Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity.

Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells. In this study, we utilized our Organ-on-Chip assay to categorize sepsis patients into distinct phenotypes using patient data, neutrophil functional analysis, and proteomics. Methods: Following informed consent, neutrophils and plasma were isolated from sepsis patients in the Temple University Hospital ICU (n=45) and healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) were cultured in the Organ-on-Chip and treated with buffer or cytomix ((TNF/IL-1ß/IFNγ). Neutrophil adhesion and migration across HLMVEC in the Organ-on-Chip were used to categorize functional neutrophil phenotypes. Quantitative label-free global proteomics was performed on neutrophils to identify differentially expressed proteins. Plasma levels of sepsis biomarkers and neutrophil extracellular traps (NETs) were determined by ELISA. Results: We identified three functional phenotypes in critically ill ICU sepsis patients based on ex vivo neutrophil adhesion and migration patterns. The phenotypes were classified as: Hyperimmune characterized by enhanced neutrophil adhesion and migration, Hypoimmune that was unresponsive to stimulation, and Hybrid with increased adhesion but blunted migration. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group demonstrated higher oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. Patients with the Hyperimmune neutrophil phenotype had significantly increased circulating neutrophils and elevated plasma levels NETs. Conclusion: Neutrophils and NETs play a critical role in vascular barrier dysfunction in sepsis and elevated NETs may be a key biomarker identifying the Hyperimmune group. Our results establish significant associations between specific neutrophil functional phenotypes and disease severity and identify important functional parameters in sepsis pathophysiology that may provide a new approach to classify sepsis patients for specific therapeutic interventions.

Epidemiology and practice variations of shunt surgery for hydrocephalus: a nationwide registry-based study.

OBJECTIVE: Indications for surgical treatment of hydrocephalus (HC) can vary across centers. The authors sought to investigate the frequencies of surgically treated HC disorders and to study variations in the practice of shunt surgery in Norway, a country with universal and free healthcare. METHODS: This is a nationwide registry-based study using data from the Norwegian Patient Registry. Four neurosurgical centers serve exclusively in 4 defined geographic regions. All patients who underwent shunt surgery in Norway between January 1, 2008, and December 31, 2021, were included and regional differences and time trends were explored. RESULTS: The national annual rate of shunt surgery in the study period was 6.0 per 100,000. A total of 4139 individuals (49.5% male) underwent primary shunt surgeries, and a total of 9262 operations including revision surgeries were performed. There were statistically significant regional differences between the 4 treating centers in Norway in terms of patients' age (median 61 years, range 53-65 years); mean annual rate of primary shunt surgery (5.1-7.6 per 100,000); annual rate of primary shunt surgery in patients of different age groups (0.9-1.2 in 0-17 years, 1.8-2.7 in 18-64 years, and 1.6-3.9 in ≥ 65 years); annual rate of revision surgeries (2.4-5.7 per 100,000); annual rate of primary surgery for communicating HC (0.7-2.0 per 100,000); annual rate of primary surgery for normal pressure HC (0.5-1.8 per 100,000); and annual rate of primary surgery for HC associated with cerebrovascular disease (0.5-2.0 per 100,000). There was significant variation in overall shunt surgeries during the study period (p = 0.026), and there was an overall decrease in revision surgeries over time (p < 0.001). There appears to be a homogenization of revision surgeries over time. CONCLUSIONS: There are significant and large practice variations in the surgical management of HC in Norway. There are significant differences between regions, particularly in terms of rates of shunt surgery for some diagnoses (communicating HC, normal pressure HC, and HC associated with cerebrovascular disease) as well as revision rates.

Endoscopic third ventriculostomy for adults with hydrocephalus: creating a prognostic model for success: protocol for a retrospective multicentre study (Nordic ETV).

INTRODUCTION: Endoscopic third ventriculostomy (ETV) is becoming an increasingly widespread treatment for hydrocephalus, but research is primarily based on paediatric populations. In 2009, Kulkarni et al created the ETV Success score to predict the outcome of ETV in children. The purpose of this study is to create a prognostic model to predict the success of ETV for adult patients with hydrocephalus. The ability to predict who will benefit from an ETV will allow better primary patient selection both for ETV and shunting. This would reduce additional second procedures due to primary treatment failure. A success score specific for adults could also be used as a communication tool to provide better information and guidance to patients. METHODS AND ANALYSIS: The study will adhere to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis reporting guidelines and conducted as a retrospective chart review of all patients≥18 years of age treated with ETV at the participating centres between 1 January 2010 and 31 December 2018. Data collection is conducted locally in a standardised database. Univariate analysis will be used to identify several strong predictors to be included in a multivariate logistic regression model. The model will be validated using K-fold cross validation. Discrimination will be assessed using area under the receiver operating characteristic curve (AUROC) and calibration with calibration belt plots. ETHICS AND DISSEMINATION: The study is approved by appropriate ethics or patient safety boards in all participating countries. TRIAL REGISTRATION NUMBER: NCT04773938; Pre-results.

