Category: Statistics

Epilepsia. 2022 Feb 17. doi: 10.1111/epi.17193. Online ahead of print.

ABSTRACT

OBJECTIVE: A broad spectrum of emotional-behavioral problems have been reported in pediatric temporal lobe epilepsy (TLE), but with considerable variability in their presence and nature of expression, which hampers precise identification and treatment. The present study aimed to empirically identify latent patterns or behavioral phenotypes and their correlates.

METHODS: Data included parental ratings of emotional-behavioral status on the Behavior Assessment System for Children, 2nd Edition (BASC-2) of 81 children (mean age = 11.79, standard deviation [SD] = 3.93) with TLE. The nine clinical subscales were subjected to unsupervised machine learning to identify behavioral subgroups. To explore concurrent validity and the underlying composition of the identified clusters, we examined demographic factors, seizure characteristics, psychosocial factors, neuropsychological performance, psychiatric status, and health-related quality of life (HRQoL).

RESULTS: Three behavioral phenotypes were identified, which included no behavioral concerns (Cluster 1, 43% of sample), externalizing problems (Cluster 2, 41% of sample), and internalizing problems (Cluster 3, 16% of sample). Behavioral phenotypes were characterized by important differences across clinical seizure variables, psychosocial/familial factors, everyday executive functioning, and HRQoL. Cluster 2 was associated with younger child age, lower maternal education, and higher rate of single-parent households. Cluster 3 was associated with older age at epilepsy onset and higher rates of hippocampal sclerosis and parental psychiatric history. Both Cluster 2 and 3 demonstrated elevated family stress. Concurrent validity was demonstrated through the association of psychiatric (i.e., rate of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) disorders and psychotropic medication) and parent-rated HRQoL variables.

SIGNIFICANCE: Youth with TLE present with three distinct behavioral phenotypes that correspond with important clinical and sociodemographic markers. The current findings demonstrate the variability of behavioral presentations in youth with TLE and provide a preliminary framework for screening and targeting intervention to enhance support for youth with TLE and their families.

PMID:35174484 | DOI:10.1111/epi.17193

Epilepsia. 2022 Feb 17. doi: 10.1111/epi.17195. Online ahead of print.

ABSTRACT

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication prescribed to women during childbearing age. The impact of LEV on placental transporters is poorly understood. This study aimed to assess the effect of LEV exposure on the messenger RNA (mRNA) expression of placental transporters for hormones and nutrients and to correlate their expression with the drug’s serum concentration in pregnant mice.

METHODS: Studies were conducted on gestational days (GD) 13 and 18, following oral treatment with 100 mg/kg LEV or the vehicle every 24 h after weaning. Serum LEV measurements were performed by High-performance liquid chromatography with a UV detector (HPLC-UV). The weight, height, and width of the fetuses were also analyzed. In addition, the placental expression of transporters xCt, Lat1, Oatp4a1, Fr-α, Rfc, and Snat4 was evaluated through semi-quantitative real-time polymerase chain reaction (qPCR). The Kruskal-Wallis and the Mann-Whitney U tests were used to determine the statistical significance (p < .05). The correlation between serum LEV concentration and placental gene expression was evaluated using the Spearman test.

RESULTS: The weight, height, and width were lower in the fetuses exposed to LEV compared with the control group (p < .05). The number of fetuses was lower in the LEV-exposed group than in the control GD 13 group (p < .001). No significant differences were detected in the mRNA expression level at GD 13. At GD 18, the expression of Lat1, Oatp4a1, xCT, and Snat4 was higher in the group treated with LEV compared with the control group (p < .05), whereas the expression of Rfc was lower (p < .05). No correlation was identified between serum LEV concentrations and gene expression levels.

SIGNIFICANCE: The repression of the Rfc transcript by LEV at GD 18 suggests that the protein expression would be abolished contributing to the observed intrauterine growth restriction (IUGR). Furthermore, the significant increase in mRNA of xCt, Snat4, Oatp4a1, and Lat1 might be a compensatory mechanism for fetal survival at GD 18.

