Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain-Barré syndrome.

BACKGROUND: Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain-Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS. METHODS: We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12 months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). RESULTS: The sNfL Z-score was higher for GBSDS > 2 at 3 months (median [IQR], 3.5 ng/L [3.2-4.0], vs 2.6 [1.7-3.4], p = 0.008) and at 12 months (3.6 ng/L [3.5-3.8] vs 2.6 [1.8-3.5], p = 0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58-0.93, p < 0.0001) for GBSDS > 2 at 3 months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55-0.78, p = 0.0018) and for the NfL index 0.86 (95% CI 0.78-0.93, p < 0.0001). DISCUSSION: Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.

Artificial intelligence-assisted ultrasound-guided regional anaesthesia: An explorative scoping review.

Purpose: The present study reviews the available scientific literature on artificial intelligence (AI)-assisted ultrasound-guided regional anaesthesia (UGRA) and evaluates the reported intraprocedural parameters and postprocedural outcomes. Methods: A literature search was performed on 19 September 2023, using the Medline, EMBASE, CINAHL, Cochrane Library and Google Scholar databases by experts in electronic searching. All study designs were considered with no restrictions regarding patient characteristics or cohort size. Outcomes assessed included the accuracy of AI-model tracking, success at the first attempt, differences in outcomes between AI-assisted and unassisted UGRA, operator feedback and case-report data. Results: A joint adaptive median binary pattern (JAMBP) has been applied to improve the tracking procedure, while a particle filter (PF) is involved in feature extraction. JAMBP combined with PF was most accurate on all images for landmark identification, with accuracy scores of 0.83, 0.93 and 0.93 on original, preprocessed and filtered images, respectively. Evaluation of first-attempt success of spinal needle insertion revealed first-attempt success in most patients. When comparing AI application versus UGRA alone, a significant statistical difference (p < 0.05) was found for correct block view, correct structure identification and decrease in mean injection time, needle track adjustments and bone encounters in favour of having AI assistance. Assessment of operator feedback revealed that expert and nonexpert operator feedback was overall positive. Conclusion: AI appears promising to enhance UGRA as well as to positively influence operator training. AI application of UGRA may improve the identification of anatomical structures and provide guidance for needle placement, reducing the risk of complications and improving patient outcomes. Level of Evidence: Level IV.

ICURE: Intensive care unit (ICU) risk evaluation for 30-day mortality. Developing and evaluating a multivariable machine learning prediction model for patients admitted to the general ICU in Sweden.

BACKGROUND: A prediction model that estimates mortality at admission to the intensive care unit (ICU) is of potential benefit to both patients and society. Logistic regression models like Simplified Acute Physiology Score 3 (SAPS 3) and APACHE are the traditional ICU mortality prediction models. With the emergence of machine learning (machine learning) and artificial intelligence, new possibilities arise to create prediction models that have the potential to sharpen predictive accuracy and reduce the likelihood of misclassification in the prediction of 30-day mortality. METHODS: We used the Swedish Intensive Care Registry (SIR) to identify and include all patients ≥18 years of age admitted to general ICUs in Sweden from 2008 to 2022 with SAPS 3 score registered. Only data collected within 1 h of ICU admission was used. We had 153 candidate predictors including baseline characteristics, previous medical conditions, blood works, physiological parameters, cause of admission, and initial treatment. We stratified the data randomly on the outcome variable 30-day mortality and created a training set (80% of data) and a test set (20% of data). We evaluated several hundred prediction models using multiple ML frameworks including random forest, gradient boosting, neural networks, and logistic regression models. Model performance was evaluated by comparing the receiver operator characteristic area under the curve (AUC-ROC). The best performing model was fine-tuned by optimizing hyperparameters. The model's calibration was evaluated by a calibration belt. Ultimately, we simplified the best performing model with the top 1-20 predictors. RESULTS: We included 296,344 first-time ICU admissions. We found age, Glasgow Coma Scale, creatinine, systolic blood pressure, and pH being the most important predictors. The AUC-ROC was 0.884 in test data using all predictors, specificity 95.2%, sensitivity 47.0%, negative predictive value of 87.9% and positive predictive value of 70.7%. The final model showed excellent calibration. The ICU risk evaluation for 30-day mortality (ICURE) prediction model performed equally well to the SAPS 3 score with only eight variables and improved further with the addition of more variables. CONCLUSION: The ICURE prediction model predicts 30-day mortality rate at first-time ICU admission superiorly compared to the established SAPS 3 score.

