A heatmap for expected cumulative live birth rate in preimplantation genetic testing for monogenic disorders and chromosomal structural rearrangements.

PURPOSE: Our objective is to predict the cumulative live birth rate (CLBR) and identify the specific subset within the population undergoing preimplantation genetic testing for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR) which is likely to exhibit a diminished expected CLBR based on various patient demographics. METHODS: We performed a single-centre retrospective cohort study including 1522 women undergoing 3130 PGT cycles at a referral centre for PGT. A logistic regression analysis was performed to predict the CLBR per ovarian stimulation in women undergoing PGT-M by polymerase chain reaction (PCR) or single-nucleotide polymorphism (SNP) array, and in women undergoing PGT-SR by SNP array, array comparative genomic hybridization (CGH) or next-generation sequencing (NGS). RESULTS: The mean age of women was 32.6 years, with a mean AMH of 2.75 µg/L. Female age and AMH significantly affected the expected CLBR irrespective of the inheritance mode or PGT technology. An expected CLBR < 10% was reached above the age of 42 years and AMH ≤ 1.25 µg/L. We found no significant difference in outcome per ovarian stimulation between the different PGT technologies, i.e. PCR, SNP array, array CGH and NGS. Whereas per embryo transfer, we noticed a significantly higher probability of live birth when SNP array, array CGH and NGS were used as compared to PCR. CONCLUSION: In a PGT-setting, couples with an unfavourable female age and AMH should be informed of the prognosis to allow other reproductive choices. The heatmap produced in this study can be used as a visual tool for PGT couples.

Systematic review and meta-analysis of the diagnostic value of optokinetic after-nystagmus in vestibular disorders.

Introduction: To date, no systematic review or meta-analysis has critically evaluated the relevance of using optokinetic after-nystagmus (OKAN) in diagnosis of vestibular disorders. To assess the role of OKAN in diagnosis of vestibular disorders, the OKAN time constant (TC) between patients with vestibular disorders and healthy participants will be compared. Methods: Automated search strategies were carried out in the Embase, Medline PubMed, Web of Science, and Scopus databases from inception to December 2023. The following inclusion criteria were applied: (1) evaluation of OKAN in individuals with vestibular disorders, (2) clinical trials, and (3) inclusion of healthy individuals as the control group. Exclusion criteria were: (1) animal studies, (2) non-clinical trial study designs, (3) assessment of non-vestibular disorders, (4) no examination of OKAN TC, (5) only examination of healthy participants, (6) studies published in a language other than English, (7) no healthy participants as control group, (8) case reports, and (9) only abstract available. The random-effects model was used to pool the data. The Joanna Briggs Institute (JBI) Critical Appraisal Tools was used to assess the risk of bias. The quality assessment was performed with the aid of the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, provided by NHLBI. The PRISMA guidelines were used as reporting guidelines. The main outcome of this study was the between-group mean difference (MDbetween) in OKAN TC and its 95% confidence interval between patients with vestibular disorders and healthy participants. Results: Seven out of 244 screened articles were included that studied 289 participants. The overall mean difference (MD = -7.08) with a 95% CI of [-10.18; -3.97] was significant (p = 0.014). The heterogeneity was significant (p = 0.02). Quality assessment was generally good (76%). The risk of bias was low in five studies and moderate in two studies. Conclusion: The results demonstrate that OKAN TC is significantly shorter in patients with vestibular disorders compared to healthy controls. This finding is important for future research, particularly with the emergence of novel clinical tools and diagnostic syndromes. Systematic Review: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=442695.

Comparing physical therapy students' attitudes and beliefs regarding chronic low back pain and knee osteoarthritis: an international multi-institutional comparison between 2013 and 2020 academic years.

