Small Sample Research Articles

Rapid response to antidepressants and correlation with response and remission after acute treatment.

BackgroundPharmacological treatment of depression with antidepressants is well established, but the desired therapeutic effect may take several weeks to manifest. Few studies have compared response time and improvement rates and its prognostic value for different antidepressants. An accurate response predictor could help guide decisions on whether to maintain an antidepressant for longer or switch. MethodsA secondary analysis data from four clinical trials involving four different antidepressants (venlafaxine, sertraline, mirtazapine, and fluoxetine) and placebo was performed to evaluate the relationship between response time and acute treatment outcome. All patients from the four trials were diagnosed as having a Major Depression episode. Contingency tables were built from the combination of dichotomous variables for all groups. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and accuracy were determined. ResultsResponse > 50% after two weeks of treatment was associated with remission at the end of the acute phase (eight weeks) of treatment for all antidepressants tested, except fluoxetine. Response to mirtazapine within one week was a predictor of response and/or remission after acute treatment, having a high level of accuracy as a predictor of remission for early improvement > 50%. Mirtazapine also promoted a more rapid response compared with the other antidepressants trialed. LimitationsSeverity at baseline varied among the trials and only a small sample was included in the fluoxetine group. ConclusionsThe present study revealed that early evaluation (at 1-2 weeks) might be beneficial as a treatment strategy, given the heterogeneous patterns of response between antidepressants.

Estimation of Cronbach reliability based on sample size, gender, and the grades

<span lang="EN-US">The study tries to see the effect of different sample sizes on the reliability of creativity tests using Cronbach’s alpha. In addition, the background of the sample (gender and grade) is also detected. The study has a practical significance for designing a sample for estimating reliability using Cronbach alpha. The secondary data are used for analysis. The sample of creativity test is determined purposively, that is, has been administered to 1,960 students. The α-coefficient calculation uses the SPSS program. The result proves in the total sample, the creativity test is reliable (α=0.852). In small sample sizes, the α-coefficients values vary greatly in the different test groups. In the larger sample size, the α-coefficients are closer to constant in the different test groups. For a polytomous scale test with a length of 20 items, the α-coefficients obtained close to constant on the sample size of more than 80 testees. This result indicates for the optimum result the sample size is at least four times larger than the number of test items in reliability analysis, especially Cronbach alpha. Based on the gender aspect, descriptively the α-coefficient in the male group (0.846) was almost equal to the female group (0.851). By grouping the testees based on the grades, there are slight differences in α-coefficients in class IV (0.850), class V (0.841), and class VI (0.809). Regarding the results of this study, in the reliability estimation of test development, it is suggested to consider the adequacy and the characteristic of samples.</span>

Single Institution Evaluation of Electromagnetic Navigation Bronchoscopy for Diagnosis of Pulmonary Lesions.

Electromagnetic navigation bronchoscopy (ENB) utilizes three-dimensional reconstructions based on computed tomography to guide the biopsy of pulmonary lesions. Various limitations have been described; however, supporting data have been limited by small sample sizes. Cases of ENB for evaluation of a pulmonary lesion at a single institution during a 1-year span were reviewed for demographics, lesion location, procedural details, and final tissue diagnosis. ENB was performed by 3 pulmonologists using the Veran platform with rapid on-site evaluation. T test or Mann-Whitney U test compared continuous variables and χ 2 or Fisher exact test compared categorical variables as appropriate. A patient with a negative or inconclusive biopsy was followed for 1 year postprocedure. A total of 107 pulmonary lesions were evaluated. The population studied had a mean age of 67 and a median pulmonary lesion size of 26.0 mm. For malignant lesions, the pathologic diagnostic yield from ENB was 52.1% (37/71). The diagnostic yield of benign lesions was much lower at 16.7% (6/36). The overall procedural complication rate was 8.4% (9/107). Complications were more likely to occur in patients with malignant lesions. The most common complication was pneumothorax, occurring in 5.6% of all biopsies and 7.0% of patients with malignant lesions. This study demonstrates significant differences in diagnostic accuracy between lesions found to be malignant versus benign. Our observed complication rate was slightly higher than other groups have reported, with a greater frequency occurring in patients with malignant lesions; however, the rate of pneumothorax was still lower than computed tomography-guided transcutaneous biopsies.