PMID:35174498 | DOI:10.1111/epi.17195

Ann Nucl Med. 2022 Feb 16. doi: 10.1007/s12149-022-01725-9. Online ahead of print.

ABSTRACT

OBJECTIVE: Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of [(¹²³)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(¹²³)I] FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults.

METHODS: We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject’s striatum and then converted the [¹²³I] FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60 years).

RESULTS: When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding.

CONCLUSION: Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.

PMID:35174441 | DOI:10.1007/s12149-022-01725-9

Pharm Res. 2022 Feb 16. doi: 10.1007/s11095-022-03201-5. Online ahead of print.

ABSTRACT

Model-based meta-analysis (MBMA) is a quantitative approach that leverages published summary data along with internal data and can be applied to inform key drug development decisions, including the benefit-risk assessment of a treatment under investigation. These risk-benefit assessments may involve determining an optimal dose compared against historic external comparators of a particular disease indication. MBMA can provide a flexible framework for interpreting aggregated data from historic reference studies and therefore should be a standard tool for the model-informed drug development (MIDD) framework.In addition to pairwise and network meta-analyses, MBMA provides further contributions in the quantitative approaches with its ability to incorporate longitudinal data and the pharmacologic concept of dose-response relationship, as well as to combine individual- and summary-level data and routinely incorporate covariates in the analysis.A common application of MBMA is the selection of optimal dose and dosing regimen of the internal investigational molecule to evaluate external benchmarking and to support comparator selection. Two case studies provided examples in applications of MBMA in biologics (durvalumab + tremelimumab for safety) and small molecule (fenebrutinib for efficacy) to support drug development decision-making in two different but well-studied disease areas, i.e., oncology and rheumatoid arthritis, respectively.Important to the future directions of MBMA include additional recognition and engagement from drug development stakeholders for the MBMA approach, stronger collaboration between pharmacometrics and statistics, expanded data access, and the use of machine learning for database building. Timely, cost-effective, and successful application of MBMA should be part of providing an integrated view of MIDD.

PMID:35174432 | DOI:10.1007/s11095-022-03201-5

Brain Struct Funct. 2022 Feb 17. doi: 10.1007/s00429-022-02464-3. Online ahead of print.

ABSTRACT

Visual disturbances are a common disease manifestation in multiple sclerosis (MS) due to lesions damaging white matter tracts involved in vision. Vertical occipital fasciculus (VOF), a tract located vertically in the occipital lobe, was neglected for more than a century. We hypothesize that VOF is involved in integrating information between dorsal and ventral visual streams. Thus, its damage in MS, as well as its probable role in visual processing (by using MS as a VOF damage model) needs to be clarified. To study fiber characteristics of VOF in MS, and their clinical and visual learning associations, 57 relapsing-remitting MS (RRMS) and 25 healthy controls (HC) were recruited. We acquired MS Functional Composite, Expanded Disability Status Scale (EDSS), and Brief Visuospatial Memory Test-Revised (BVMT-R), and diffusion MRI scans. Tractography of VOF and optic radiation (OR) was done. VOF’s metrics were statistically tested for between-group differences and clinical and visual tests associations. Along-tract analysis and laterality were also tested. RRMS patients had higher mean, axial, and radial diffusivity (nearly in all fiber points), and lower fractional anisotropy in bilateral VOFs compared to HC. No laterality was noted. These were associated with poor clinical outcomes, poor visual scores in EDSS, and lower total immediate and delayed recall in BVMT-R in RRMS, after adjusting for age, gender, and fiber metrics of OR. VOF damage is present in RRMS and is associated with visual symptoms and visuospatial learning impairments. It seems VOF is involved in integrating information between visual streams.

PMID:35174417 | DOI:10.1007/s00429-022-02464-3

Acta Orthop Belg. 2021 Dec;87(4):761-764. doi: 10.52628/87.4.23.

