Category: Statistics

J Magn Reson Imaging. 2023 Aug 7. doi: 10.1002/jmri.28931. Online ahead of print.

ABSTRACT

BACKGROUND: Gadolinium (Gd)-based contrast agents (GBCAs) have been widely used for acute ischemic stroke (AIS) patients. GBCAs or AIS alone may cause the adverse effects on kidney tissue, respectively. However, whether GBCAs and AIS would generate a synergistic negative effect remains undefined.

PURPOSE: To evaluate synergistic negative effects of AIS and GBCAs on renal tissues in a mouse model of AIS, and to compare the differences of these negative effects between linear and macrocyclic GBCAs.

STUDY TYPE: Animal study.

ANIMAL MODEL: Seventy-two healthy mice underwent transient middle cerebral artery occlusion (tMCAO) and sham operation to establish AIS and sham model (N = 36/model). 5.0 mmol/kg GBCAs (gadopentetate or gadobutrol) or 250 μL saline were performed at 4.5 hours and 1 day after model establishing (N = 12/group).

ASSESSMENT: Inductively coupled plasma mass spectrometry (ICP-MS) was performed to detect Gd concentrations. Serum biochemical analyzer was performed to measure the serum creatinine (Scr), uric acid (UA), and blood urea nitrogen (BUN). Pathological staining was performed to observe tubular injury, cell apoptosis, mesangial hyperplasia, and interstitial fibrosis.

STATISTICAL TESTS: Two-way analysis of variances with post hoc Sidak’s tests and independent-samples t-tests were performed. A P-value <0.05 was considered statistically significant.

RESULTS: AIS groups showed higher Gd concentration than sham group on day 1 p.i. regardless of gadopentetate or gadobutrol used. Increased total Gd concentration was also found in AIS + gadopentetate group compared with the sham group on day 28 p.i. Significantly higher rates for renal dysfunction, higher tubular injury scores, and higher numbers of apoptotic cells on days 1 or 28 p.i. were found for AIS mice injected with GBCA. AIS + gadopentetate group displayed more severe renal damage than the AIS + gadobutrol group.

DATA CONCLUSION: AIS and GBCAs may cause increased total Gd accumulation and nephrotoxicity in a mouse, especially linear GBCAs were used.

LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

PMID:37548106 | DOI:10.1002/jmri.28931

Int J Eat Disord. 2023 Aug 7. doi: 10.1002/eat.24040. Online ahead of print.

ABSTRACT

OBJECTIVE: Precision medicine (i.e., individually tailored treatments) represents an optimal goal for treating complex psychiatric disorders, including eating disorders. Within the eating disorders field, most treatment development efforts have been limited in their ability to identify individual-level models of eating disorder psychopathology and to develop and apply an individually tailored treatment for a given individual’s personalized model of psychopathology. In addition, research is still needed to identify causal relationships within a given individual’s model of eating disorder psychopathology. Addressing this limitation of the current state of precision medicine-related research in the field will allow us to progress toward advancing research and practice for eating disorders treatment.

METHOD: We present a novel set of analytic tools, causal discovery analysis (CDA) methods, which can facilitate increasingly fine-grained, person-specific models of causal relations among cognitive, behavioral, and affective symptoms.

RESULTS: CDA can advance the identification of an individual’s causal model that maintains that individuals’ eating disorder psychopathology.

DISCUSSION: In the current article, we (1) introduce CDA methods as a set of promising analytic tools for developing precision medicine methods for eating disorders including the potential strengths and weaknesses of CDA, (2) provide recommendations for future studies utilizing this approach, and (3) outline the potential clinical implications of using CDA to generate personalized models of eating disorder psychopathology.

PUBLIC SIGNIFICANCE STATEMENT: CDA provides a novel statistical approach for identifying causal relationships among variables of interest for a given individual. Person-specific causal models may offer a promising approach to individualized treatment planning and inform future personalized treatment development efforts for eating disorders.

PMID:37548100 | DOI:10.1002/eat.24040

Br J Clin Pharmacol. 2023 Aug 7. doi: 10.1111/bcp.15871. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation.

EXPERIMENTAL APPROACH: In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome – graft function at one year – was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury.

KEY RESULTS: Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After one year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant.

CONCLUSION AND IMPLICATIONS: This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.

PMID:37548047 | DOI:10.1111/bcp.15871

Ann Neurol. 2023 Aug 7. doi: 10.1002/ana.26758. Online ahead of print.