A generic plug & play diffusion-based denosing module for medical image segmentation

Medical image segmentation faces challenges because of the small sample size of the dataset and the fact that images often have noise and artifacts. In recent years, diffusion models have proven very effective in image generation and have been used widely in computer vision. This paper presents a new feature map denoising module (FMD) based on the diffusion model for feature refinement, which is plug-and-play, allowing flexible integration into popular used segmentation networks for seamless end-to-end training. We evaluate the performance of the FMD module on four models, UNet, UNeXt, TransUNet, and IB-TransUNet, by conducting experiments on four datasets. The experimental data analysis shows that adding the FMD module significantly positively impacts the model performance. Furthermore, especially for small lesion areas and minor organs, adding the FMD module allows users to obtain more accurate segmentation results than the original model.

355 Risk Factors for Intrathecal Baclofen Pump Implantation Infections: A Retrospective Database Analysis

INTRODUCTION: Baclofen, a GABAB receptor agonist, can be delivered via intrathecal baclofen (ITB) pumps for patients with intractable spasticity. Prior literature has shown infection rates ranging between 10-30%. METHODS: A multi-institutional de-identified database TriNetX was queried to identify patients with: 1) implantation of ITB pump + infection within 6 months or 2) implantation of ITB pump without infection within 6 months. Two populations were analyzed: only pediatric patients, then patients of all ages. Characteristics were compared using log-rank tests and independent-sample t-tests. RESULTS: 1,880 patients were identified in the pediatric cohort, of which 236 (12.6%) developed infection. 13,936 patients of all ages were identified, of which 1955 (14.0%) developed infection. In pediatric patients who developed infection, there were higher rates of diagnoses of overweight and obesity, malnutrition, and hypokalemia; the prevalence of diabetes was also higher, but this analysis was limited by small sample size. In patients of all ages, all medical diagnoses assessed were significantly more prevalent in patients with infection. Erythrocyte sedimentation rates and platelets were significantly higher in all patients with an infection. Additionally, the number of emergency department visits within 6 months was significantly higher in the infection group for pediatric (t = 3.571, p = 0.0004) and all-age (t = 7.882, p < 0.0001) patients. CONCLUSIONS: This study suggests that patients with certain comorbidities are at increased risk for infection post-ITB implantation. Since prevalence of diabetes, abnormal coagulation profile, tracheostomy, and B-vitamin deficiency remained significantly different between infection vs. no-infection cohorts as sample size increased with the addition of adults, these diagnoses should be considered when calculating the infection risk of ITB pump. Studies are underway to investigate the time of highest infection risk post-ITB implantation and the optimal time for ITB reimplantation after removal for infection.

Pengaruh Gaya Kepemimpinan Terhadap Kinerja Karyawan dengan Komunikasi Sebagai Variabel Antara

Human resources have a strategic role in the organization and need to be managed properly to achieve organizational effectiveness and efficiency. Leadership style has a significant influence on employee performance. Communication is also an important factor affecting employee performance. The aims of this study were to determine the effect of leadership style on employee performance, effect of leadership style on communication, the effect of communication on employee performance, and the effect of leadership style on employee performance with communication as an intervening variabel. This study involved employees of the Faculty of Medicine, Maranataha Christian University who were used as research samples. Structural Equation Model - Partial Least Square (SEM-PLS) is a data processing method used because the research conducted involves a small sample size with a minimum sample size in the range of 30 - 100 samples. Based on the results of the research conducted, it shows that leadership style has no effect on employee performance, leadership style has a positive and significant effect on communication, communication has a positive and significant effect on employee performance, and leadership style has a positive and significant effect on employee performance with communication as an intermediate var

Diffsig: Associating Risk Factors With Mutational Signatures.

Somatic mutational signatures elucidate molecular vulnerabilities to therapy and therefore detecting signatures and classifying tumors with respect to signatures has clinical value. However, identifying the etiology of the mutational signatures remains a statistical challenge, with both small sample sizes and high variability in classification algorithms posing barriers. As a result, few signatures have been strongly linked to particular risk factors. Here we develop a statistical model, Diffsig, for estimating the association of one or more continuous or categorical risk factors with DNA mutational signatures. Diffsig takes into account the uncertainty associated with assigning signatures to samples as well as multiple risk factors' simultaneous effect on observed DNA mutations. We applied Diffsig to breast cancer data to assess relationships between five established breast-relevant mutational signatures and etiologic variables, confirming known mechanisms of cancer development. In simulation, our model was capable of accurately estimating expected associations in a variety of contexts. Diffsig allows researchers to quantify and perform inference on the associations of risk factors with mutational signatures. We expect Diffsig to provide more robust associations of risk factors with signatures to lead to better understanding of the tumor development process and improved models of tumorigenesis.

