose-dependently decreased 24-h free feeding. In Experiment 2, subjects received the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 µl) into the NTS just prior to NPY (0 and 1µg/0.5 µl) in the PVN. PVN injection of NPY stimulated feeding, and administration of MTII (50, 100 and 200 pmol) into the NTS significantly and dose-dependently decreased NPY-induced feeding at 2, 4, 6 and 6-24-h. These data suggest that there could be a neuronal association between melanocortin in the NTS and NPY in the PVN, and that the melanocortin system in the NTS has an antagonistic effect on NPY-induced feeding in the PVN.

A Urine-based Genomic Assay Improves Risk Stratification for Patients with High-risk Hematuria Stratified According to the American Urological Association Guidelines.

BACKGROUND: According to the recent American Urological Association (AUA) guideline on hematuria, patients are stratified into groups with low, intermediate, and high risk of urothelial carcinoma (UC). These risk groups are based on clinical factors and do not incorporate urine-based tumor markers. OBJECTIVE: To evaluate whether a urine-based genomic assay improves the redefined AUA risk stratification for hematuria. DESIGN, SETTING, AND PARTICIPANTS: We selected patients with complete biomarker status, as assessed on urinary DNA, from a previously collected prospective Dutch hematuria cohort (n = 838). Patients were stratified into the AUA risk categories on the basis of sex, age, and type of hematuria. Biomarker status included mutation status for the FGFR3, TERT, and HRAS genes, and methylation status for the OTX1, ONECUT2, and TWIST1 genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the diagnostic model performance for different hematuria risk groups. Further analyses assessed the pretest and post-test UC probability in the hematuria subgroups using a Fagan nomogram. RESULTS AND LIMITATIONS: Overall, 65 patients (7.8%) were classified as low risk, 106 (12.6%) as intermediate risk, and 667 (79.6%) as high risk. The UC incidence differed significantly between the gross hematuria (21%, 98/457) and microscopic hematuria (4%, 14/381) groups (p < 0.001). All cancer cases were in the high-risk group, which had UC incidence of 16.8% (112/667). Application of the diagnostic model revealed robust performance among all risk groups (area under the receiver operating characteristic curve 0.929-0.971). Depending on the risk group evaluated, a negative urine assay was associated with post-test UC probability of 0.3-2%, whereas a positive urine assay was associated with post-test UC probability of 31-42%. CONCLUSIONS: This study shows the value that a urine-based genomic assay adds to the AUA guideline stratification for patients with hematuria. It seems justified to safely withhold cystoscopy for patients with AUA low risk who have a negative urine assay. In addition, evaluation should be expedited for patients with AUA intermediate or high risk and a positive urine assay. PATIENT SUMMARY: Patients who have blood in their urine (hematuria) can be classified as having low, intermediate, or high risk of having cancer in their urinary tract. We found that use of a urine-based genetic test improves the accuracy of predicting which patients are most likely to have cancer. Patients with a negative test may be able to avoid invasive tests, while further tests could be prioritized for patients with a positive test.

Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer.

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. PATIENT SUMMARY: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria.

PURPOSE: Microhematuria is a prevalent condition and the American Urological Association has developed a new risk-stratified approach for the evaluation of patients with microhematuria. Our objective was to provide the first evaluation of this important guideline. MATERIALS AND METHODS: This multinational cohort study combines contemporary patients from 5 clinical trials and 2 prospective registries who underwent urological evaluation for hematuria. Patients were stratified into American Urological Association risk strata (low, intermediate or high risk) based on sex, age, degree of hematuria, and smoking history. The primary end point was the incidence of bladder cancer within each risk stratum. RESULTS: A total of 15,779 patients were included in the analysis. Overall, 727 patients (4.6%) were classified as low risk, 1,863 patients (11.8%) were classified as intermediate risk, and 13,189 patients (83.6%) were classified as high risk. The predominance of high risk patients was consistent across all cohorts. A total of 857 bladder cancers were diagnosed with a bladder cancer incidence of 5.4%. Bladder cancer was more prevalent in men, smokers, older patients and patients with gross hematuria. The cancer incidence for low, intermediate and high risk groups was 0.4% (3 patients), 1.0% (18 patients) and 6.3% (836 patients), respectively. CONCLUSIONS: The new risk stratification system separates hematuria patients into clinically meaningful categories with differing likelihoods of bladder cancer that would justify evaluating the low, intermediate and high risk groups with incremental intensity. Furthermore, it provides the relative incidence of bladder cancer in each risk group which should facilitate patient counseling regarding the risks and benefits of evaluation for bladder cancer.

A Urine Based Genomic Assay to Triage Patients with Hematuria for Cystoscopy.

