Publisher Correction: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

This paper was originally published under a standard Springer Nature license

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

No abstract available

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Smartphone-derived keystroke dynamics are sensitive to relevant changes in multiple sclerosis

Background: To investigate smartphone keystroke dynamics (KD), derived from regular typing, on sensitivity to relevant change in disease activity, fatigue, and clinical disability in multiple sclerosis (MS). Methods: Preplanned interim analysis of a cohort study with 102 MS patients assessed at baseline and 3-month follow-up for gadolinium-enhancing lesions on magnetic resonance imaging, relapses, fatigue and clinical disability outcomes. Keyboard interactions were unobtrusively collected during typing using the Neurokeys App. From these interactions 15 keystroke features were derived and aggregated using 16 summary and time series statistics. Responsiveness of KD to clinical anchor-based change was assessed by calculating the area under the receiver operating characteristic curve (AUC). The optimal cut-point was used to determine the minimal clinically important difference (MCID) and compared to the smallest real change (SRC). Commonly used clinical measures were analyzed for comparison. Results: A total of 94 patients completed the follow-up. The five best performing keystroke features had AUC-values in the range 0.72–0.78 for change in gadolinium-enhancing lesions, 0.67–0.70 for the Checklist Individual Strength Fatigue subscale, 0.66–0.79 for the Expanded Disability Status Scale, 0.69–0.73 for the Ambulation Functional System, and 0.72–0.75 for Arm function in MS Questionnaire. The MCID of these features exceeded the SRC on group level. KD had higher AUC-values than comparative clinical measures for the study outcomes, aside from ambulatory function. Conclusions: Keystroke dynamics demonstrated good responsiveness to changes in disease activity, fatigue, and clinical disability in MS, and detected important change beyond measurement error on group level. Responsiveness of KD was better than commonly used clinical measures

Project Y: The search for clues explaining phenotype variability in MS

Background: To study phenotypic variability in MS patients, well-defined unbiased cohort studies are necessary. The most common and probably most important confounding factor when studying disease phenotype in MS is age. Objective: To describe study design and subject characteristics of a unique birth cohort (Project Y). The overall aim of Project Y is to identify determinants associated with phenotypic variability in MS, eliminating the possibility of confounding by age. Methods: Project Y is a population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Patients and healthy controls were subjected to comprehensive examinations: functional and static imaging, physical and cognitive measurements, and lifestyle factors early and later in life. In addition body fluids were collected and stored for future biomarker research. Results: 452 eligible MS patients were identified. Between December 2017 and January 2021, 367 MS patients and 125 healthy controls participated. The total number of identified cases results in a current prevalence of at least 189/100.000 for people born in the year 1966 in The Netherlands. Conclusion: Project Y is a unique cohort designed to identify factors associated with phenotypic variability in MS patients without the confounding effects of age. This first description of the Project Y cohort indicates that the prevalence of MS in the Netherlands might be higher than previously presumed. Various studies using Project Y data are ongoing and results will be published in upcoming years

Postnatal Cardiac Gene Editing Using CRISPR/Cas9 With AAV9-Mediated Delivery of Short Guide RNAs Results in Mosaic Gene Disruption

RATIONALE: CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9)-based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. OBJECTIVE: To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. METHODS AND RESULTS: We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression. As a proof-of-concept, we delivered short guide RNAs targeting 3 genes critical for cardiac physiology, Myh6, Sav1, and Tbx20, using a cardiotropic adeno-associated viral vector 9. Despite a similar degree of DNA disruption and subsequent mRNA downregulation, only disruption of Myh6 was sufficient to induce a cardiac phenotype, irrespective of short guide RNA exposure or the level of Cas9 expression. DNA sequencing analysis revealed target-dependent mutations that were highly reproducible across mice resulting in differential rates of in- and out-of-frame mutations. Finally, we applied a dual short guide RNA approach to effectively delete an important coding region of Sav1, which increased the editing efficiency. CONCLUSIONS: Our results indicate that the effect of postnatal CRISPR/Cas9-based cardiac gene editing using adeno-associated virus serotype 9 to deliver a single short guide RNA is target dependent. We demonstrate a mosaic pattern of gene disruption, which hinders the application of the technology to study gene function. Further studies are required to expand the versatility of CRISPR/Cas9 as a robust tool to study novel cardiac gene functions in vivo

Neuroaxonal and Glial Markers in Patients of the Same Age With Multiple Sclerosis

BACKGROUND AND OBJECTIVES: The specificity of novel blood biomarkers for multiple sclerosis (MS)-related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age. METHODS: sNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC. RESULTS: sNfL (9.83 pg/mL [interquartile range {IQR}: 7.8-12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5-84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0-10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1-68.3]) (p < 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8-9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0-10,265.8]) (p = 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p = 0.009 and p = 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = -0.52) and between sGFAP with deep gray matter volume (ρ = - 0.56) in primary progressive patients. DISCUSSION: In our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS

Precancerous liver diseases do not cause increased mutagenesis in liver stem cells

Inflammatory liver disease increases the risk of developing primary liver cancer. The mechanism through which liver disease induces tumorigenesis remains unclear, but is thought to occur via increased mutagenesis. Here, we performed whole-genome sequencing on clonally expanded single liver stem cells cultured as intrahepatic cholangiocyte organoids (ICOs) from patients with alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), and primary sclerosing cholangitis (PSC). Surprisingly, we find that these precancerous liver disease conditions do not result in a detectable increased accumulation of mutations, nor altered mutation types in individual liver stem cells. This finding contrasts with the mutational load and typical mutational signatures reported for liver tumors, and argues against the hypothesis that liver disease drives tumorigenesis via a direct mechanism of induced mutagenesis. Disease conditions in the liver may thus act through indirect mechanisms to drive the transition from healthy to cancerous cells, such as changes to the microenvironment that favor the outgrowth of precancerous cells