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.

The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed. Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia. Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.

High-resolution X-Ray imaging of small animal samples based on Commercial-Off-The-Shelf CMOS image sensors.

An automated system for acquiring microscopic-resolution radiographic images of biological samples was developed. Mass-produced, low-cost, and easily automated components were used, such as Commercial-Off-The-Self CMOS image sensors (CIS), stepper motors, and control boards based on Arduino and RaspberryPi. System configuration, imaging protocols, and Image processing (filtering and stitching) were defined to obtain high-resolution images and for successful computational image reconstruction. Radiographic images were obtained for animal samples including the widely used animal models zebrafish (Danio rerio) and the fruit-fly (Drosophila melanogaster), as well as other small animal samples. The use of phosphotungstic acid (PTA) as a contrast agent was also studied. Radiographic images with resolutions of up to (7±0.6)μm were obtained, making this system comparable to commercial ones. This work constitutes a starting point for the development of more complex systems such as X-ray attenuation micro-tomography systems based on low-cost off-the-shelf technology. It will also bring the possibility to expand the studies that can be carried out with small animal models at many institutions (mostly those working on tight budgets), particularly those on the effects of ionizing radiation and absorption of heavy metal contaminants in animal tissues.

Plasma beta-hydroxy-beta-methylbutyrate availability after enteral administration during critical illness after trauma: An exploratory study.

During critical illness skeletal muscle wasting occurs rapidly. Although beta-hydroxy-beta-methylbutyrate (HMB) is a potential treatment to attenuate this process, the plasma appearance and muscle concentration is uncertain. This was an exploratory study nested within a blinded, parallel group, randomized clinical trial in which critically ill patients after trauma received enteral HMB (3 g daily) or placebo. Plasma samples were collected at 0, 60, and 180 min after study supplement administration on day 1. Needle biopsies of the vastus lateralis muscle were collected (baseline and day 7 of the HMB treatment intervention period). An external standard curve was used to calculate HMB concentrations in plasma and muscle. Data were available for 16 participants (male n = 12 (75%), median [interquartile range] age 50 [29-58] years) who received placebo and 18 participants (male n = 14 (78%), age 49 [34-55] years) who received HMB. Plasma HMB concentrations were similar at baseline but increased after HMB (T = 60 min: placebo 0.60 [0.44-1.31]  µM; intervention 51.65 [22.76-64.72]  µM). Paired muscle biopsies were collected from 11 participants (placebo n = 7, HMB n = 4). Muscle HMB concentrations were similar at baseline between groups (2.35 [2.17-2.95]; 2.07 [1.78-2.31] µM). For participants in the intervention group who had the repeat biopsy within 4 h of HMB administration, concentrations were greater (7.2 and 12.3 µM) than those who had the repeat biopsy >4 h after HMB (2.7 and 2.1 µM). In this exploratory study, enteral HMB administration increased plasma HMB availability. The small sample size limits interpretation of the muscle HMB findings.

Continuous Rotation Group Equivariant Network Inspired by Neural Population Coding

Neural population coding can represent continuous information by neurons with a series of discrete preferred stimuli, and we find that the bell-shaped tuning curve plays an important role in this mechanism. Inspired by this, we incorporate a bell-shaped tuning curve into the discrete group convolution to achieve continuous group equivariance. Simply, we modulate group convolution kernels by Gauss functions to obtain bell-shaped tuning curves. Benefiting from the modulation, kernels also gain smooth gradients on geometric dimensions (e.g., location dimension and orientation dimension). It allows us to generate group convolution kernels from sparse weights with learnable geometric parameters, which can achieve both competitive performances and parameter efficiencies. Furthermore, we quantitatively prove that discrete group convolutions with proper tuning curves (bigger than 1x sampling step) can achieve continuous equivariance. Experimental results show that 1) our approach achieves very competitive performances on MNIST-rot with at least 75% fewer parameters compared with previous SOTA methods, which is efficient in parameter; 2) Especially with small sample sizes, our approach exhibits more pronounced performance improvements (up to 24%); 3) It also has excellent rotation generalization ability on various datasets such as MNIST, CIFAR, and ImageNet with both plain and ResNet architectures.