ABSTRACT

OBJECTIVE: GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype-phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders and to delineate the correlation between the underlying molecular mechanisms and clinical severity.

METHODS: Sixteen individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P) were examined with repeated clinical assessments, video-EEG monitoring, and brain MRI. The molecular pathology of each variant was delineated using a molecular deconvoluting platform.

RESULTS: The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to inter-patient variability but rather to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms.

INTERPRETATION: The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. This article is protected by copyright. All rights reserved.

PMID:37548038 | DOI:10.1002/ana.26758

Hypertension. 2023 Aug 7. doi: 10.1161/HYPERTENSIONAHA.123.21514. Online ahead of print.

ABSTRACT

BACKGROUND: The prognostic value of on-treatment mean cumulative ambulatory blood pressures (BPs) in type 2 diabetes has never been investigated. We aimed to assess it in a prospective cohort of 647 individuals with type 2 diabetes.

METHODS: Clinic-office and ambulatory BPs were measured at baseline and serially during follow-up. Multivariable Cox analyses assessed the associations between baseline and mean cumulative BPs with the occurrence of cardiovascular events, major adverse cardiovascular events, all-cause and cardiovascular mortality, and microvascular outcomes (microalbuminuria, renal failure, retinopathy, and peripheral neuropathy). C statistics and the integrated discrimination improvement (IDI) index evaluated the improvement in risk discrimination by using cumulative ambulatory BPs instead of baseline BPs.

RESULTS: Over a median follow-up of 10.6 years, there were 202 cardiovascular events (163 major adverse cardiovascular events), 254 all-cause deaths (118 cardiovascular); 125 individuals had microalbuminuria development/progression, 104 developed advanced renal failure, 159 had retinopathy, and 174 individuals had peripheral neuropathy development/progression. The risks associated with mean cumulative ambulatory BPs were in general higher than those associated with baseline BPs, particularly for cardiovascular (HR, 1.42 versus 1.25 for increments of 1 SD in 24-hour systolic blood pressure) and mortality outcomes (1.56 versus 1.26). Compared with cumulative clinic BPs, mean cumulative ambulatory BPs improved risk discrimination for most outcomes, with IDIs from 11% to 14% for major adverse cardiovascular events and mortality up to 24% to 26% for microalbuminuria and neuropathy.

CONCLUSIONS: Compared with clinic-office BPs, mean cumulative ambulatory BPs during follow-up improve risk discrimination for most complications and mortality in individuals with type 2 diabetes. Serial ambulatory BP monitoring shall be more widely used in clinical management.

PMID:37548035 | DOI:10.1161/HYPERTENSIONAHA.123.21514

Cancer. 2023 Aug 7. doi: 10.1002/cncr.34958. Online ahead of print.

ABSTRACT

BACKGROUND: There are limited to no data regarding the use of immune checkpoint inhibitors (ICIs) in patients who have preexisting organ dysfunction because these patients are frequently excluded from clinical trials. The authors’ objective was to evaluate the effects of ICIs in patients with chronic kidney disease (CKD), cirrhosis, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF).

METHODS: Data were obtained retrospectively for patients older than 18 years with solid organ malignancies who received at least one dose of an ICI between January 1, 2015, and January 1, 2021, and had either CKD (n = 90), cirrhosis (n = 20), COPD (n = 142), or CHF (n = 82) before ICI initiation at the authors’ institution. Descriptive statistics were used to summarize patient characteristics, treatment characteristics, immune-related adverse events (IrAEs), and outcomes. An independent samples t-test or the Wilcoxon rank-sum test was used to assess differences in continuous variables; the χ² test or the Fisher exact test was used to assess differences in categorical variables between patients with and without IrAEs. Progression-free survival (PFS) was assessed using Kaplan-Meier curves, and the log-rank test was used to assess differences in PFS.

RESULTS: In all four cohorts, there were no statistically significant differences in patient characteristics, treatment characteristics, or outcomes, such as the number of hospitalizations and PFS, among those who experienced IrAEs compared with those who did not. In the CKD cohort, patients with IrAEs were significantly less likely to die than those without IrAEs (52% vs. 81% [p = .009] for all patients; 53% vs. 83% [p = .008] for patients with stage II/III disease who received no definitive local treatment and patients with stage IV disease); this difference was not observed in the cirrhosis, COPD, or CHF cohorts. There was no statistically significant difference in the number of heart failure and COPD exacerbations during the receipt of ICIs in the CHF and COPD cohorts, respectively. The incidence and time to onset of IrAEs in this study appeared to be similar to those reported previously in clinical trials that excluded patients with significant comorbidities.

