Category: Statistics

Neurology. 2024 Jan 9;102(1):e207806. doi: 10.1212/WNL.0000000000207806. Epub 2023 Dec 15.

ABSTRACT

BACKGROUND AND OBJECTIVE: We aimed to investigate the association between glycemic variability (GV) and neuroimaging markers of white matter hyperintensities (WMH), beta-amyloid (Aβ), brain atrophy, and cognitive impairment.

METHODS: This was a retrospective cohort study that included participants without dementia from a memory clinic. They all had Aβ PET, brain MRI, and standardized neuropsychological tests and had fasting glucose (FG) levels tested more than twice during the study period. We defined GV as the intraindividual visit-to-visit variability in FG levels. Multivariable linear regression and logistic regression were used to identify whether GV was associated with the presence of severe WMH and Aβ uptake with DM, mean FG levels, age, sex, hypertension, and presence of APOE4 allele as covariates. Mediation analyses were used to investigate the mediating effect of WMH and Aβ uptake on the relationship between GV and brain atrophy and cognition.

RESULTS: Among the 688 participants, the mean age was 72.2 years, and the proportion of female participants was 51.9%. Increase in GV was predictive of the presence of severe WMH (coefficient [95% CI] 1.032 [1.012-1.054]; p = 0.002) and increased Aβ uptake (1.005 [1.001-1.008]; p = 0.007). Both WMH and increased Aβ uptake partially mediated the relationship between GV and frontal-executive dysfunction (GV → WMH → frontal-executive; direct effect, -0.319 [-0.557 to -0.080]; indirect effect, -0.050 [-0.091 to -0.008]) and memory dysfunction (GV → Aβ → memory; direct effect, -0.182 [-0.338 to -0.026]; indirect effect, -0.067 [-0.119 to -0.015]), respectively. In addition, increased Aβ uptake completely mediated the relationship between GV and hippocampal volume (indirect effect, -1.091 [-2.078 to -0.103]) and partially mediated the relationship between GV and parietal thickness (direct effect, -0.00101 [-0.00185 to -0.00016]; indirect effect, -0.00016 [-0.00032 to -0.000002]).

DISCUSSION: Our findings suggest that increased GV is related to vascular and Alzheimer risk factors and neurodegenerative markers, which in turn leads to subsequent cognitive impairment. Furthermore, GV can be considered a potentially modifiable risk factor for dementia prevention.

PMID:38165363 | DOI:10.1212/WNL.0000000000207806

Neurology. 2024 Jan 23;102(2):e207976. doi: 10.1212/WNL.0000000000207976. Epub 2023 Dec 22.

ABSTRACT

BACKGROUND AND OBJECTIVES: The neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy (EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide.

METHODS: REPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney U test and multiple linear regression.

RESULTS: Sixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (p = 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range [IQR], 2.54-21.81) in patients with placebo (p = 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error [SE], 60%) in the white matter (p = 0.03) and by 340% (SE, 140%) in the basal ganglia (p = 0.02) in the nerinetide group compared with placebo after adjusting for confounders.

DISCUSSION: This study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth.

TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02930018.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.

PMID:38165335 | DOI:10.1212/WNL.0000000000207976

J Magn Reson Imaging. 2023 Dec 29. doi: 10.1002/jmri.29203. Online ahead of print.

ABSTRACT

BACKGROUND: Diffusion imaging holds great potential for the non-invasive assessment of the glymphatic system in humans. One technique, diffusion tensor imaging along the perivascular space (DTI-ALPS), has introduced the ALPS-index, a novel metric for evaluating diffusivity within the perivascular space. However, it still needs to be established whether the observed reduction in the ALPS-index reflects axonal changes, a common occurrence in neurodegenerative diseases.

PURPOSE: To determine whether axonal alterations can influence change in the ALPS-index.

STUDY TYPE: Retrospective.

POPULATION: 100 participants (78 cognitively normal and 22 with mild cognitive impairments) aged 50-90 years old.

FIELD STRENGTH/SEQUENCE: 3T; diffusion-weighted single-shot spin-echo echo-planar imaging sequence, T1-weighted images (MP-RAGE).

ASSESSMENT: The ratio of two radial diffusivities of the diffusion tensor (i.e., λ2/λ3) across major white matter tracts with distinct venous/perivenous anatomy that fulfill (ALPS-tracts) and do not fulfill (control tracts) ALPS-index anatomical assumptions were analyzed.

STATISTICAL TESTS: To investigate the correlation between λ2/λ3 and age/cognitive function (RAVLT) while accounting for the effect of age, linear regression was implemented to remove the age effect from each variable. Pearson correlation analysis was conducted on the residuals obtained from the linear regression. Statistical significance was set at p < 0.05.