Shunt complications and revisions in children: A retrospective single institution study.

INTRODUCTION: Shunt surgery in children is associated with high revision and complication rates. We investigated revision rates and postoperative complications to specify current challenges associated with pediatric shunt surgery. METHODS: All patients aged < 18 years admitted to St. Olavs University Hospital, Norway, from January 2008 through December 2017, who underwent primary shunt insertions, were reviewed. Follow-up ranged from 1 to 10 years. Ventriculoperitoneal, cystoperitoneal, and ventriculoatrial shunts were included. All subsequent shunt revisions and 30-day postoperative complication rates were registered. RESULTS: 81 patients underwent 206 surgeries in the study period. 47 patients (58%) required minimum one revision during follow-up. In 14 (29.8%), the first revision was due to the misplacement of hardware. Proximal occlusion was the most common cause of revision (30.4%), followed by misplacement (18.5%) and infection (9.6%). Young age and MMC were associated with revision surgery in a univariable analysis, but were not significant in multivariable analyses. Congenital hydrocephalus was associated with infection (p = .028). In approximately 30% of procedures, complications occurred within 30 days postoperatively, the most common being revision surgery. In approximately 5% of the procedures, medical complications occurred. CONCLUSION: Children are prone to high revision and complication rates, and in this study, misplacement of hardware and proximal occlusion were the most common. Complication rates should not be limited to revision rates only, as 30-day complication rates indicate a significant rate of other complications as well. Multi-targeted approaches, perhaps focusing on measures to reduce misplacement, may be key to reducing revision rates.

Revision and complication rates in adult shunt surgery: a single-institution study.

BACKGROUND: CSF diversion with shunt placement is frequently associated with need for later revisions as well as surgical complications. We sought to review revision and complication rates following ventriculoperitoneal, ventriculoatrial and cystoperitoneal shunt placement in adult patients, and to identify potential risk factors for revision surgery and postoperative complications. METHOD: Included patients were adults (≥ 18 years) who underwent primary shunt insertion at St. Olavs Hospital in Trondheim, Norway, from 2008 through 2017. The electronic medical records and diagnostic imaging from all hospitals in our catchment area were retrospectively reviewed. Follow-up ranged from 1 to 11 years. Complications were graded according to the Landriel Ibañez classification system. RESULTS: Of the 227 patients included, 47 patients (20.7%) required revision surgery during the follow-up. In total, 90 revision surgeries were performed during follow-up. The most common cause for the first revision was infection (5.7%) and for all revisions proximal occlusion (30.0%). A total of 103 patients (45.4%) experienced ≥ 1 complication(s). Mild to moderate complications (grade I and II) were detected in 35.0% of all procedures. Severe or fatal complications (grade III and IV) were observed in 8.2% of all procedures. Urinary tract infections and pneumonia were common postoperatively (13.9% and 7.3%, respectively), and the most common IIb complication was shunt misplacement (proximally or distally). Two out of fourteen deaths within 30 days were directly associated with surgery. We did not find that aetiology/indication, age or gender influenced the occurrence of revision surgery or a grade III or IV complication. CONCLUSIONS: Shunt surgery continues to be a challenge both in terms of revision rates and procedure-related complications. However, the prediction of patients at risk remains difficult. A multidimensional focus is probably needed to reduce risks.

Accuracy and complication rates of external ventricular drain placement with twist drill and bolt system versus standard trephine and tunnelation: a retrospective population-based study.

BACKGROUND: An external ventricular drain (EVD) is typically indicated in the presence of hydrocephalus and increased intracranial pressure (ICP). Procedural challenges have prompted the development of different methods to improve accuracy, safety, and logistics. OBJECTIVES: EVD placement and complications rates were compared using two surgical techniques; the standard method (using a 14-mm trephine burrhole with the EVD tunnelated through the skin) was compared to a less invasive method (EVD placed through a 2.7-3.3-mm twist drill burrhole and fixed to the bone with a bolt system). METHODS: Retrospective observational study in a single-centre setting between 2008 and 2018. EVD placement was assessed using the Kakarla scoring system. We registered postoperative complications, surgery duration and number of attempts to place the EVD. RESULTS: Two hundred seventy-two patients received an EVD (61 bolt EVDs, 211 standard EVDs) in the study period. Significant differences between the bolt system and the standard method were observed in terms of revision surgeries (8.2% vs. 21.5%, p = 0.020), surgery duration (mean 16.5 vs. 28.8 min, 95% CI 7.64, 16.8, p < 0.001) and number of attempts to successfully place the first EVD (mean 1.72 ± 1.2 vs. 1.32 ± 0.8, p = 0.017). There were no differences in accuracy of placement or complication rates. CONCLUSIONS: The two methods show similar accuracy and postoperative complication rates. Observed differences in both need for revisions and surgery duration favoured the bolt group. Slightly, more attempts were needed to place the initial EVD in the bolt group, perhaps reflecting lower flexibility for angle correction with a twist drill approach.