High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and ß, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPß and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.

Acute-Phase Neurofilament Light and Glial Fibrillary Acidic Proteins in Cerebrospinal Fluid Predict Long-Term Outcome After Severe Traumatic Brain Injury.

BACKGROUND: This study investigated trajectory profiles and the association of concentrations of the biomarkers neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ventricular cerebrospinal fluid (CSF) with clinical outcome at 1 year and 10-15 years after a severe traumatic brain injury (sTBI). METHODS: This study included patients with sTBI at the Neurointensive Care Unit at Sahlgrenska University Hospital, Gothenburg, Sweden. The injury was regarded as severe if patients had a Glasgow Coma Scale ≤ 8 corresponding to Reaction Level Scale ≥ 4. CSF was collected from a ventricular catheter during a 2-week period. Concentrations of NfL and GFAP in CSF were analyzed with enzyme-linked immunosorbent assay. The Glasgow Outcome Scale (GOS) was used to assess the 1-year and 10-15-year outcomes. After adjustment for age and previous neurological diseases, logistic regression was performed for the outcomes GOS 1 (dead) or GOS 2-5 (alive) and GOS 1-3 (poor) or GOS 4-5 (good) versus the independent continuous variables (NfL and GFAP). RESULTS: Fifty-three patients with sTBI were investigated; forty-seven adults are presented in the article, and six children (aged 7-18 years) are described in Supplement 1. The CSF concentrations of NfL gradually increased over 2 weeks post trauma, whereas GFAP concentrations peaked on days 3-4. Increasing NfL and GFAP CSF concentrations increased the odds of GOS 1-3 outcome 1 year after trauma (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.80, p = 0.025; and OR 1.61, 95% CI 1.09-2.37, p = 0.016, respectively). Similarly, increasing CSF concentrations of NfL and GFAP increased the odds for GOS 1-3 outcome 10-15 years after trauma (OR 2.04, 95% CI 1.05-3.96, p = 0.035; and OR 1.60, 95% CI 1.02-2.00, p = 0.040). CONCLUSIONS: This study shows that initial high concentrations of NfL and GFAP in CSF are both associated with higher odds for GOS 1-3 outcome 1 year and 10-15 years after an sTBI, implicating its potential usage as a prognostic marker in the future.

Progressive changes in pulmonary gas exchange during invasive respiratory support for COVID-19 associated acute respiratory failure: A retrospective study of the association with 90-day mortality.

BACKGROUND: Ratio of arterial pressure of oxygen and fraction of inspired oxygen (P/F ratio) together with the fractional dead space (Vd/Vt) provides a global assessment of pulmonary gas exchange. The aim of this study was to assess the potential value of these variables to prognosticate 90-day survival in patients with COVID-19 associated ARDS admitted to the Intensive Care Unit (ICU) for invasive ventilatory support. METHODS: In this single-center observational, retrospective study, P/F ratios and Vd/Vt were assessed up to 4 weeks after ICU-admission. Measurements from the first 2 weeks were used to evaluate the predictive value of P/F ratio and Vd/Vt for 90-day mortality and reported by the adjusted hazard ratio (HR) and 95% confidence intervals [95%CI] by Cox proportional hazard regression. RESULTS: Almost 20,000 blood gases in 130 patients were analyzed. The overall 90-day mortality was 30% and using the data from the first ICU week, the HR was 0.85 [0.77-0.94] for every 10 mmHg increase in P/F ratio and 1.61 [1.20-2.16] for every 0.1 increase in Vd/Vt. In the second week, the HR for 90-day mortality was 0.82 [0.75-0.89] for every 10 mmHg increase in P/F ratio and 1.97 [1.42-2.73] for every 0.1 increase in Vd/Vt. CONCLUSION: The progressive changes in P/F ratio and Vd/Vt in the first 2 weeks of invasive ventilatory support for COVID-19 ARDS were significant predictors for 90-day mortality.