ABSTRACT

Hindfoot deformities are often surgically corrected with calcaneal osteotomy. These are increasingly performed via a minimally invasive approach. Identifying a neurovascular “safe zone” for this approach is important in reducing iatrogenic injury. We aimed to identify a safe zone for minimally invasive calcaneal osteotomy without neurovascular injury. Three individuals independently assessed 100 con- secutive magnetic resonance imaging ankle studies. The distance of the medial neurovascular bundle from the level of the centre of the Achilles tendon insertion was measured. The points measured were centralised in three planes (axial, sagittal and coronal). The three sets of observations were statistically analysed with confidence intervals and intraclass correlation coefficient was calculated. The mean distance measured by the three observers were 22.91 mm (range 18.2-28.5 mm); 22.81 mm (range 18.7-26.7 mm); and 23.41 mm (range 19.2- 28.4 mm); overall mean 23.0 mm. The mean inter- observer variation was 1.1 mm. 95% confidence interval for observer 1 ranges from 22.45-23.25 mm, observer 2 ranges from 22.52-23.1 mm and observer 3 ranges from 22.97-23.65 mm. Overall 95% confidence interval ranges from 22.8-23.2 mm. Intraclass correlation coefficient for inter-observer reliability is 0.7, indicating strong agreement between the observers. This radiological study suggests an anatomical “safe zone” for minimally invasive medial calcaneal osteotomy is at least 18 mm (mean: 23 mm) from the level of insertion of the Achilles tendon. Individual variation between patients must be taken in to consideration during preoperative planning.

PMID:35172445 | DOI:10.52628/87.4.23

Zhonghua Xin Xue Guan Bing Za Zhi. 2022 Feb 24;50(2):132-136. doi: 10.3760/cma.j.cn112148-20211124-01016.

ABSTRACT

Objective: To investigate whether atrial fibrillation (AF) before transcatheter aortic valve implantation (TAVI) will affect the prognosis of patients post TAVI. Methods: This is a single center retrospective study. A total of 115 patients with severe aortic stenosis (AS) who were admitted to General Hospital of Northern Theater Command from May 2016 to November 2020 and successfully received TAVI treatment were included. According to absence or accompaniment of AF pre-TAVI, they were divided into AF group (21 cases) and non-AF group (94 cases). The patients were followed up for postoperative antithrombotic treatment and the occurrence of the net adverse clinical and cerebrovascular events (NACCE) at 12 months post TAVI, including cardiogenic death, readmission to hospital for heart failure, nonfatal myocardial infarction, ischemic stroke and severe bleeding (BARC levels 3-5). Univariate logistic regression was used to analyze the related factors of NACCE. Results: Among the 115 selected patients, age was (73.8±6.9) years, there were 63 males. And 21 cases (18.2%) were diagnosed as AFbefore TAVI. In terms of postoperative antithrombotic therapy, 48.9% (46/94) of the patients in the non-AF group received monotherapy and 47.9% (45/94) received dual antiplatelet therapy. In the AF group, 47.6% (10/21) received anticoagulants and 33.3% (7/21) received dual antiplatelet therapy. The proportion of patients in the AF group taking non-vitamin K antagonist oral anticoagulants (NOAC) was higher than that in the non-AF group (38.1% (8/21) vs. 2.1% (2/94), P<0.001). Patients in both groups were followed up to 12 months after TAVI. During the 12 months follow-up, the incidence of NACCE after TAVI was 14.3% (3/21) in the AF group, which was numerically higher than that in the non-AF group (6.4% (6/94)), but the difference was not statistically significant (P=0.441). The incidence of severe bleeding was significantly higher in the AF group than in the non-AF group (9.5% (2/21) vs. 0, P=0.032). Univariate logistic regression analysis showed that hypertension was associated with the risk of NACCE (OR=8.308, P=0.050), while AF was not associated with the risk of NACCE (P=0.235). Conclusion: The incidence of severe bleeding after TAVI is higher in patients with AF than in patients without AF prior TAVI, and there is a trend of increased risk of NACCE post TAVI in AF patients.

PMID:35172456 | DOI:10.3760/cma.j.cn112148-20211124-01016

Acta Orthop Belg. 2021 Dec;87(4):713-721. doi: 10.52628/87.4.16.