BACKGROUND: In 2013, physical therapy students demonstrated low guideline-adherent recommendations regarding chronic low back pain (CLBP) for spinal pathology, activity, and work. OBJECTIVES: To assess the differences in physical therapy students' attitudes, beliefs, and adherence to guideline recommendations regarding CLBP and knee osteoarthritis between 2013 and 2020. METHODS: In 2013 and 2020, second and fourth-year physical therapy students were recruited from 6 Belgian and 2 Dutch institutions. Attitudes and beliefs regarding CLBP and knee OA were evaluated using the Pain Attitudes and Beliefs Scale for Physiotherapists (PABS-PT), the Health Care Providers' Pain and Impairment Relationship Scale (HC-PAIRS), and a questionnaire regarding therapeutic exercise and knee osteoarthritis. A clinical vignette was used to measure guideline-adherent recommendations regarding spinal pathology, activity, and work. RESULTS: In 2013, 927 second-year and 695 fourth-year students; in 2020, 695 second-year and 489 fourth-year students; were recruited to participate in the study. Compared to 2013, students had less biomedical and stronger biopsychosocial attitudes and beliefs regarding CLBP, more guideline-adherent recommendations for activity, and more biopsychosocial beliefs regarding the benefits of exercise for patients with knee osteoarthritis in both the second and fourth year. Only fourth-year students in 2020 scored significantly better on HC-PAIRS and guideline-adherent recommendation relating to spinal pathology. No differences were found regarding work recommendations. CONCLUSIONS: Between 2013 and 2020, physical therapy students made a positive shift towards a more biopsychosocial approach to CLBP and knee osteoarthritis management. Guideline-adherent recommendations for CLBP concerning activity improved, however, concerning work and spinal pathology, it remained low.

Exercise-Induced Hypoalgesia in Patients with Chronic Whiplash-Associated Disorders: Differences between Subgroups Based on the Central Sensitization Inventory.

BACKGROUND: Physical exercise is an important element in the rehabilitation of chronic whiplash-associated disorders, with the physiological process underlying pain reduction called exercise-induced hypoalgesia. In chronic whiplash-associated disorders, exercise-induced hypoalgesia appears impaired, and the research suggests a relationship with symptoms of dysfunctional nociceptive processing, such as central sensitization. This study improves our understanding of exercise-induced hypoalgesia in chronic whiplash-associated disorders by examining the differences between the extent of exercise-induced hypoalgesia in subgroups based on scores on the central sensitization inventory (CSI). METHODS: Data were collected from 135 participants with chronic whiplash-associated disorders who completed a set of questionnaires. Pain pressure thresholds and temporal summations were assessed before and after a submaximal aerobic bicycle exercise test. RESULTS: We observed no interaction effect between exercise-induced hypoalgesia and the CSI scores for both pain pressure threshold and temporal summation. No overall statistical effect was measured in the analysis of the effect of time. The pain pressure threshold significantly related to the CSI. The temporal summation showed no correlation. CONCLUSIONS: During this study, we did not find evidence for a difference in the presence of exercise-induced hypoalgesia when the subgroups were created based on the central sensitization cluster calculator. Limited evidence was found for the influence of CSI scores on the delta pain pressure threshold.

Integration of Cognitive Behavioral Therapy for Insomnia in Best-Practice Care for Patients With Knee Osteoarthritis and Insomnia: A Randomized Controlled Trial Protocol.

OBJECTIVE: Knee osteoarthritis (KOA) is a common musculoskeletal problem worldwide and its key symptom is pain. Guidelines recommend incorporating comorbidity-specific therapies into patient-centered care. Patients diagnosed with KOA frequently have insomnia, which is associated with higher-pain severity. For this reason, this study protocol outlines the methodology of a randomized controlled trial (RCT) investigating the effectiveness of cognitive behavioral therapy for insomnia (CBTi) combined with best-practice KOA care (BPC) compared to best-practice KOA care and lifestyle education. METHODS: A 2-arm RCT in patients with KOA and insomnia is conducted, in which a total of 128 patients are randomly allocated to an intervention or control group. The experimental intervention consists of 12 sessions of physical therapist-led BPC with an additional 6 sessions of CBTi. The control intervention also receives BPC, which is supplemented with 6 general lifestyle information sessions. The primary outcome is the between-group difference in change in pain severity at 6 months after intervention. Secondary outcomes are pain-related outcomes, sleep-related outcomes, symptoms of anxiety and depression, level of physical activity and function, perceived global improvement, biomarkers of inflammation, and health-related quality of life. Assessments are conducted at baseline, immediately after intervention, and 3, 6, and 12 months after intervention. Furthermore, a cost-utility analysis for the proposed intervention will be performed alongside the RCT. IMPACT: This is the first RCT investigating the clinical and cost-effectiveness of a physical therapist-led intervention integrating CBTi into BPC in patients with KOA and insomnia. The results of this trial will add to the growing body of evidence on the effectiveness of individualized and comorbidity-specific KOA care, which can inform clinical decision-making and assist policymakers and other relevant stakeholders in optimizing the care pathway for patients with KOA.