RESULTS: λ2 was ~50% higher than λ3 and demonstrated a consistent pattern across both ALPS and control tracts. Additionally, in both ALPS and control tracts a reduction in the λ2/λ3 ratio was observed with advancing age (r = -0.39, r = -0.29, association and forceps tract, respectively) and decreased memory function (r = 0.24, r = 0.27, association and forceps tract, respectively).

DATA CONCLUSIONS: The results unveil a widespread radial asymmetry of white matter tracts that changes with aging and neurodegeration. These findings highlight that the ALPS-index may not solely reflect changes in the diffusivity of the perivascular space but may also incorporate axonal contributions.

LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

PMID:38156600 | DOI:10.1002/jmri.29203

J Am Heart Assoc. 2023 Dec 29:e030263. doi: 10.1161/JAHA.123.030263. Online ahead of print.

ABSTRACT

BACKGROUND: Research on the cardiovascular toxicity of angiogenesis inhibitors among patients with cancer in Taiwan is lacking. This observational study explored the risk of major adverse cardiovascular events (MACEs) associated with angiogenesis inhibitors in Taiwan.

METHODS AND RESULTS: We conducted a nested case-control study using the TCR (Taiwan Cancer Registry) linked with the Taiwan National Insurance Claim Database. We matched every case with 4 controls using risk-set sampling by index date, age, sex, cancer type, and cancer diagnosis date. Conditional logistic regression was used to evaluate the risks of MACEs and different cardiovascular events using propensity score adjustment or matching. Sensitivity analyses were used to evaluate the risks matched by cancer stages or exposure within 1 year. Among a cohort of 284 292 after the exclusion of prevalent cases, the incidences of MACEs among the overall cohort and those exposed to angiogenesis inhibitors were 22.5 and 32.5 events per 1000 person-years, respectively. We matched 17 817 cases with 70 740 controls, with a mean age of 74.9 years, and 56.8% of patients were men. After propensity score adjustment, angiogenesis inhibitors were associated with increased risks of MACEs (odds ratio, 4.56; 95% CI, 1.78-11.59). Significantly increased risks were noted for heart failure hospitalization, myocardial infarction, cerebrovascular accident, and venous thromboembolism, but not for new-onset atrial fibrillation. Similar results were observed after matching by cancer stage or restriction of 1-year exposure.

CONCLUSIONS: Angiogenesis inhibitors were associated with increased risks of MACEs among patients with various malignancies in Taiwan but were not associated with new-onset atrial fibrillation.

PMID:38156594 | DOI:10.1161/JAHA.123.030263

Vopr Virusol. 2023 Sep 21;68(4):291-301. doi: 10.36233/0507-4088-181.

ABSTRACT

INTRODUCTION: The discovery of two types of Epstein-Barr virus (EBV) (EBV-1 and EBV-2) that have different biological properties stimulated the search for neoplasms associated with each type of the virus. The aim of the work is to study the nature of the association of nasopharyngeal cancer (NPC) with EBV-1 and EBV-2, serological activity for each viral type and the concentration of EBV DNA in the blood plasma of two gender, age and ethnic groups of NPC patients that represent geographically and climatically different regions of Russia,.

MATERIALS AND METHODS: In the blood plasma of patients with NPC and other non- EBV associated tumors of oral cavity (OTOC^EBV-) from the North Caucasian (NCFD) and Central (CFD) Federal Districts of Russia, the types of EBV and the concentration of viral DNA were determined using respectively «nested» and real time PCR; titers of IgG and IgA antibodies to viral capsid antigen (VCA) were measured in indirect immunofluorescence assay.

RESULTS: The blood plasma samples testing showed that NPC and OTOC^EBV- patients were infected with both types of EBV in approximately equal proportions. In two groups of NPC patients infected with one of the virus types only, EBV-1 or EBV-2, respectively, no statistically significant differences were found between the geometric mean values of IgG and IgA anti-EBV antibody titers and viral DNA concentrations in blood plasma. The distribution of virus types was not affected by either patient gender or ethnogeographic origin. The difference was found only between age groups: EBV-2 dominated in NPC patients up to 60 years, and EBV-1 was prevalent in patients over 60 years.

CONCLUSION: The lack of the predominance of one of EBV types in NPC patients that are the representatives of different ethnic groups from geographically and climatically different regions, suggests that none of these factors play an important role in the NPC carcinogenesis. Evidently, each type of EBV, EBV-1 or EBV-2, if the necessary conditions arise, are able to exhibit its oncogenic potential to initiate tumor development.

PMID:38156586 | DOI:10.36233/0507-4088-181

Vopr Virusol. 2023 Dec 26;68(6):549-556. doi: 10.36233/0507-4088-206.