A Model to Identify Sarcopenia in Patients With Cirrhosis.

BACKGROUND & AIMS: The severe depletion of muscle mass at the third lumbar vertebral level (sarcopenia) is a marker of malnutrition and is independently associated with mortality in patients with cirrhosis. Instead of monitoring sarcopenia by cross-sectional imaging, we investigated whether ultrasound-based measurements of peripheral muscle mass, measures of muscle function, along with nutritional factors, are associated with severe loss of muscle mass. METHODS: We performed a prospective study of 159 outpatients with cirrhosis (56% male; mean age, 58 ± 10 years; mean model for end-stage liver disease score, 10 ± 3; 60% Child-Pugh class A) evaluated at the Cirrhosis Care Clinic at the University of Alberta Hospital from March 2011 through September 2012. Lumbar skeletal muscle indices were determined by computed tomography or magnetic resonance imaging. We collected clinical data and data on patients' body composition, nutrition, and thigh muscle thickness (using ultrasound analysis). We also measured mid-arm muscle circumference, mid-arm circumference, hand grip, body mass index, and serum level of albumin; patients were evaluated using the subjective global assessment scale. Findings from these analyses were compared with those from cross-sectional imaging, for each sex, using logistic regression analysis. RESULTS: Based on cross-sectional imaging analysis, 43% of patients had sarcopenia (57% of men and 25% of women). Results from the subjective global assessment, serum level of albumin, and most nutritional factors were significantly associated with sarcopenia. We used multivariate analysis to develop a model to identify patients with sarcopenia, and developed a nomogram based on body mass index and thigh muscle thickness for patients of each sex. Our model identified men with sarcopenia with an area under the receiver operating characteristic curve value of 0.78 and women with sarcopenia with an area under the receiver operating characteristic curve value of 0.89. CONCLUSIONS: In a prospective study of patients with cirrhosis, we found that the combination of body mass index and thigh muscle thickness (measured by ultrasound) can identify male and female patients with sarcopenia almost as well as cross-sectional imaging (area under the receiver operating characteristic curve values of 0.78 and 0.89, respectively). These factors might be used in screening and routine nutritional monitoring of patients with cirrhosis.

Systematic review on human resources for health interventions to improve maternal health outcomes: evidence from low- and middle-income countries.

There is a broad consensus and evidence that shows qualified, accessible, and responsive human resources for health (HRH) can make a major impact on the health of the populations. At the same time, there is widespread recognition that HRH crises particularly in low- and middle-income countries (LMICs) impede the achievement of better health outcomes/targets. In order to achieve the Sustainable Development Goals (SDGs), equitable access to a skilled and motivated health worker within a performing health system is need to be ensured. This review contributes to the vast pool of literature towards the assessment of HRH for maternal health and is focused on interventions delivered by skilled birth attendants (SBAs). Studies were included if (a) any HRH interventions in management system, policy, finance, education, partnership, and leadership were implemented; (b) these were related to SBA; (c) reported outcomes related to maternal health; (d) the studies were conducted in LMICs; and (e) studies were in English. Studies were excluded if traditional birth attendants and/or community health workers were trained. The review identified 25 studies which revealed reasons for poor maternal health outcomes in LMICs despite the efforts and policies implemented throughout these years. This review suggested an urgent and immediate need for formative evidence-based research on effective HRH interventions for improved maternal health outcomes. Other initiatives such as education and empowerment of women, alleviating poverty, establishing gender equality, and provision of infrastructure, equipment, drugs, and supplies are all integral components that are required to achieve SDGs by reducing maternal mortality and improving maternal health.

Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials.