Predicting return to work after traumatic brain injury using machine learning and administrative data.

BACKGROUND: Accurate patient-specific predictions on return-to-work after traumatic brain injury (TBI) can support both clinical practice and policymaking. The use of machine learning on large administrative data provides interesting opportunities to create such prognostic models. AIM: The current study assesses whether return-to-work one year after TBI can be predicted accurately from administrative data. Additionally, this study explores how model performance and feature importance change depending on whether a distinction is made between mild and moderate-to-severe TBI. METHODS: This study used a population-based dataset that combined discharge, claims and social security data of patients hospitalized with a TBI in Belgium during the year 2016. The prediction of TBI was attempted with three algorithms, elastic net logistic regression, random forest and gradient boosting and compared in their performance by their accuracy, sensitivity, specificity and area under the receiver operator curve (ROC AUC). RESULTS: The distinct modelling algorithms resulted in similar results, with 83% accuracy (ROC AUC 85%) for a binary classification of employed vs. not employed and up to 76% (ROC AUC 82%) for a multiclass operationalization of employment outcome. Modelling mild and moderate-to-severe TBI separately did not result in considerable differences in model performance and feature importance. The features of main importance for return-to-work prediction were related to pre-injury employment. DISCUSSION: While clearly offering some information beneficial for predicting return-to-work, administrative data needs to be supplemented with additional information to allow further improvement of patient-specific prognose.

Neuromuscular end-point predictive capability of published rocuronium pharmacokinetic/pharmacodynamic models: An observational trial.

BACKGROUND: Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s STUDY OBJECTIVE: The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements. DESIGN: Observational trial. SETTING: Tertiary Belgian hospital, from August 2020 up to September 2021. PATIENTS AND INTERVENTIONS: Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria). MAIN RESULTS: Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance. CONCLUSIONS: Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics. TRIAL REGISTRATION: NCT04518761 (clinicaltrials.gov), registered on 19 August 2020.

Effects of lactate, super-GDF9, and low oxygen tension during bi-phasic in vitro maturation on the bioenergetic profiles of mouse cumulus-oocyte complex†.

In vitro maturation (IVM) is an alternative assisted reproductive technology with reduced hormone-related side effects and treatment burden compared to conventional IVF. Capacitation (CAPA)-IVM is a bi-phasic IVM system with improved clinical outcomes compared to standard monophasic IVM. Yet, CAPA-IVM efficiency compared to conventional IVF is still suboptimal in terms of producing utilizable blastocysts. Previously, we have shown that CAPA-IVM leads to a precocious increase in cumulus cell (CC) glycolytic activity during cytoplasmic maturation. In the current study, considering the fundamental importance of CCs for oocyte maturation and cumulus-oocyte complex (COC) microenvironment, we further analyzed the bioenergetic profiles of maturing CAPA-IVM COCs. Through a multi-step approach, we (i) explored mitochondrial function of the in vivo and CAPA-IVM matured COCs through real-time metabolic analysis with Seahorse analyzer, and to improve COC metabolism (ii) supplemented the culture media with lactate and/or super-GDF9 (an engineered form of growth differentiation factor 9) and (iii) reduced culture oxygen tension. Our results indicated that the pre-IVM step is delicate and prone to culture-related disruptions. Lactate and/or super-GDF9 supplementations failed to eliminate pre-IVM-induced stress on COC glucose metabolism and mitochondrial respiration. However, when performing pre-IVM culture under 5% oxygen tension, CAPA-IVM COCs showed similar bioenergetic profiles compared to in vivo matured counterparts. This is the first study providing real-time metabolic analysis of the COCs from a bi-phasic IVM system. The currently used analytical approach provides the quantitative measures and the rational basis to further improve IVM culture requirements.

Parenteral Nutrition, Sepsis, Acute Heart Failure and Hepatotoxic Drugs Are Related to Liver Test Disturbances in Critically Ill Patients.