ABSTRACT

INTRODUCTION: Although domestic pigs and wild boars are the main reservoir of zoonotic hepatitis E virus (HEV) genotypes in temperate countries, the presence of antibodies to HEV (anti-HEV) in the indigenous population of circumpolar territories, i.e. outside the habitat of wild and domestic pigs, indicates the presence of an alternative reservoir of the virus. Reindeer (Rangifer tarandus) may be a potential reservoir for HEV in the polar regions. The purpose of the study was to determine the prevalence of anti-HEV among domestic reindeer in the Republic of Sakha (Yakutia).

MATERIALS AND METHODS: Sera from 497 domestic reindeer from the Oymyakon (n = 425) and Ust-Yansky districts (n = 72) of the Republic of Sakha (Yakutia) were tested for anti-HEV. A commercial ELISA kit DS-ELISA-ANTI-HEV-G (Diagnostic Systems-Stolitsa LLC, Russia) was used for detection of anti-HEV IgG, but a rabbit polyclonal antibody against deer IgG labeled with horseradish peroxidase (KPL, USA) at a dilution of 1 : 100 in phosphate-buffered saline were used instead of the human specific conjugate from the kit.

RESULTS: The average detection rate of anti-HEV in reindeer sera was 15.5% (95% CI: 12.6-19.0%). The detection rate of anti-HEV significantly increased with age, from 3.5% (95% CI: 1.1-9.0%) in calves aged 3-6 months to 25.0% (95% CI: 1.6 -36.5%) in deer aged 2-4 years (p < 0.0001). From this age group, anti-HEV detection rates reached a plateau, not differing significantly between older age groups (p > 0.05). The average anti-HEV detection rate among reindeer 2 years of age and older was 19.0% (95% CI: 15.3-23.4%). There were no statistically significant differences in the frequency of anti-HEV detection between female and male reindeer, both among adult animals and among calves.

CONCLUSION: The observed anti-HEV detection rates among domestic reindeer in the Republic of Sakha (Yakutia) indicate that infection caused by HEV or an antigenically similar virus is common in these animals. The dynamics of antibody accumulation in the reindeer population indicates that infection apparently occurs during the first two years of life.

PMID:38156570 | DOI:10.36233/0507-4088-206

J Am Heart Assoc. 2023 Dec 29:e030328. doi: 10.1161/JAHA.123.030328. Online ahead of print.

ABSTRACT

BACKGROUND: The widely used Bentall procedure is the criterion standard treatment for aortic root pathology. Studies comparing the long-term outcomes of bioprosthetic and mechanical valves in patients undergoing the Bentall procedure are limited.

METHODS AND RESULTS: Patients who underwent the Bentall procedure with a bioprosthetic or mechanical valve between 2001 and 2018 were identified from Taiwan’s National Health Insurance Research Database. The primary outcome of interest was all-cause mortality. Inverse probability of treatment weighting was performed to compare the 2 prosthetic types. In total, 1052 patients who underwent the Bentall procedure were identified. Among these patients, 351 (33.4%) and 701 (66.6%) chose bioprosthetic and mechanical valves, respectively. After inverse probability of treatment weighting, no significant differences in the in-hospital mortality (odds ratio, 0.96 [95% CI, 0.77-1.19]; P=0.716) and all-cause mortality (34.1% vs. 38.1%; hazard ratio, 0.90 [95% CI, 0.78-1.04]; P=0.154) were observed between the groups. The benefits of relative mortality associated with mechanical valves were apparent in younger patients and persisted until ≈50 years of age.

CONCLUSIONS: No differences in survival benefits were observed between the valves in patients who underwent the Bentall procedure. Additionally, bioprosthetic valves may be a reasonable choice for patients aged >50 years when receiving the Bentall procedure in this valve-in-valve era.

PMID:38156561 | DOI:10.1161/JAHA.123.030328

J Am Heart Assoc. 2023 Dec 29:e031447. doi: 10.1161/JAHA.123.031447. Online ahead of print.

ABSTRACT

BACKGROUND: Despite the health effects of basal metabolic rate (BMR), the causal effect of BMR on cardiovascular diseases (CVDs) remains undetermined. To elucidate the causal nature, Mendelian randomization (MR) analyses were performed.