PURPOSE: Current clinical guidelines recommend cystoscopy in patients who present with hematuria to rule out a bladder tumor. We evaluated whether our previously developed urine assay was able to triage patients with hematuria for cystoscopy in a large prospective cohort. MATERIALS AND METHODS: A urine sample was collected before cystoscopy and mutation/methylation status of 6 genes was determined on cellular DNA. The existing diagnostic model was validated on this cohort. Logistic regression was applied to investigate other potential variables. The primary end point was the model performance as indicated by the AUC. Secondary end points were sensitivity, specificity and negative predictive value. Clinical usefulness was determined by the net benefit approach. RESULTS: In 838 patients biomarker status could be determined for all genes. Urothelial cancer was observed in 112 patients (98 of 457 in the gross and 14 of 381 in the microscopic hematuria group). Validation of the existing model resulted in an AUC of 0.93. Logistic regression analysis identified type of hematuria as a significant additional variable. Adding type of hematuria resulted in an AUC of 0.95 (96% sensitivity, 73% specificity, 99% negative predictive value). The assay identified all upper tract tumors not visible by cystoscopy (in 6). Net benefit analysis showed that the urine assay should be preferred over current clinical practice. Implementing the urine assay as a triage tool could lead to a 53% reduction in cystoscopies. CONCLUSIONS: The urine assay detected urothelial cancer with a very high accuracy and can be used to triage patients presenting with hematuria for cystoscopy.

The prevalence and risk factors of canine demodicosis: A retrospective long-term study of 409 cases.

Canine demodicosis is a common skin disorder with multiple risk factors, including age and breed predisposition. There is relatively limited information about the risk factors for canine demodicosis in large canine populations. This retrospective case-control study was conducted by searching the electronic records of dogs with skin lesions for the presence of Demodex mites in skin scrapings. Diagnosis of demodicosis was based on the presence of skin lesions and mites in skin scrapings. Multivariate analysis was conducted using logistic regression analysis to estimate the relative risk and odds ratio of variables hypothesized to influence the risk of canine demodicosis, such as age, sex, breed, season, and parasitic infection. The results of multivariate logistic regression analysis showed a positive correlation between the dogs' age and demodicosis. Dogs older than three years, as well as puppies, had a high risk of demodicosis (P0.05). Breeds with the greatest association (odds ratio) with demodicosis included the American Staffordshire Terrier (OR=0.9) and Moscow Watchdog (OR=0.2). The presence of intestinal parasites, such as Diphyllobothrium latum, was significantly associated with demodicosis.

Management of Hemodynamically Unstable Pelvic Ring Fractures.

Hemodynamically unstable pelvic fractures are challenging high-energy traumas. In many cases, these severely injured patients have additional traumatic injuries that also require a trauma surgeon's attention. However, these patients are often in extremis and require a multidisciplinary approach that needs to be set up in minutes. This calls for an evidence-based treatment algorithm. We think that the treatment of hemodynamically unstable pelvic fractures should primarily involve thorough resuscitation, mechanical stabilization, and preperitoneal pelvic packing. Angioembolization should be considered in patients that remain hemodynamically unstable. However, it should be used as an adjunct, rather than a primary means to achieve hemodynamic stability as most of the exsanguinating bleeding sources in pelvic trauma are of venous origin. Time is of the essence in these patients and should therefore be used appropriately. Hence, the hemodynamic status and physiology should be the driving force behind each decision-making step within the algorithm.

Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While MIBC subtyping has primarily been based on messenger RNA (mRNA), long non-coding RNAs (lncRNAs) may provide additional resolution. METHODS: LncRNA expression was quantified from microarray data of a MIBC cohort treated with neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) (n = 223). Unsupervised consensus clustering of highly variant lncRNAs identified a four-cluster solution, which was characterized using a panel of MIBC biomarkers, regulon activity profiles, gene signatures, and survival analysis. The four-cluster solution was confirmed in The Cancer Genome Atlas (TCGA) cohort (n = 405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and validated in two independent cohorts (n = 255 and n = 94). RESULTS: NAC and TCGA cohorts both contained an lncRNA cluster (LC3) with favorable prognosis that was enriched with tumors of the luminal-papillary (LP) subtype. In both cohorts, patients with LP tumors in LC3 (LPL-C3) were younger and had organ-confined, node-negative disease. The LPL-C3 tumors had enhanced FGFR3, SHH, and wild-type p53 pathway activity. In the TCGA cohort, LPL-C3 tumors were enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts. CONCLUSIONS: Using lncRNA expression profiles, we identified a biologically distinct subgroup of luminal-papillary MIBC with a favorable prognosis. These data suggest that lncRNAs provide additional information for higher-resolution subtyping, potentially improving precision patient management.

Urinary peptide panel for prognostic assessment of bladder cancer relapse.