Anaesthesia practice, quality indices including all-cause 30-day mortality associate to wrist fracture repositioning and surgery in Sweden: A perioperative register-based study 2018-2021.

BACKGROUND: Wrist fracture is one of most common fractures frequently requiring surgical anaesthesia. There is limited information related to the anaesthetic practice and quality including 30-day mortality associated with wrist fracture in Sweden in recent years. AIM: The aim of the present register-based study was to investigate the anaesthesia techniques used and quality indices including 30-day mortality associated with wrist fracture surgery in Sweden during the period 2018-2021. MATERIALS AND METHODS: All fracture repositions, and surgical interventions related to wrist fracture requiring anaesthesia in patients aged >18 years registered in the Swedish Perioperative Register (SPOR) between 2018 and 2021 were included in the analysis. Information on age, ASA class, anaesthesia technique, severe operative events, most reported side-effects during recovery room stay and all-cause 30-day mortality was collected. RESULTS: The data set included 25,147 procedures split into 14,796 females and 10,252 males (missing information n = 99) with a mean age of 52.9 ± 18.7 years and a significant age difference between females and males, 60.3 ± 15.4 and 42.2 ± 17.7 years, respectively. Mean age and ASA class increased during the study period (2018-2021), from 52.8 ± 18.6 to 54.0 ± 18.4 and ASA class 3-5 from 8.1% to 9.4% (p < .001 and p < .041, respectively). General anaesthesia (GA), GA combined with regional anaesthesia (RA), RA with or without sedation and sedation only was used in 41%, 13%, 40% and 6% of procedures, respectively, with minor changes over the study period. Pain at arrival in the recovery room (RR), (3.4%), severe pain during RR stay (2.1%), hypothermia (1.4%), postoperative nausea and vomiting (PONV) (1.2%) and urinary retention (0.5%) were the most reported side-effects during the RR stay. (RA) was associated with significantly lower occurrence of pain and PONV, and shorter RR stay, compared with GA (p < .001). The all-cause 30-day mortality was low (19 of 25,147 (0.08%)) with no differences over the period studied or anaesthetic technique. CONCLUSION: General anaesthesia or general anaesthesia combined with regional anaesthesia are the most used anaesthetic techniques for wrist fracture procedures in Sweden. Recovery room pain, PONV, hypothermia and urinary retention is reported in overall low frequencies, with no change over the period studied, but in lower frequencies for regional anaesthesia. All-cause 30-day mortality was low; 0.08% with no change over time or between anaesthetic techniques. Thus, the present quality review based on SPOR data supports high quality of perioperative anaesthesia care.

Radiological appearance and lung function six months after invasive ventilation in ICU for COVID-19 pneumonia: An observational follow-up study.

BACKGROUND: Respiratory functional sequelae in COVID-19 patients admitted to the intensive care unit for invasive ventilation are sparsely reported. The aim of this study was to investigate the radiological lung appearance, lung function and their association at 6 months after hospital discharge. It was hypothesized that the degree of pathological morphology on CT scans would correlate with lung function at the time of follow-up. METHODS AND FINDINGS: In this single-centre prospective observational study, 86 from 154 patients admitted to ICU due to COVID-19 between March 2020 and May 2021 were followed up at 6 months post discharge with computed tomography (CT) of the chest and pulmonary function tests (PFTs). The PFT results were expressed as z-scores calculated as the difference between the measured and predicted values divided by the standard deviation obtained from a reference population. Correlations were evaluated by Spearman's rho including the 95% confidence interval. Pathological changes on CT were found in 78/85 participants with fibrous parenchymal bands being the most prevalent finding (91%) followed by traction bronchiectasis (64%) and ground glass opacities (41%). Sixty-five participants performed PFTs, and a restrictive pattern was the most prevalent abnormality (34%). Diffusing capacity of the lung for carbon monoxide (DLCO) was reduced in 66% of participants. The CT severity score weakly correlated with forced vital capacity (FVC) z-score (0.295, p = 0.006), DLCO z-score (-0.231, p = 0.032) and alveolar volume (VA) z-score (0.253, p = 0.019). CONCLUSIONS: Most patients showed persistent radiological abnormalities on CT and reduced lung volumes, impaired diffusion capacity and patterns of restrictive lung function at 6 months post discharge from the ICU. The correlations between abnormalities on CT and lung function tests were weak. Further, studies with a long-term follow-up of lung function in this group of patients are needed.