BACKGROUND: Parenteral nutrition (PN) is often associated with liver dysfunction in the ICU, although other factors such as sepsis, acute heart failure (AHF), and hepatotoxic drugs can be equally present. The relative impact of PN on liver dysfunction in critically ill patients is largely unknown. METHODS: We recorded the presence of pre-existing liver disturbances, AHF, sepsis, daily PN volume, and commonly used hepatotoxic drugs in adult ICU patients, together with daily aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkalic phosphatase (AP), total bilirubin (TB), and INR values in patients with three or more PN treatment days. A linear mixed-effects model was used to assess the relative contribution of each liver parameter. Nutritional adequacy was defined as intake/needs. RESULTS: We included 224 ICU patients with PN treatment lasting more than 3 days between 1 January 2017 and 31 December 2019. For AST, pre-existing liver disturbances (+180% ± 11%) and the presence of AHF (+75% ± 14%) were the main predictors of deterioration, whereas PN volume caused only a limited increase of 14% ± 1%/L. Similar results were observed for ALT. GGT, INR, and TB are mainly influenced by the presence of sepsis/septic shock and pre-existing liver disturbances, with no impact of PN or hepatotoxic drugs. Carbohydrate intake exceeded recommendations, and protein and lipid intake were insufficient in this study cohort. CONCLUSIONS: Liver test disturbances in ICU patients on PN are multifactorial, with sepsis and AHF having the highest influence, with only limited impact from PN and hepatotoxic drugs. Feeding adequacy can be improved.

Assessment of Retinal Pigment Epithelium Alterations and Chorioretinal Vascular Network Analyses in Patients under Treatment with BRAF/MEK Inhibitor for Different Malignancies: A Pilot Study.

In the last two decades, an increasing number of so-called molecular-targeted therapies have become available for the treatment of patients with advanced malignancies. These drugs have included inhibitors of proteins in the MAPK pathway, such as BRAF and MEK inhibitors, which are characterized by a distinct toxicity profile. The eye is particularly susceptible to adverse effects due to MEK inhibitors, and the term MEKAR (MEK-inhibitor-associated retinopathy) indicates the presence of subretinal fluid, mimicking central serous chorioretinopathy (CSC). The pathogenesis of the retinal alterations related to MAPK pathway inhibitors is still unclear, and questions are still open. The present study aims to assess the presence of retinal pigment epithelium alterations as predictive parameters for retinal toxicity, analyzing, at the same time, the chorioretinal vascular network in patients undergoing BRAF/MEK inhibitor treatment for different malignancies.

Nursing students' attitudes regarding euthanasia due to unbearable mental suffering: Cross-sectional study using the adapted and validated Euthanasia Attitude Scale.

AIM: To explore final year nursing students' attitudes towards euthanasia due to unbearable mental suffering by using the adapted and validated Euthanasia Attitude Scale. DESIGN: Cross-sectional survey. METHODS: Explorative, descriptive cross-sectional study conducted using an e-mail survey between October 2020 and March 2021 by a sample of final-year baccalaureate nursing students (n = 273) from eight of the eleven Flemish university colleges. The actual questionnaire contains 21 questions and was developed based on a consensus reached following independent translations. The psychometric properties of the Euthanasia Attitude Scale were assessed, including reliability and validity. Independent-sample Mann-Whitney U-test was used to investigate relation between demographic and education-related data, and domain and total score of the UMS-EAS-NL. This study received ethical approval from the Ethical Committee of the University Hospital Brussels, Belgium. RESULTS: McDonald's omega was 0.838 for the total Euthanasia Attitude Scale scores, supporting the validity of the questionnaire. A statistically significant difference in 'Naturalistic beliefs' score was found relating to the year of birth. There are clinically important results between those students who have been involved in euthanasia and those who have not. CONCLUSIONS: Most of the final-year nursing students supported the probability of patients' access to euthanasia due to unbearable mental suffering. To monitor adequate care, it is necessary to prepare nursing students adequately for this complex matter. IMPACT: To date, no large-scale study has examined nursing students' attitudes towards euthanasia because of unbearable mental suffering. It is expected that nursing students may be confronted with such a euthanasia request during an internship, or later in their professional career, in countries where euthanasia is legal. Students showed a high acceptability towards UMS-euthanasia. Clinically significant differences were found for students who had ever been involved in euthanasia.

Traumatic brain injury hospitalizations in Belgium: A brief overview of incidence, population characteristics, and outcomes.