Non-invasive tools stratifying bladder cancer (BC) patients according to the risk of relapse are urgently needed to guide clinical intervention. As a follow-up to the previously published study on CE-MS-based urinary biomarkers for BC detection and recurrence monitoring, we expanded the investigation towards BC patients with longitudinal data. Profiling datasets of BC patients with follow-up information regarding the relapse status were investigated. The peptidomics dataset (n = 98) was split into training and test set. Cox regression was utilized for feature selection in the training set. Investigation of the entire training set at the single peptide level revealed 36 peptides being strong independent prognostic markers of disease relapse. Those features were further integrated into a Random Forest-based model evaluating the risk of relapse for BC patients. Performance of the model was assessed in the test cohort, showing high significance in BC relapse prognosis [HR = 5.76, p-value = 0.0001, c-index = 0.64]. Urinary peptide profiles integrated into a prognostic model allow for quantitative risk assessment of BC relapse highlighting the need for its incorporation in prospective studies to establish its value in the clinical management of BC.

Fabrication of Decellularized Cartilage-derived Matrix Scaffolds.

Osteochondral defects lack sufficient intrinsic repair capacity to regenerate functionally sound bone and cartilage tissue. To this extent, cartilage research has focused on the development of regenerative scaffolds. This article describes the development of scaffolds that are completely derived from natural cartilage extracellular matrix, coming from an equine donor. Potential applications of the scaffolds include producing allografts for cartilage repair, serving as a scaffold for osteochondral tissue engineering, and providing in vitro models to study tissue formation. By decellularizing the tissue, the donor cells are removed, but many of the natural bioactive cues are thought to be retained. The main advantage of using such a natural scaffold in comparison to a synthetically produced scaffold is that no further functionalization of polymers is required to drive osteochondral tissue regeneration. The cartilage-derived matrix scaffolds can be used for bone and cartilage tissue regeneration in both in vivo and in vitro settings.

[Exercise and fasting induced movement disorder in children: think of the GLUT1 deficiency syndrome]. / Een bewegingsstoornis na inspanning en vasten bij kinderen.

BACKGROUND: Glucose transporter type 1 (GLUT1) enables glucose to pass through the blood-brain barrier. A hereditary deficiency of this protein may lead to clinical symptoms when blood glucose levels are decreasing. CASE DESCRIPTION: A 7-year-old girl with therapy-resistant childhood absence epilepsy presented with an exercise and fasting induced dystonic and atactic movement pattern. The movement pattern disappears postprandial. Based on a reduced glucose in the liquor, and also a reduced liquor glucose/serum glucose ratio, the diagnosis of GLUT1 deficiency syndrome was considered. Through genetic diagnostics a mutation of the SLC2A1 gene was identified, thereby confirming the initial diagnosis. The patient was referred to a tertiary centre for advice on following a ketogenic diet. After initiation of this treatment she no longer experienced absence epilepsy or paroxysmal dyskinesia episodes. CONCLUSION: GLUT1 deficiency syndrome is a relatively underdiagnosed disease. The recommended therapy is adherence to a ketogenic diet. With this diet the symptoms are treated, yet at the same time the further development of the brain is stimulated.

HIV and viral hepatitis coinfection analysis using surveillance data from 15 US states and two cities.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Recommendations for follow-up of muscle-invasive bladder cancer patients: A consensus by the international bladder cancer network.

RATIONALE: Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference. METHODS: A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up-frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up. OUTCOME: An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data.

Comparison of rocuronium-induced neuromuscular blockade in second trimester pregnant women and non-pregnant women.

BACKGROUND: This study set out to compare the onset and duration of rocuronium-induced neuromuscular blockade in second trimester pregnant women and non-pregnant women receiving general anesthesia. METHODS: Forty-seven pregnant (Group P) and forty-seven non-pregnant (Group C) women were enrolled. Anesthesia was induced with propofol 2.0 mg/kg and rocuronium 0.6 mg/kg, and neuromuscular blockade was assessed with an accelerometric sensor using train-of-four stimulation (TOF-Watch® SX). Tracheal intubation was performed at maximum depression of the first twitch (T1) and anesthesia was maintained with sevoflurane 1.5-2.5% and 50% oxygen in air. We recorded the times to maximum T1 depression and 5% and 25% T1 recovery, as well as the mean arterial pressure and heart rate at baseline, injection of rocuronium, intubation, and 5% and 25% T1 recovery. RESULTS: The onset of rocuronium-induced neuromuscular blockade (time to maximum T1 depression) did not differ significantly between the groups. The duration (time to 25% T1 recovery) was significantly longer in Group P than in Group C (45.7 ±â€¯12.9 min vs 40.6 ±â€¯10.4 min, P <0.037). During the recovery period from the blockade, the mean arterial pressure was significantly lower in Group P than in Group C. CONCLUSION: Our data showed that the rocuronium-induced neuromuscular blockade did not significantly differ in onset but lasted significantly longer in second trimester pregnant women compared with non-pregnant women.