Dimensional assessment of self-reported musculoskeletal symptoms by workers: Amulti-case study.

Work-related musculoskeletal disorders (WMSD) encompass a range of conditions affecting muscles, tendons, and nerves. Visual diagrams are widely used to identify symptoms and to generate musculoskeletal discomfort metrics. However, there is no consensus on the number of discomfort dimensions that can originate from self-reported musculoskeletal symptoms by individuals. This study aimed to test the fit of WMSD symptom models from workers in two samples of different sizes. A combination of Full-Information Item Factor Analysis (FIFA) and Item Response Theory (IRT) was utilized to analyze and test the models. The study was conducted in two samples of workers (n1 = 6944 and n2 = 420) who had their symptoms identified with the aid of a human body diagram. An analysis was conducted considering each sample's unidimensional and three multidimensional models. The unidimensional model (general musculoskeletal discomfort), bi-dimensional model (discomfort in upper and lower body), and tridimensional model (discomfort in the upper limbs, lower limbs, and trunk) showed good values of factor loading and communalities, along with satisfactory item discrimination ability. Regardless of sample size, parameter estimation for IRT and FIFA proceeded without issues, presenting suitable fit parameters. Three models were valid and reliable for more extensive and smaller samples. However, the tridimensional model was best for generating discomfort scores in body regions. Companies and safety professionals can use these findings to devise strategies to mitigate musculoskeletal pains based on perceived symptom locations.

Abstract 6145: A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer

Abstract Introduction: Cervical cancer is the second most common cause of cancer-related deaths among women worldwide. Genome-wide association studies (GWAS) have identified genetic variants associated with cervical cancer. However, these discoveries have been limited by the small sample sizes of the individual cohorts. To identify additional novel loci associated with cervical cancer, we performed a trans-ethnic meta-analysis. Methods: GWAS summary data for trans-ethic meta-analysis were identified in women of European ancestry from the UK Biobank, East Asian ancestry from Biobank Japan, and African ancestries from the pan-UK Biobank and Johannesburg cancer study. Meta-analyses were performed using fixed effect inverse variance weighted method implemented in GWAMA. To localize putative genomic loci associated with cervical cancer, we performed fine mapping using the Bayesian approach by calculating the marginal posterior probability of causality for each single nucleotide polymorphisms (SNPs) and 99% credible set size. Results: Our meta-analysis identified four additional novel genomic loci associated with cervical cancer. These loci include: rs147778467 (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.16, P-value = 3.12 x 10-08) in RGS21, rs53150478 (OR =1.03, 95%CI = 1.01-1.05, P-value = 4.48 x 10-08) in MAN1C1, rs113842373 (OR = 0.68, 95%CI = 0.56-0.81, P-value = 2.31 x 10-09) in LINCO1850 and rs75372437 (OR = 0.80, 95%CI = 0.72-0.88, P-value = 3.32 x 10-08) in RNU6-356P. These loci are implicated in carcinogenic pathways. Moreover, our Bayesian fine mapping identified five loci with a marginal posterior probability of causality > 1 and reduced the 99% credible set sizes. Conclusion: We identified additional novel loci associated with cervical cancer and our fine mapping identified loci with a high posterior probability of being causal. Citation Format: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew. A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6145.

Abstract 3399: Prediction of cardiac adverse events (AE) in trastuzumab treated breast cancer patients (pts) via a comprehensive genomic and DNA methylation blood based assay