METHODS AND RESULTS: Summary genome-wide association statistics regarding BMR and 5 CVDs were obtained from European databases. A 2-sample bidirectional MR was performed to assess the causal association between BMR and CVDs. The causal effects were estimated using inverse variance weighting. Simultaneously, multiple sensitivity analyses were performed to validate the robustness and reliability of the results. Our results indicated that genetically predicted BMR was significantly positively associated with the risk of heart failure (odds ratio, 1.53 [95% CI, 1.39-1.67]; P<0.001), atrial fibrillation and flutter (odds ratio, 2.12 [95% CI, 1.87-2.40]; P<0.001), and aortic aneurysm (odds ratio, 1.64 [95% CI, 1.41-1.92]; P<0.001). Genetically predicted BMR may not be causally associated with coronary artery disease and ischemic stroke risk. Furthermore, a significant causal effect of CVDs on BMR was not found in the reverse MR analysis. Multivariable MR was applied to further assess the direct effect of BMR on CVDs. Multivariable MR indicated that a high level of BMR still increased the risk of heart failure and atrial fibrillation and flutter after adjustment independent of possible confounders. However, the P value of aortic aneurysm was not significant.

CONCLUSIONS: The present study provides robust evidence that genetically predicted BMR is independently causally associated with heart failure and atrial fibrillation and flutter but not vice versa. These findings have implications for the prevention and treatment of CVDs in clinical practice.

PMID:38156559 | DOI:10.1161/JAHA.123.031447

G Ital Nefrol. 2023 Dec 22;40(6):2023-vol6.

ABSTRACT

Background. Estimated GFR (eGFR) is calculated using serum creatinine (SCr) based equations which have their own limitations. Novel biomarkers like beta trace protein (BTP) are studied for eGFR estimation. The aim of this study is to determine the serum levels of BTP in healthy controls and chronic kidney disease (CKD) cases and to find out the correlation of BTP levels with that of SCr and SCr-based eGFR formulas. Methods. The control group comprised of 20 healthy adults. The cases comprised of 20 patients each in CKD stages 3, 4, and 5, categorized based on eGFR calculated using MDRD formula. Baseline characteristics of the study population were recorded. BTP was measured by ELISA (Enzyme Linked Immunosorbent Assay) method and SCr by modified Jaffe’s method. The statistical analyses were performed with the SPSS for Windows, version 16.0. Results. The median value of blood urea nitrogen (BUN) in the cases was 26.50 mg/dL (IQR 19.25-37) and for control it was 9.5 mg/dL (IQR 8-12). The median value of SCr in the cases was 2.75 mg/dL (IQR 1.725-4.45) and in the controls, it was 0.7mg/dL (IQR 0.6 -0.8). The median value of BTP in cases was 6389.25 ng/ml (IQR 5610.875-10713.75) and in controls, it was 1089.5 ng/ml (IQR 900.5-1309.75). Conclusion. Serum BTP levels correlated with SCr levels and renal function. We could establish the relationship between the two biomarkers, SCr and BTP, and derive a regression equation.

PMID:38156542

Otolaryngol Head Neck Surg. 2023 Dec 29. doi: 10.1002/ohn.631. Online ahead of print.

ABSTRACT

OBJECTIVE: Olfactory dysfunction has gained considerable interest with its association to the coronavirus pandemic. Due to the limited literature on olfactory-related adverse events (ORAE) associated with medications, this study investigated ORAE reported in the Food and Drug Administration Adverse Event Reporting System (FAERS) to identify the most frequent medications associated with these reactions.

STUDY DESIGN: Cross-sectional analysis SETTING: FAERS database.

METHODS: The FAERS database was accessed to obtain ORAEs from 2012 to 2022. Disproportionality analysis was conducted by calculating the proportional reporting ratios (PRR) and reporting odds ratio (ROR) for anosmia, parosmia, hyposmia, and olfactory dysfunction. A PRR > 2 or ROR > 1 was significant. A multivariate logistical model was used to estimate adjusted ROR for gender and country of origin.

RESULTS: Our final study population consisted of 1111 cases with the following symptoms: anosmia (672), parosmia (364), hyposmia (71), and olfactory dysfunction (4). The most significant ROR signal scores were found for secukinumab (3.42; 95% confidence interval, CI [1.9, 4.01]) for anosmia, levofloxacin (8.86; 95% CI [2.83, 9.8]) for hyposmia, and pregabalin (6.88; 95% CI [2.23, 8.01]) for parosmia. No significant PRR signal scores were found for anosmia, but significant signals were found for citalopram hydrobromide (17.25; 95% CI [17.01, 17.49]) in hyposmia, and dimethyl fumarate (3.18; 95% CI [3.09, 3.27]) in parosmia. No valid PRR or ROR values were found for olfactory dysfunction. Multivariate analysis did not reveal statistically significant differences between genders for any symptoms, but individuals from non-US countries did exhibit statistically significant elevated risk of anosmia (1.3 (95% CI [1.01, 1.68]).

CONCLUSION: Pharmacovigilance studies provide an opportunity to evaluate the safety profile of medications regarding ORAE, particularly for those commonly prescribed for sinonasal symptoms. Findings from this study may function as a resource for prescribers and patients.

PMID:38156529 | DOI:10.1002/ohn.631