Background: There is a need for complete and accurate epidemiological studies for traumatic brain injury (TBI). Secondary use of administrative data can provide country-specific population data across the full spectrum of disease. Aim: This study aims to provide a population-based overview of Belgian TBI hospital admissions as well as their health-related and employment outcomes. Methods: A combined administrative dataset with deterministic linkage at individual level was used to assess all TBI hospitalizations in Belgium during the year 2016. Discharge data were used for patient selection and description of injuries. Claims data represented the health services used by the patient and health-related follow-up beyond hospitalization. Finally, social security data gave insight in changes to employment situation. Results: A total of 17,086 patients with TBI were identified, with falls as the predominant cause of injury. Diffuse intracranial injury was the most common type of TBI and 53% had injuries to other body regions as well. In-hospital mortality was 6%. The median length of hospital stay was 2 days, with 20% being admitted to intensive care and 28% undergoing surgery. After hospitalization, 23% had inpatient rehabilitation. Among adults in the labor force pre-injury, 72% of patients with mild TBI and 59% with moderate-to-severe TBI returned to work within 1 year post-injury. Discussion: Administrative data are a valuable resource for population research. Some limitations need to be considered, however, which can in part be overcome by enrichment of administrative datasets with other data sources such as from trauma registries.

Optimization of Performance by Combining Most Sensitive and Specific Models in Data Science Results in Majority Voting Ensemble.

Ensemble modeling is an increasingly popular data science technique that combines the knowledge of multiple base learners to enhance predictive performance. In this paper, the idea was to increase predictive performance by holding out three algorithms when testing multiple classifiers: (a) the best overall performing algorithm (based on the harmonic mean of sensitivity and specificity (HMSS) of that algorithm); (b) the most sensitive model; and (c) the most specific model. This approach boils down to majority voting between the predictions of these three base learners. In this exemplary study, a case of identifying a prolonged QT interval after administering a drug-drug interaction with increased risk of QT prolongation (QT-DDI) is presented. Performance measures included accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Overall performance was measured by calculating the HMSS. Results show an increase in all performance measure characteristics compared to the original best performing algorithm, except for specificity where performance remained stable. The presented approach is fairly simple and shows potential to increase predictive performance, even without adjusting the default cut-offs to differentiate between high and low risk cases. Future research should look at a way of combining all tested algorithms, instead of using only three. Similarly, this approach should be tested on a multiclass prediction problem.

Randomized Trial Comparing Burr Hole Craniostomy, Minicraniotomy, and Twist Drill Craniostomy for Treatment of Chronic Subdural Hematoma.

BACKGROUND: The mainstay of treatment for symptomatic or large chronic subdural hematoma (CSDH) is surgery, but controversy still exists regarding the best surgical technique. Three different techniques are commonly used: burr hole craniostomy (BHC), minicraniotomy (MC), and twist drill craniostomy (TDC). OBJECTIVE: To determine which surgical technique for drainage of CSDH offers best results. METHODS: We set up a multicenter prospective randomized trial (Comparison of Chronic Subdural Hematoma Treatment [COMPACT] trial) comparing BHC, MC, and TDC for the surgical treatment of CSDH. The primary end point was reoperation rate, and secondary end points included complication rates and clinical outcome. Patients were considered to have good outcome when they did not undergo reoperation, suffered no surgical or medical complication, and had no related mortality. Clinical outcome was also evaluated by evolution of the Markwalder score and the modified Rankin score. RESULTS: Two-hundred forty-five patients were included in the final analysis: 79 BHC, 84 MC, and 82 TDC. Mean duration of surgery was shorter for TDC than for BHC and MC ( P < .001). Reoperation rate was 7.6% for BHC, 13.1% for MC, and 19.5% for TDC ( P = .07). This trend toward better results for BHC was not statistically significant in logistic regression analysis. The proportion of patients with good outcome was 78.5% for BHC group, 76.2% for MC, and 69.5% for TDC ( P = .4). Evolution of the Markwalder score and modified Rankin score were not significantly different between treatment groups. CONCLUSION: All 3 techniques are effective at treating patients with CSDH with eventual 6-month outcome being similar. Although not reaching statistical significance in our study, BHC offers the lowest recurrence rate combined with manageable complication rate.

Three Months of Strength Training Changes the Gene Expression of Inflammation-Related Genes in PBMC of Older Women: A Randomized Controlled Trial.

