Where do Models go Wrong? Parameter-Space Saliency Maps for Explainability

Conventional saliency maps highlight input features to which neural network predictions are highly sensitive. We take a different approach to saliency, in which we identify and analyze the network parameters, rather than inputs, which are responsible for erroneous decisions. We find that samples which cause similar parameters to malfunction are semantically similar. We also show that pruning the most salient parameters for a wrongly classified sample often improves model behavior. Furthermore, fine-tuning a small number of the most salient parameters on a single sample results in error correction on other samples that are misclassified for similar reasons. Based on our parameter saliency method, we also introduce an input-space saliency technique that reveals how image features cause specific network components to malfunction. Further, we rigorously validate the meaningfulness of our saliency maps on both the dataset and case-study levels

Perioperative probiotics attenuates postoperative cognitive dysfunction in elderly patients undergoing hip or knee arthroplasty: A randomized, double-blind, and placebo-controlled trial

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication in elderly patients following surgery. The preventive and/or treatment strategies for the incidence remain limited.ObjectiveThis study aimed to investigate the preventive effect of perioperative probiotic treatment on POCD in elderly patients undergoing hip or knee arthroplasty.MethodsAfter obtaining ethical approval and written informed consent, 106 patients (age ≥60 years) were recruited, who scheduled elective hip or knee arthroplasty, from 16 March 2021 to 25 February 2022 for this randomized, double-blind, and placebo-controlled trial. They were randomly assigned with a 1:1 ratio to receive either probiotics or placebo treatment (four capsules, twice/day) from hospital admission until discharge. Cognitive function was assessed with a battery of 11 neuropsychological tests on the admission day and the seventh day after surgery, respectively.ResultsA total of 96 of 106 patients completed the study, and their data were finally analyzed. POCD occurred in 12 (26.7%) of 45 patients in the probiotic group and 29 (56.9%) of 51 patients in the placebo group (relative risk [RR], 0.47 [95% confidence interval [CI], 0.27 to 0.81]; P = 0.003). Among them, mild POCD occurred in 11 (24.4%) in the probiotic group and 24 (47.1%) in the placebo group (RR, 0.52 [95% CI, 0.29 to 0.94]; P = 0.022). No significant difference in severe POCD incidence was found between the two groups (P = 0.209). Compared with the placebo group, the verbal memory domain cognitive function was mainly improved in the probiotic group.ConclusionProbiotics may be used perioperatively to prevent POCD development and improve verbal memory performance in elderly patients receiving hip or knee arthroplasty.Clinical trial registrationwww.chictr.org.cn, identifier: ChiCTR2100045620

Association Between Polymorphisms in Estrogen Receptor Genes and Depression in Women: A Meta-Analysis

Objective: It is suggested that estrogen receptors (ERs) might be associated with the disproportionate vulnerability of women to depressive episodes. Several variants in ER-alpha (ERα) and ER-beta (ERβ) have been linked to depression, but the results were not consistent. Hence, we conducted a meta-analysis to evaluate the association between ERα/ERβ and depression in a cohort of women.Methods: A comprehensive literature search was performed in public databases. The genetic association between polymorphisms in Erα/ERβ and depression risk in a cohort of women was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). Cochran’s Q test and the I2 index were used to evaluate heterogeneity.Results: In total, 10 studies and 4 SNPs (rs2234693, rs9340799, rs4986938, rs1256049) were included in our meta-analysis. rs2234693 genotype was significantly associated with the risk of depression in women by dominant model (CC + CT vs TT, OR = 1.30, 95% CI: 1.09–1.55, p = 0.0031), recessive model (CC vs CT + TT, OR = 1.64, 95% CI: 1.00–2.67, p = 0.0478), additive model (CC vs TT, OR = 1.93, 95% CI: 1.12–3.35, p = 0.0189) and allelic model (C vs T, OR = 1.24, 95% CI: 1.10–1.39, p = 0.0003). For rs9340799, the frequencies of risk genotypes according to the dominant (GG + GA vs AA, OR = 1.47, 95% CI = 1.10–1.98, p = 0.0096, I2 = 0%, p = 0.43) and allelic (G vs A, OR = 1.33, 95% CI: 1.04–1.69, p = 0.0236, I2 = 0%, p = 0.39) models were significantly lower in women with depression than in controls within the Asian subgroup. For rs1256049, risk genotypes were significantly more frequent in depressed subjects than in controls under the dominant model (AA+ GA vs GG, OR = 1.62, 95% CI: 1.19–2.21, p = 0.0024) and the allelic model (A vs G, OR = 1.35, 95% CI: 1.07–1.72, p = 0.012) after sensitivity analysis by omitting one study which induce the heterogeneity.Conclusions: The current meta-analysis is the first and most comprehensive investigation of the association between ERs and depression in women, and the findings support the concept that ERs participate in the etiology of sex heterogeneity in depression