α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders.

INTRODUCTION: Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders. METHODS: The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n = 55), MSA (n = 27), CBD (n = 7), and PSP (n = 16), as well as healthy controls (HC, n = 24). RESULTS: The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p < 0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p < 0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p < 0.0001) despite the overlapping symptoms in these diseases. CONCLUSION: These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.

Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury.

Importance: Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples. Objectives: To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year. Design, Setting, and Participants: This prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021. Exposures: Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury. Main Outcomes and Measures: Associations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3). Results: Among the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, -22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, -6.4 to 23.0 pg/mL]; serum NfL, -5.4 pg/mL [95% CI, -99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL). Conclusions and Relevance: This study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.

Fractional spinal anesthesia and systemic hemodynamics in frail elderly hip fracture patients.

Background: Systemic haemodynamic effects of intrathecal anaesthesia in an aging and frail population has not been well investigated. We examined the systemic haemodynamics of fractional spinal anaesthesia following intermittent microdosing of a local anaesthetic and an opioid. Methods: We included 15 patients aged over 65 with significant comorbidities, planned for hip fracture repair. Patients received a spinal catheter and cardiac output monitoring using the LiDCOplus system. All measurements were performed prior to start of surgery. Invasive mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), heart rate and stroke volume index (SVI) were registered. Two doses of bupivacaine 2.25 mg and fentanyl 15 µg were administered with 25-minute intervals. Hypotension was defined as a fall in MAP by >30% or a MAP <65 mmHg. Results: The incidence of hypotension was 30%. Hypotensive patients (n=5) were treated with low doses of norepinephrine (0.01-0.12 µg/kg/min). MAP showed a maximum reduction of 17% at 10 minutes following the first dose. CI, systemic vascular resistance index and stroke volume index decreased by 10%, 6%, and 7%, respectively, while heart rate was unchanged over time. After the second dose, none of the systemic haemodynamic variables were affected. Conclusions: Fractional spinal anaesthesia administered prior to surgery induced a minor to moderate fall in MAP, mainly caused by a reduction in cardiac output, induced by systemic venodilation, causing a fall in venous return. Our results are contrary to the widely held belief that hypotension is mainly the result of a reduction of systemic vascular resistance.

Presence of neural surface and onconeural autoantibodies in cerebrospinal fluid and serum in neurological diseases presents a potential risk for misdiagnosis.

BACKGROUND AND PURPOSE: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not. METHODS: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants. RESULTS: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older. CONCLUSIONS: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.

SCRN1: A cerebrospinal fluid biomarker correlating with tau in Alzheimer's disease.

INTRODUCTION: Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or Pick's disease. METHODS: We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n = 25) and controls (n = 28), clinically diagnosed Parkinson's disease (PD; n = 38), multiple system atrophy (MSA; n = 31), PSP (n = 20), CBD (n = 8), healthy controls (n = 37), and neuropathology-confirmed AD (n = 47). RESULTS: CSF SCRN1 was significantly increased in AD (P < 0.01, fold change = 1.4) compared to controls (receiver operating characteristic area under the curve = 0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R = 0.78, P = 1.1 × 10-13 ), phosphorylated tau181 (R = 0.64, P = 3.2 × 10-8 ), and Braak stage and negatively correlated with Mini-Mental State Examination score. DISCUSSION: CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology. HIGHLIGHTS: We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.