Here, we investigate changes in inflammation-related gene-expression in peripheral mononuclear blood cells (PBMC) by strength training. A total of 14 women aged ≥65 years were randomized into 3 months of either 3×/week intensive strength training (IST: 3×10 rep at 80% 1RM), strength endurance training (SET: 2×30 reps at 40% 1RM) or control (CON: 3×30 sec stretching). Differentially expressed genes (fold change ≤0.67 or ≥1.5) were identified by targeted RNA-sequencing of 407 inflammation-related genes. A total of 98 genes (n = 61 pro-inflammatory) were significantly affected. IST and SET altered 14 genes in a similar direction and 19 genes in the opposite direction. Compared to CON, IST changed the expression of 6 genes in the same direction, and 17 genes in the SET. Likewise, 18 and 13 genes were oppositely expressed for, respectively, IST and SET compared to CON. Changes in gene expression affected 33 canonical pathways related to chronic inflammation. None of the altered pathways overlapped between IST and SET. Liver X Receptor/Retinoid X Receptor Activation (LXR/RXR) and Triggering Receptor Expressed On Myeloid Cells 1 (TREM1) pathways were enriched oppositely in both training groups. We conclude that three months IST and SET can induce changes in CLIP-related gene expression in PBMC, but by affecting different genes and related pathways.

Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring.

Scoring of tumor-infiltrating lymphocytes (TILs) in breast cancer specimens has gained increasing attention, as TILs have prognostic and predictive value in HER2+ and triple-negative breast cancer. We evaluated the intra- and interrater variability when scoring TILs by visual inspection of hematoxylin and eosin-stained tissue sections. We further addressed whether immunohistochemical staining of these sections for immune cell surface markers CD45, CD3, CD4, and CD8 and combination with nanoString nCounter® gene expression analysis could refine TIL scoring. Formalin-fixed paraffin-embedded and fresh-frozen core needle biopsies of 12 female and treatment-naive breast cancer patients were included. Scoring of TILs was performed twice by three independent pathologists with a washout period of 3 days. Increasing intra- and interrater variability was observed with higher TIL numbers. The highest reproducibility was observed on tissue sections stained for CD3 and CD8. The latter TIL scores correlated well with the TIL scores obtained through nanoString nCounter® gene expression analysis. Gene expression analysis also revealed 104 and 62 genes that are positively and negatively related to both TIL scores. In conclusion, integration of immunohistochemistry and gene expression analysis is a valuable strategy to refine TIL scoring in breast tumors.

Quantifying injury severity for traumatic brain injury with routinely collected health data.

BACKGROUND: Routinely collected health data (RCHD) offers many opportunities for traumatic brain injury (TBI) research, in which injury severity is an important factor. OBJECTIVE: The use of clinical injury severity indices in a context of RCHD is explored, as are alternative measures created for this specific purpose. To identify useful scales for full body injury severity and TBI severity this study focuses on their performance in predicting these currently used indices, while accounting for age and comorbidities. DATA: This study utilized an extensive population-based RCHD dataset consisting of all patients with TBI admitted to any Belgian hospital in 2016. METHODS: Full body injury severity is scored based on the (New) Injury Severity Score ((N)ISS) and the ICD-based Injury Severity Score (ICISS). For TBI specifically, the Abbreviated Injury Scale (AIS) Head, Loss of Consciousness and the ICD-based Injury Severity Score for TBI injuries (ICISS) were used in the analysis. These scales were used to predict three outcome variables strongly related to injury severity: in-hospital death, admission to intensive care and length of hospital stay. For the prediction logistic regressions of the different injury severity scales and TBI severity indices were used, and error rates and the area under the receiver operating curve were evaluated visually. RESULTS: In general, the ICISS had the best predictive performance (error rate between 0.06 and 0.23; AUC between 0.82 [0.81;0.83] and 0.86 [0.85;0.86]). A clearly increasing error rate can be noticed with advancing age and accumulating comorbidity. CONCLUSION: Both for full body injury severity and TBI severity, the ICISS tends to outperform other scales. It is therefore the preferred scale for use in research on TBI in the context of RCHD. In their current form, the severity scales are not suitable for use in older populations.

Non-invasive neurally adjusted ventilatory assist in preterm infants with RDS: effect of changing NAVA levels.