The effects of low-carbohydrate (LC) diets on body weight and cardiovascular risk are unclear, and previous studies have found varying results. Our aim was to conduct a meta-analysis of randomised controlled trials (RCT), assessing the effects of LC diets v. low-fat (LF) diets on weight loss and risk factors of CVD. Studies were identified by searching MEDLINE, Embase and Cochrane Trials. Studies had to fulfil the following criteria: a RCT; the LC diet was defined in accordance with the Atkins diet, or carbohydrate intake of <20% of total energy intake; twenty subjects or more per group; the subjects were previously healthy; and the dietary intervention had a duration of 6 months or longer. Results from individual studies were pooled as weighted mean difference (WMD) using a random effect model. In all, eleven RCT with 1369 participants met all the set eligibility criteria. Compared with participants on LF diets, participants on LC diets experienced a greater reduction in body weight (WMD -2·17 kg; 95% CI -3·36, -0·99) and TAG (WMD -0·26 mmol/l; 95% CI -0·37, -0·15), but a greater increase in HDL-cholesterol (WMD 0·14 mmol/l; 95% CI 0·09, 0·19) and LDL-cholesterol (WMD 0·16 mmol/l; 95% CI 0·003, 0·33). This meta-analysis demonstrates opposite change in two important cardiovascular risk factors on LC diets--greater weight loss and increased LDL-cholesterol. Our findings suggest that the beneficial changes of LC diets must be weighed against the possible detrimental effects of increased LDL-cholesterol.

The 22/11 risk prediction model: a validated model for predicting 30-day mortality in patients with cirrhosis and spontaneous bacterial peritonitis.

OBJECTIVES: Clinicians do not have a validated tool for estimating the short-term mortality associated with spontaneous bacterial peritonitis (SBP). Accurate prognosis assessment is important for risk stratification and for individualizing therapy. We aimed therefore to develop and validate a model for the prediction of 30-day mortality in SBP patients receiving standard medical treatment (antibiotics and if indicated by guidelines, intravenous albumin therapy). METHODS: We retrospectively identified SBP patients treated at a tertiary care center between 2003 and 2011 (training set). Multivariate regression modeling and receiver operating characteristic (ROC) curves were utilized for statistical analysis. An external data set of 109 SBP patients was utilized for validation. RESULTS: Of the 184 patients in the training set, 66% were men with a median age of 55 years, a median MELD (Model for End-Stage Liver Disease) score of 20, and a 30-day mortality of 27%. Peripheral blood leukocyte count ≥11×109 cells/l (odds ratio (OR) 2.5; 95% confidence interval CI: 1.2-5.2) and MELD score ≥22 (OR 4.6; 95% CI: 2.3-9.6) were independent predictors of 30-day mortality. Patients with neither, one, or both variables had 30-day mortality rates of 8%, 32%, and 52%, respectively. The findings in the validation set mirrored the training set. CONCLUSIONS: In cirrhotic patients with SBP receiving standard therapy, MELD score ≥22 and peripheral blood leukocyte count ≥11×109 cells/l are validated independent predictors of mortality. The mortality in a patient without either poor prognostic variable is ≤10% and with both variables is ≥50%. Trials aiming to reduce mortality should target patients in the moderate-risk to high-risk groups.

Low-dose heparin use and the patency of peripheral IV catheters in children: a systematic review.

OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the efficacy of low-dose heparin for prolonging patency of peripheral intravenous (PIV) catheters in the pediatric population. METHODS: We searched Medline, Embase, CINAHL, and Cochrane Central Register of Controlled Trials to identify studies up to June 6, 2012. Additional citations were retrieved from the bibliography of selected articles. The eligible studies were RCTs of low-dose heparin used in PIV catheters as compared with control and measured any one of the following outcomes: duration of catheter patency, infusion failure rates, or phlebitis. Data were extracted by 1 reviewer by using a standardized form and checked for accuracy by a second reviewer. Discrepancies were resolved by consensus. RESULTS: Thirteen RCTs were identified (3 RCTs of continuous infusion and 10 RCTs of intermittent flush). Catheters using heparin had longer patency (mean difference [95% confidence interval]: 26.51 hours [2.37 to 50.65], P < .001, for the infusion studies and 2.82 hours [-0.04 to 5.67], P = .05, for intermittent flush studies). Heparin usage also resulted in a lower rate of infusion failure (rate ratio [95% confidence interval]: 0.78 [0.62 to 0.99], P = .04, for the infusion studies and 0.88 [0.72 to 1.09], P = .25, for intermittent flush studies). Lower phlebitis rates were also observed with heparin usage; however, the results did not reach significance. There was no increase in heparin-related side effects noted. CONCLUSIONS: Low-dose heparin as continuous infusion in PIV catheters resulted in clinically significant benefits in terms of catheter patency and fewer episodes of infusion failures. Heparin's use in intermittent flush solutions showed minimal benefits.