Abstract Background: ERBB2 (HER2) targeted therapy is an important therapeutic class used to treat HER2-positive breast cancer (BC) but has been associated with a risk of cardiotoxicity. Identifying pts likely to experience this AE could allow for early intervention and/or a change in treatment plan. Previous studies have demonstrated the ability to detect changes in methylation patterns of pts who had cardiotoxicity from anti-HER2 therapy. Here, we report a retrospective study assessing the feasibility of using the Guardant Infinity platform (genomic and epigenomic NGS analysis) to predict severe cardiac AE in pts treated with trastuzumab. Methods: Samples (n=46) from female pts with BC undergoing treatment with trastuzumab without prior record of heart failure and with a blood sampling <300 days prior to a documented heart failure event defined a positive case cohort. 70 blood samples were matched to the positive case cohort in all above attributes but without record of patient heart failure to comprise a negative cohort. The >20K differentially methylated regions on Guardant Infinity platform may be useful for detection of specific disease attributes such as treatment-associated AE. To explore this, mixture models were first trained using 880 BC samples unrelated to heart failure to distinguish methylation signals coming from tumor versus non-tumor cfDNA. The resulting normalized methylation signals represent the posterior probabilities of the region molecules to be derived from tumor cells. A subset of methylation regions were selected based on significance of association between heart failure status and normalized methylation signals in the positive and negative AE cohorts. A penalized logistic regression model was then trained on the normalized signals of the selected methylation regions to predict whether a patient would have future cardiac AE. Results: A 10-fold cross validation of the penalized logistic regression models trained on normalized methylation signals produced an area under the curve of 0.78 for predicting heart failure status, suggesting feasibility of using blood-based methylation signals to predict cardiac AE on this platform. The differentially methylated regions selected as model predictors show a clear separation in hypermethylation status between positive versus negative cohorts. Conclusion: Our results show the prediction of cardiac AE in BC pts undergoing trastuzumab treatment in advance of documented heart failure using a blood-based assay designed for simultaneous comprehensive genomic and epigenomic profiling. Given the relatively small sample size within this study, further refinement and validation of the classification models is warranted and ongoing. Citation Format: Sean Gordon, Catalin Barbacioru, Daniel Gaile, Denis Tolkunov, Nicole Zhang, Carin Espenschied, Jing Wang, Tara Dinman, Kimberly Banks, Amar Das, Han-Yu Chuang, Helmy Eltoukhy. Prediction of cardiac adverse events (AE) in trastuzumab treated breast cancer patients (pts) via a comprehensive genomic and DNA methylation blood based assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3399.

Learning preferences of emergency medicine residents: Does context matter?

Background Delivery of education varies between Emergency Medicine (EM) residencies. EM requires residents to be trained in three domains of foundational knowledge: pathophysiology, procedure skills, and clinical reasoning. The “Visual, Auditory, Read, and Kinesthetics” (VARK) learning model has been studied previously in the medical professions. These methods pertain to viewing material, listening to content, reading or writing content and to performing activities, respectively. EM residents may prefer different VARK methods, and furthermore their preferences may change depending on the foundational knowledge domain to be learned. Methods In a multi-site survey-based study, 90 EM residents of various post-graduate year (PGY) levels completed a 30-question questionnaire on SurveyMonkey™ about their learning preferences of the foundational knowledge based on the VARK learning model. Demographic information was obtained. Data was analyzed via a Kruskal-Wallis test and followed by post-hoc analyses for statistical significance. Results For clinical knowledge questions, EM residents favored Kinesthetics, followed closely by Vision (p = 0.0010). For pathophysiology, they overwhelmingly favored Vision over other learning methods (p <.0001). For procedure questions, they preferred Vision, followed closely by Kinesthetics (p <.0001). PGY1 residents had a higher preference for Kinesthetic (p = 0.0198) and PGY3-4 residents had a slightly higher preference for Read and Vision learning methods (Read p = 0.0234, Vision p = 0.0131). These results are statistically significant. There was no significant difference between residents of different genders in learning preferences. Conclusion Emergency medicine residents may prefer different learning methods depending on the content of material being learned. A relatively small sample size is a limitation of the study. Future studies could investigate if tailoring educational delivery to residents’ preferences may improve outcomes.

Professional Skills in Family Support: A Systematic Review

Family support encompasses a wide variety of professionals, sectors, and intervention paradigms that make it difficult to systematize and standardize the skills needed by the family support workforce. The present study aimed to describe the relevant skills of professionals, organize the main skills into different categories, and contribute to the development of intervention standardization guidelines in the field of family support. So, a systematic literature review was conducted following the PRISMA guidelines. The search was carried out in five databases and included the analysis of quantitative, qualitative, and mixed-methods studies, and all studies were qualitatively assessed. Of the initial 3334 articles identified, 59 studies were included, and four categories were identified: professionals’ qualities, essential skills common to all professions and contexts, specific knowledge, and theoretical approaches necessary for family support. Most of the studies were from the United Kingdom, qualitative, published in the last 10 years, used small samples, and included a specific group of professionals. The included studies did not specify whether some skills or characteristics were considered more effective in practice, and they had bias issues related to social desirability. The implications for family support practice are discussed, as well as the gaps to be covered in future studies.

Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women.

Distinguishing ovarian cancer (OC) from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of OC pathogenesis. Accumulating evidence suggests a link between OC and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved OC diagnosis and prevention. Here, we profiled the serum lipidome of 208 OC, including 93 patients with early-stage OC, and 117 non-OC (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning approaches. We found lipidome alterations unique to OC were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in OC in comparison to other gynecological diseases. Machine learning methods selected a panel of 17 lipids that discriminated OC from non-OC cases with an AUC of 0.85 for an independent test set. This study provides a systemic analysis of lipidome alterations in human OC, specifically in Korean women. Here, we show the potential of circulating lipids in distinguishing OC from non-OC conditions.

A comprehensive hierarchical comparison of structural connectomes in Major Depressive Disorder cases v. controls in two large population samples.

The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity. We utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case-control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection. In UKB, reductions in network efficiency were observed in MDD cases globally (d = -0.076, pFDR = 0.033), across all tiers (d = -0.069 to -0.079, pFDR = 0.020), and in hubs (d = -0.080 to -0.113, pFDR = 0.013-0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample. Our results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.

Clinical phase II trial shows that combining osimertinib and afatinib resistance EGFR recurrent mutation in EGFR-mutant lung cancer

Treatment options for patients with non-small-cell lung cancer (NSCLC) with EGFR mutations are limited due to resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib or afatinib alone, in a preclinical model, created drug-resistant clones with EGFR secondary mutations, but their combination inhibited the emergence of these mutations. In a Phase II trial, we looked into the alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC. Patients with stage IV NSCLC with an activating EGFR mutation who had never received treatment were included. Every eight weeks, osimertinib (80 mg/day) and afatinib (20 mg/day) were given in alternate cycles. Utilising circulating tumour DNA collected both before and after therapy, genomic analysis was carried out. The median progression-free survival among the 50 enrolled patients was 21.3 months. A total of 70.3% of respondents responded. Overall median survival was not attained. 35 plasma samples were acquired after the development of resistance; 5 of these samples displayed an elevated MET gene copy number and 3 displayed a BRAF mutation. However, no secondary EGFR mutation was found. The effectiveness of our approach was comparable to that of osimertinib alone, as had been observed in untreated advanced NSCLC patients with EGFR mutations in the past. The treatment may stop the emergence of EGFR secondary mutations that lead to medication resistance, despite the small sample size. To determine the importance of this treatment, more research is required.

Causal effect of severe and non-severe malaria on dyslipidemia in African Ancestry individuals: A Mendelian randomization study.

Dyslipidemia is becoming prevalent in Africa, where malaria is endemic. Observational studies have documented the long-term protective effect of malaria on dyslipidemia; however, these study designs are prone to confounding. Therefore, we used Mendelian randomization (MR, a method robust to confounders and reverse causation) to determine the causal effect of severe malaria (SM) and the recurrence of non-severe malaria (RNM) on lipid traits. We performed two-sample MR using genome wide association study (GWAS) summary statistics for recurrent non-severe malaria (RNM) from a Benin cohort (N=775) and severe malaria from the MalariaGEN dataset (N=17,000) and lipid traits from summary-level data of a meta-analyzed African lipid GWAS (MALG, N=24,215) from the African Partnership for Chronic Disease Research (APCDR) (N=13,612) and the Africa Wits-IN-DEPTH partnership for genomics studies (AWI-Gen) dataset (N=10,603). No evidence of significant causal association was obtained between RNM and high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglycerides. However, a notable association emerged between severe malarial anaemia (SMA) which is a subtype of severe malaria and reduced HDL-C levels, suggesting a potential subtype-specific effect. Nonetheless, we strongly believe that the small sample size likely affects our estimates, warranting cautious interpretation of these results. Our findings challenge the hypothesis of a broad causal relationship between malaria (both severe and recurrent non-severe forms) and dyslipidemia. The isolated association with SMA highlights an intriguing area for future research. However, we believe that conducting larger studies to investigate the connection between malaria and dyslipidemia in Africa will enhance our ability to better address the burden posed by both diseases.