We aimed to examine the effect of changing levels of support (NAVA level) during non-invasive neurally adjusted ventilatory assist (NIV-NAVA) in preterm infants with respiratory distress syndrome (RDS) on electrical diaphragm activity. This is a prospective, single-centre, interventional, exploratory study in a convenience sample. Clinically stable preterm infants supported with NIV-NAVA for RDS were eligible. Patients were recruited in the first 24 h after the start of NIV-NAVA. Following a predefined titration protocol, NAVA levels were progressively increased starting from a level of 0.5 cmH2O/µV and with increments of 0.5 cmH2O/µV every 3 min, up to a maximum level of 4.0 cmH2O/µV. We measured the evolution of peak inspiratory pressure and the electrical signal of the diaphragm (Edi) during NAVA level titration. Twelve infants with a mean (SD) gestational age at birth of 30.6 (3.5) weeks and birth weight of 1454 (667) g were enrolled. For all patients a breakpoint could be identified during the titration study. The breakpoint was on average (SD) at a level of 2.33 (0.58) cmH2O/µV. With increasing NAVA levels, the respiratory rate decreased significantly. No severe complications occurred.Conclusions: Preterm neonates with RDS supported with NIV-NAVA display a biphasic response to changing NAVA levels with an identifiable breakpoint. This breakpoint was at a higher NAVA level than commonly used in this clinical situation. Immature neural feedback mechanisms warrant careful monitoring of preterm infants when supported with NIV-NAVA.Trial registration: clinicaltrials.gov NCT03780842. Date of registration December 12, 2018. What is Known: • Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) is a safe, feasible and effective way to support respiration in preterm infants. • Intact neural feedback mechanisms are needed to protect the lung from overdistension in neurally adjusted ventilatory assist. What is New: • Preterm infants with acute RDS have a similar pattern of respiratory unloading as previously described. • Neural feedback mechanisms seem to be immature with the risk of insufficient support and lung injury due to overdistension of the lung.

Dialyzer Performance During Hemodialysis Without Systemic Anticoagulation Using a Heparin-Grafted Dialyzer Combined With a Citrate-Enriched Dialysate: Results of the Randomized Crossover Noninferiority EvoCit Study.

RATIONALE & OBJECTIVE: The EvoCit study was designed to evaluate performance of a heparin-grafted dialyzer during hemodialysis with and without systemic anticoagulation. STUDY DESIGN: Randomized, crossover, noninferiority trial. Noninferiority was defined as a difference of≤10% for the primary outcome. SETTING & PARTICIPANTS: Single hemodialysis center; 26 prevalent patients treated with 617 hemodialysis sessions. INTERVENTIONS: Hemodialysis using a heparin-grafted dialyzer combined with a 1.0mmol/L citrate-enriched dialysate ("EvoCit") without systemic anticoagulation compared with hemodialysis performed with a heparin-grafted dialyzer with systemic heparin ("EvoHep"). Patients were randomly allocated to a first period of 4 weeks and crossed over to the alternative strategy for a second period of 4 weeks. OUTCOMES: The primary end point was the difference in Kt/Vurea between EvoCit and EvoHep. Secondary end points were urea reduction ratio, middle molecule removal, treatment time, thrombin generation, and reduction in dialyzer blood compartment volume. RESULTS: The estimated difference in Kt/Vurea between EvoCit and EvoHep was-0.03 (95% CI, -0.06 to-0.007), establishing noninferiority with mean Kt/Vurea of 1.47±0.05 (SE) for EvoCit and 1.50±0.05 for EvoHep. Noninferiority was also established for reduction ratios of urea and ß2-microglobulin. Premature discontinuation of dialysis was required for 4.2% of sessions among 6 patients during EvoCit and no sessions during EvoHep. Effective treatment time was 236±5 minutes for EvoCit and 238±1 minutes for EvoHep. Thrombin generation was increased and there was greater reduction in dialyzer blood compartment volume after treatments with EvoCit compared with EvoHep. LIMITATIONS: The effects of avoiding systemic anticoagulation on clinical outcomes were not evaluated. CONCLUSIONS: EvoCit is noninferior to EvoHep with respect to solute clearance but results in a greater number of shortened treatments, more membrane clotting, and greater thrombin generation TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03887468.