The Association Between the Clinical Frailty Scale and Adverse Health Outcomes in Older Adults in Acute Clinical Settings - A Systematic Review of the Literature.

Background: Frail older adults experience higher rates of adverse health outcomes. Therefore, assessing pre-hospital frailty early in the course of care is essential to identify the most vulnerable patients and determine their risk of deterioration. The Clinical Frailty Scale (CFS) is a frailty assessment tool that evaluates pre-hospital mobility, energy, physical activity, and function to generate a score that ranges from very fit to terminally ill. Purpose: To synthesize the evidence of the association between the CFS degree and all-cause mortality, all-cause readmission, length of hospital stay, adverse discharge destination, and functional decline in patients >65 years in acute clinical settings. Design: Systematic review with narrative synthesis. Methods: Electronic databases (PubMed, EMBASE, CINAHL, Scopus) were searched for prospective or retrospective studies reporting a relationship between pre-hospital frailty according to the CFS and the outcomes of interest from database inception to April 2020. Results: Our search yielded 756 articles, of which 29 studies were included in this review (15 were at moderate risk and 14 at low risk of bias). The included studies represented 26 cohorts from 25 countries (N = 44166) published between 2011 and 2020. All included studies showed that pre-hospital frailty according to the CFS is an independent predictor of all adverse health outcomes included in the review. Conclusion: A primary purpose of the CFS is to grade clinically increased risk (i.e. risk stratification). Our results report the accumulated knowledge on the risk-predictive performance of the CFS and highlight the importance of routinely including frailty assessments, such as the CFS, to estimate biological age, improve risk assessments, and assist clinical decision-making in older adults in acute care. Further research into the potential of the CFS and whether implementing the CFS in routine practice will improve care and patients' quality of life is warranted.

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders.

BACKGROUND: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. OBJECTIVE: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. METHODS: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1  = 51, n2  = 101), corticobasal degeneration (CBD) (n1  = 11, n2  = 3), progressive supranuclear palsy (PSP) (n1  = 22, n2  = 21), multiple system atrophy (MSA) (n1  = 31, n2  = 26), and healthy control (HC) (n1  = 48, n2  = 30) participants, as well as Alzheimer's disease (AD) (n2  = 23) patients in the second cohort. RESULTS: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25-0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; ß-estimate = -0.025 to -0.038, P < 0.05) and cognitive decline (NPTX2; ß-estimate = 0.32, P = 0.021). CONCLUSIONS: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interactive Interventions Can Improve Hand Hygiene and Aseptic Techniques During Perioperative Care-Experience From the "Safe Hands" Project.

PURPOSE: This paper evaluates a theory-driven, interactive hand hygiene (HH) intervention, the Safe Hands project, based on theories of organizational learning and culture including leadership support, dialogue and co-creation. DESIGN: This prospective quasi-experimental study used unobtrusive overt observations to evaluate adherence to HH recommendations after implementing an infection-prevention intervention. METHODS: The primary outcome was differences in HH practices "Before aseptic/clean procedure" (WHO moment 2), "After body fluid exposure risk" (WHO moment 3) and performance of aseptic techniques. One operating room (OR) department served as the study hospital and the other as the control hospital, both at Swedish university hospitals. Adherence to HH guidelines was measured 4 times during 2015 to 2017. FINDINGS: The intervention site displayed a significant improvement in adherence to HH guidelines and aseptic techniques. WHO 2; from 23.8% to 36.2%, (P = .014), WHO 3; from 22.2% to 42.3%, (P = .002), and aseptic techniques; from 17.5% to 31.6%, (P = .003). No changes in adherence were identified at the control site. The use of contaminated gloves decreased post intervention at the study operating department. CONCLUSIONS: This study shows that implementing tailored interventions that are underpinned by theories from organizational learning and culture can improve adherence to hand hygiene in a complex setting as the OR up to 6 months post-intervention. The interprofessional co-creation of standards operating procedures addressing specific care procedures and emphasizing the importance of aseptic techniques can be an acceptable and feasible way to reduce the risks of contaminating medical devices and patients during perioperative care.