CONCLUSIONS: The current results demonstrate that ICIs are well tolerated by patients who have preexisting organ dysfunction.

PMID:37548033 | DOI:10.1002/cncr.34958

J Vasc Access. 2023 Aug 7:11297298231191374. doi: 10.1177/11297298231191374. Online ahead of print.

ABSTRACT

OBJECTIVE: The novel ultrasound magnetic needle navigation technique can visualize the entire needle and identify its projected trajectory. We hypothesized that this technique increases the first-attempt success rate of central venous puncture by novice learners compared with the conventional needle navigation technique.

METHODS: This prospective, randomized, controlled trial with a crossover design included 50 participants with limited prior experience in US-guided procedures. Participants were randomly assigned to novel or conventional technique groups and asked to perform central venous cannulation in a phantom task trainer. After the first successful attempt, participants were allocated to the other technique group.

RESULTS: Although participants in the novel technique group had a higher first-attempt success rate than did those in the conventional technique group, this difference was not statistically significant (p = 0.17). The total number of attempts also did not significantly differ (p = 0.16). The conventional technique group had more needle redirections (p = 0.01) and a longer time to successful cannulation (p = 0.01). The number of adverse effects (p = 0.32) did not differ between groups. Participant confidence levels were higher in the novel technique group (p < 0.001).

CONCLUSIONS: Magnetic needle navigation can reduce the number of needle redirections, shorten the time to successful cannulation, and increase confidence levels by novice learners for successful US-guided central venous access.

PMID:37548027 | DOI:10.1177/11297298231191374

Am J Sports Med. 2023 Aug 7:3635465231187033. doi: 10.1177/03635465231187033. Online ahead of print.

ABSTRACT

BACKGROUND: Most outcome studies on subscapularis (SSC) tendon tears have focused on large SSC tears rather than partial SSC tendon tears. Therefore, the optimal treatment for partial SSC tendon tears more than half of the first facet of the entire SSC footprint has not yet been clearly defined.

PURPOSE: To prospectively investigate the clinical and radiological results between the arthroscopic repair group and the debridement group in SSC partial tear (Yoo and Rhee classification, type 2B: SSC tendon tears of more than half of the entire first facet).

STUDY DESIGN: Randomized controlled trial; Level of evidence, 1.

METHODS: A total of 65 patients with SSC tendon type 2B tears were randomized to arthroscopic debridement (n = 33) or arthroscopic repair (n = 32). Clinical evaluation of the patients was performed on the day before surgery and 6 months, 1 year, 2 years, and 5 years postoperatively using active range of motion measurements and other validated scores (pain visual analog scale scores, function visual analog scale scores, Constant score, American Shoulder and Elbow Surgeons score). In addition, SSC muscle strength was measured using instruments in the belly-press position. Magnetic resonance imaging (upper and lower SSC muscle diameters, Goutallier grades) was performed on the day before operation as well as 6 months and 2 years postoperatively.

RESULTS: There were no clinically or statistically significant differences between the arthroscopic debridement and arthroscopic repair groups with respect to active range of motion, pain visual analog scale scores, function visual analog scale scores, Constant scores, or American Shoulder and Elbow Surgeons scores. There was a statistically significant increase in SSC muscle strength in the repair group compared with the debridement group at 5 years postoperatively (P = .013). Magnetic resonance imaging assessment was also not significantly different between the 2 groups.

CONCLUSION: There were no differences in the patient-reported outcomes of patients with partial SSC tears treated with either arthroscopic debridement or repair, although there was an increase in SSC muscle strength associated with repair, the clinical importance of which may warrant further research.

REGISTRATION: NCT03183466 (ClinicalTrials.gov identifier).

PMID:37548022 | DOI:10.1177/03635465231187033

Stroke. 2023 Aug 7. doi: 10.1161/STROKEAHA.123.043302. Online ahead of print.

ABSTRACT

BACKGROUND: Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA₂DS₂-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up.

METHODS: Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA₂DS₂-VASc score.

RESULTS: We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA₂DS₂-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]).

CONCLUSIONS: In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures.

PMID:37548011 | DOI:10.1161/STROKEAHA.123.043302

Eur J Clin Invest. 2023 Aug 7:e14073. doi: 10.1111/eci.14073. Online ahead of print.

NO ABSTRACT

PMID:37548000 | DOI:10.1111/eci.14073