ABSTRACT

To date, the use of biomarkers for assessing individual severity of osteoarthritis (OA) is limited, and the correlation of histological scores with biomarkers for individual animals in the destabilization of the medial meniscus (DMM) model of OA has not been well investigated. Accordingly, this study investigated how well representative biomarkers in the DMM model reflected specific changes in individual animals. Rats were randomly divided into the OA group and the sham group. OA model was established by destabilization of the medial meniscus (DMM). After 2,4,6,8,10 and 12 weeks (n=14, each week), the concentrations of CTXII, COMP, C2C, and OC in serum were measured, and cartilage degeneration, osteophytes, and synovial membrane inflammation, typical of OA, were scored using Osteoarthritis Research Society International (OARSI) scoring system. Additionally, the correlation between each biomarker and the specific changes in osteoarthritis was analyzed for individual animals using the Generalized Estimating Equation (GEE). Statistical analysis showed a low correlation between CTXII and osteophyte score of the medial femur (coefficient = -0.0088, p= 0.0103), COMP and osteophyte score of the medial tibia (coefficient = -0.0911, p= 0.0003), and C2C and synovial membrane inflammation scores of the medial femoral (coefficient = 0.054, p= 0.0131). These results suggest that representative OA bio- markers in individual animals in the DMM model did not reflect histological scores well.

PMID:35172438 | DOI:10.52628/87.4.16

Acta Orthop Belg. 2021 Dec;87(4):643-647. doi: 10.52628/87.4.09.

ABSTRACT

Ganz periacetabular osteotomy (PAO) is a technically demanding surgical procedure. It requires cutting around the acetabulum to mobilize it under fluoro- scopic control. The radiolucent table and good quality imaging are mandatory to perform this osteotomy in a safe way. Modification of Ganz osteotomy was developed a with minimal soft tissue exposure using intra-pelvic approach which allows direct visualization of the quadrilateral plate. The purpose of the present study was to review the early results in the initial group of patients who had this procedure. The Ganz PAO was performed on 8 cases painful dysplastic hips, using the intra-pelvic approach through the Pfannenstiel incision. All of the osteotomies were performed under fluoroscopic control and direct visualizing the osteotomy site from the same incision. The acetabular fragment was medialized and redirected anterolaterally then fixed with 3 screws. The pre-operative Harris hip score mean was 66.8 and improved to be 92.7 (p value <0.0005) and this was statistically significant. Radiologically the CEA improved in the pre-operative X-ray from mean of 13.12 degree to 28.37 degrees (p value <0.0005) and this was statistically significant. Painful dysplastic hips should be treated before function becomes seriously impaired. The Ganz osteotomy through an intra-pelvic approach, can be done with minimal exposure to radiation in a relatively short time.

PMID:35172431 | DOI:10.52628/87.4.09

Acta Orthop Belg. 2021 Dec;87(4):705-712. doi: 10.52628/87.4.15.

ABSTRACT

Repeated joint bleeding leads to chronic synovitis, cartilage damage and bone alterations which result in haemophilic arthropathy and are associated with pain, functional impairment and poor quality of life. There are evidence that Hyaluronic Acid (HA) and Platelet-rich Plasma (PRP) have different mechanisms of action in the treatment of arthropathy for this reason we decided to use both components. The aim of this study is to compare, the efficacy, safety and duration of a single intra-articular injection of PRP against PRP+HA for pain, bleeding episodes and joint health, in the same patient with bilateral hemophilic knee arthropathy. Twenty-one men patients (42 knee joints) were treated with intra- articular injections of PRP or PRP+HA. All of them were haemophilia type A severe. The mean age was 36.6 years (21-72). All patients were evaluated for: Haemophilia Joint Health Score (HJHS), pain (VAS), the number of bleeding episodes (BE) in the last 30 days, before treatment, at three and six months after treatment. Statistically significant improvement were shown for both knee joints at three and six months after treatment for VAS and BE (P < 0.00001). The HJHS score did not significantly improve for either knee in the 6-month period after injection. A single PRP or PRP+HA injection is safe and effective in treating haemophilic arthropathy of the knee for up to 6 months follow-up, reducing pain, bleeding episodes and delaying total knee arthroplasty.

PMID:35172437 | DOI:10.52628/87.4.15