Sex difference in circulating soluble form of ACE2 protein in moderate and severe COVID-19 and healthy controls.

Introduction: Membrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex. Materials and methods: Soluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (µg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay. Results: In total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men. Conclusion: The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.

A co-created nurse-driven catheterisation protocol can reduce bladder distension in acute hip fracture patients - results from a longitudinal observational study.

BACKGROUND: Urinary retention is common in elderly patients undergoing acute hip fracture surgery. Avoiding overfilling the urinary bladder is important to avoid detrusor muscle damage and associated motility problems. The aim of this study was to analyse associations between the co-creation of a nurse-driven urinary catheterisation protocol and the incidence of bladder distension in patients undergoing hip fracture surgery. METHODS: This is a single-centre implementation intervention with a retrospective longitudinal observation design, using five measures points, spanning from June 2015 to March 2020. The intervention was theory driven and the participants, together with the facilitators and researcher, co-created a nurse-driven urinary catheterisation protocol. Data were retrieved from the hip fracture register. Uni- and multivariable logistic regressions were used for analyses of changes in bladder distension and urinary volume of ≥500 ml over the years. RESULTS: A total of 3078 patients were included over a five-year period. The implementation intervention was associated with a reduction in the proportion of patients with bladder distension of 31.5% (95% confidence interval 26.0-37.0), from year 1 to year 5. The multivariable analysis indicated a 39% yearly reduction in bladder distension, OR 0.61 (95% confidence interval 0.57-0.64, p <  0001). There was a reduction in the proportion of patients with a bladder volume of ≥500 ml of 42.8% (95% confidence interval 36.2-49.4), from year 1 to year 5. The multivariable analysis found a 41% yearly reduction in patients with a bladder volume of ≥500 ml, OR 0.59 (95% confidence interval 0.55-0.64, p <  0.0001). The intervention was associated with improved documentation of both catheter indications and removal plans. CONCLUSION: The use of predefined catheter indications and a tighter bladder scanning schedule were associated with a reduction in the incidence of both bladder distension and urine volume ≥ 500 ml in hip fracture patients. Registered nurses can play an active role in the facilitation of timely and appropriate catheter treatment in patients with hip fractures. TRIAL REGISTRATION: Clinical Trial Registry ISRCTN 17022695 registered retrospectively on 23 December 2021, in the end of the study, after data collection.

Reduction of early surgical site and other care related infections in 3553 hip fracture patients: lessons learned from the 5-year Safe Hands project.

BACKGROUND: Surgical site infection (SSI) after acute hip fracture surgery is a devastating complication associated with increased suffering and mortality. The aim of the study was to investigate early SSI, sepsis, pneumonia and urinary tract infections over five years, before and after the implementation of the Safe Hands project. METHODS: This was a single-centre observational study with a 5-year longitudinal design, investigating the effects of an infection-prevention intervention targeting the clinical care pathway of individuals with acute hip fracture. Statistical analyses were based on routinely collected patient outcome data comprising 3553 patients. The study conforms to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). RESULTS: The incidence of early SSIs decreased from 2.5% in years 1-2 to 1.1% in years 4-5. Similar results were observed for sepsis (2.7% to 1.3%) and urinary tract infections (14.2% to 4.2%). The multivariable regression results suggest that, for every observed year, the odds of early SSIs decreased. Male gender, procedure time, sepsis and preoperative skin damage increased the odds significantly. CONCLUSIONS: Our preventive bundle, based on partnership between researchers, managers and clinicians and a strong commitment to change from the involved professions, appear to be effective in reducing the frequency of potentially devastating SSIs and other hospital acquired infections after hip fracture surgery. The use of external and internal facilitators was crucial to enable individual and organisational learning and overcoming barriers to improvements. TRIAL REGISTRATION: Clinical Trials.gov ID: NCT02983136 Registered 6 December 2016-Retrospectively registered.

Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aß42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aß positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], ß = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], ß = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], ß = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aß and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.