Nevin Manimala

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

Stress Health. 2023 Aug 7. doi: 10.1002/smi.3299. Online ahead of print.

ABSTRACT

Interest in post-traumatic growth (PTG) as a predictor of health-related quality of life (HRQoL) is currently gaining attention. However, current evidence is still inconclusive on the nature of this relationship. The first objective of this study was to investigate the relationship between PTG and global HRQoL among cancer survivors. We further investigated the moderating role of fatigue in the association between PTG and global HRQoL. In the FiX study (Fatigue in Germany – Examination of prevalence, severity, and state of screening and treatment) cancer-related fatigue (EORTC QLQ-FA12), PTG inventory and global HRQoL (EORTC QLQ-C30) were assessed four years after cancer diagnosis in 1316 cancer-free survivors (mean age = 67.28, SD = 11.05, 51.4% female). Multiple linear regression analysis and moderation analysis were performed. The results showed that PTG had a convex quadratic relationship with global HRQoL (p < 0.001). Contrary to our hypothesis, fatigue did not moderate the relationship between PTG (linear and quadratic terms) and global HRQoL, neither when considering the overall PTG score nor for any PTG subdimension. In conclusion, PTG has a convex quadratic relationship with long-term global HRQoL that was not modified by persisting fatigue. Future statistical models investigating PTG and global HRQoL should take this non-linear relationship into account. Aiming to increase PTG might contribute to, but is likely not sufficient for high levels of global HRQoL in cancer survivors in the long run.

PMID:37547957 | DOI:10.1002/smi.3299

Echocardiography. 2023 Aug 7. doi: 10.1111/echo.15667. Online ahead of print.

ABSTRACT

BACKGROUND: Overweightness is a considerable step in the process leading to obesity. There are no sufficient studies on the effect of cardiomyopathy defined in obese patients about overweight subjects. We thought that it may be useful to examine the myocardial involvement in overweight individuals electro-mechanically with more sensitive techniques before the development of obesity cardiomyopathy.

AIM: The aim of the present study was to demonstrate whether or not there are subclinical left ventricular (LV) electrical and mechanical dysfunctions in overweight patients using frontal QRS-T (fQRS-T) angle (electrically) and 3D-speckle tracking echocardiography (mechanically).

METHODS: A total of 80 overweight patients and 80 age- and sex-matched normal weight individuals were enrolled into the study. 3D-STE examinations of the patients were performed. Electrocardiographic recordings were obtained for fQRS-T angle assessment.

RESULTS: The LV-GLS and LV-GCS were significantly depressed in the overweight group than in the normal weight group (-14.5 ± 3.4 vs. -21.7 ± 3.6, p < .001; -15.2 ± 4.6 vs. -24.3 ± 4.8, p < .001, respectively). The fQRS-T angle was found to be increased in the overweight group (142.5 ± 39.2 vs. 114.7 ± 43.5, p = < .001). Statistically significant positive linear correlations were observed between BMI with LV-GLS, LV-GCS, and fQRS-T angle. LV-GLS and LV-GCS were found to be disrupted linearly as BMI increased (r = .718 for BMI and LV-GLS, r = .653 for BMI and LV-GCS). As BMI increased, it was found that the fQRS-T angle increased (r = .692 for BMI and fQRS-T angle).

CONCLUSION: Our results support that, overweight individuals, despite their being apparently healthy, may have subclinical LV myocardial mechanical and electrical dysfunction.

PMID:37547932 | DOI:10.1111/echo.15667

Zhonghua Yi Xue Za Zhi. 2023 Aug 8;103(29):2258-2265. doi: 10.3760/cma.j.cn112137-20230223-00259.

ABSTRACT

Objective: To analyze the diagnostic and prognostic values of flow cytometry (FC) in diffuse large B cell lymphoma (DLBCL) with bone marrow involvement (BMI). Methods: The clinical data of 412 patients with newly diagnosed DLBCL, including 243 males and 169 females, aged 64 (28-92) years old, in the Department of Hematology at Peking University Third Hospital from December 2012 to June 2022 were retrospectively analyzed. All patients underwent bone marrow biopsy (BMB) and bone marrow FC. The patients with BMI by FC were further detected by fluorescence in situ hybridization (FISH) for gene analysis. The positive rates and consistency of BMI detected by BMB and FC were evaluated. According to the results of BMB and FC examinations, all patients were divided into four groups: the BMB⁺FC⁺group (115 cases), the BMB^–FC⁺group (50 cases), the BMB⁺FC^–group (8 cases, the results did not include in statistical analysis because of small sample size), and the BMB^–FC^–group (239 cases). The clinical features, treatment response rates, 5-year survival rates, and immunophenotype characteristics by FC in different groups were analyzed. Results: Among the 412 patients with DLBCL, the positivity rates of BMB and FC for BMI detection were 29.9% (123/412) and 40.0% (165/412), respectively. Good consistency between BMB and FC was found (Kappa=0.841, P=0.001). The numbers of extranodal involvement≥2, splenomegaly, huge mass, higher Ki-67 score, higher international prognostic index (IPI) score, thrombocytopenia, and elevated lactate dehydrogenase level were more prevalent in the BMB⁺FC⁺group than those in the BMB^–FC⁺group and the BMB^–FC^–group (all P<0.05). The treatment response rate in BMB⁺FC⁺group was 63.5% (73/115), which was lower than those in BMB^–FC⁺group (88.0%, 44/50, P=0.048) and BMB^–FC^–group (90.0%, 215/239, P=0.032), respectively. The 5-year overall survival rates in three groups were (53.6±9.7) %, (72.5±8.6) %, and (75.2±7.6) %, respectively, with a statistically significant difference (P=0.037). According to the FISH results of bone marrow, 102 cases were diagnosed as not otherwise specified (NOS), 48 cases were diagnosed as double hit lymphoma (DHL), and 15 cases were diagnosed as triple hit lymphoma (THL). Compared with NOS subtypes, the tumor cells in DHL or THL subtypes had higher proportion of increased side scatter (SSC), higher positive rates of CD10 expression, CD38 strong expression and CD56 expression, and lower proportion of surface immunoglobulin light chain restriction (all P<0.05). Conclusions: FC is well consistent with BMB in diagnosing DLBCL with BMI. Combined with FISH detection, FC can contribute to the auxiliary diagnosis and risk stratification for DHL and THL, and provide reference for the prognostic evaluation in DLBCL with BMI.

PMID:37544763 | DOI:10.3760/cma.j.cn112137-20230223-00259