Changes in Cortical Thickness in Patients With Early Parkinson’s Disease at Different Hoehn and Yahr Stages

Objectives: This study was designed to explore changes in cortical thickness in patients with early Parkinson’s disease (PD) at different Hoehn and Yahr (H-Y) stages and to demonstrate the association of abnormally altered brain regions with part III of the Unified Parkinson’s Disease Rating Scale (UPDRS-III).Materials and Methods: Sixty early PD patients and 29 age- and gender-matched healthy controls (HCs) were enrolled in this study. All PD patients underwent comprehensive clinical and neuropsychological evaluations and 3.0 T magnetic resonance scanning. Patients with H-Y stage ≤1.5 were included in the mild group, and all other patients were included in the moderate group. FreeSurfer software was used to calculate cortical thickness. We assessed the relationship between UPDRS-III and regional changes in cortical thinning, including the bilateral fusiform and the temporal lobe.Results: The average cortical thickness of the temporal pole, fusiform gyrus, insula of the left hemisphere and fusiform gyrus, isthmus cingulate cortex, inferior temporal gyrus, middle temporal cortex and posterior cingulate cortex of the right hemisphere exhibited significant decreasing trends in HCs group and PD groups (i.e., the mild group and moderate group). After controlling for the effects of age, gender, and disease duration, the UPDRS-III scores in patients with early PD were correlated with the cortical thickness of the left and right fusiform gyrus and the left temporal pole (p < 0.05).Conclusion: The average cortical thickness of specific brain regions reduced with increasing disease severity in early PD patients at different H-Y stages, and the UPDRS-III scores of early PD patients were correlated with cortical thickness of the bilateral fusiform gyrus and the left temporal pole

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10-19 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC

Sarcopenia-related Traits, Body Mass Index and Ovarian Cancer Risk: Investigation of Causal Relationships Through Multivariable Mendelian Randomization Analyses

Objective: This study was aimed at exploring the causal relationships of four sarcopenia-related traits (appendicular lean mass, usual walking pace, right hand grip strength, and levels of moderate to vigorous physical activity) with body mass index (BMI) and ovarian cancer risk, by using univariable and multivariable Mendelian randomization (MR) methods. Materials and Methods: Univariable and multivariable MR was performed to estimate causal relationships among sarcopenia-related traits, BMI, and ovarian cancer risk, in aggregated genome-wide association study (GWAS) data from the UK Biobank. Genetic variants associated with each variable (P < 5 × 10−8) were identified as instrumental variables. Three methods—inverse variance weighted (IVW) analysis, weighted median analysis, and MR-Egger regression—were used. Results: Univariable MR analyses revealed positive causal effects of high appendicular lean mass (P = 0.02) and high BMI (P = 0.001) on ovarian cancer occurrence. In contrast, a genetically predicted faster usual walking pace was associated with lower risk of ovarian cancer (P = 0.03). No evidence was found supporting roles of right hand grip strength and levels of moderate to vigorous physical activity in ovarian cancer development (P = 0.56 and P = 0.22, respectively). In multivariable MR analyses, the association between a genetically predicted faster usual walking pace and lower ovarian cancer risk remained significant (P = 0.047). Conclusions: Our study highlights a role of slower usual walking pace in the development of ovarian cancer. Further studies are required to validate our findings and understand the underlying mechanisms

High-frequency rTMS over bilateral primary motor cortex improves freezing of gait and emotion regulation in patients with Parkinson’s disease: a randomized controlled trial

BackgroundFreezing of gait (FOG) is a common and disabling phenomenon in patients with Parkinson’s disease (PD), but effective treatment approach remains inconclusive. Dysfunctional emotional factors play a key role in FOG. Since primary motor cortex (M1) connects with prefrontal areas via the frontal longitudinal system, where are responsible for emotional regulation, we hypothesized M1 may be a potential neuromodulation target for FOG therapy. The purpose of this study is to explore whether high-frequency rTMS over bilateral M1 could relieve FOG and emotional dysregulation in patients with PD.MethodsThis study is a single-center, randomized double-blind clinical trial. Forty-eight patients with PD and FOG from the Affiliated Hospital of Xuzhou Medical University were randomly assigned to receive 10 sessions of either active (N = 24) or sham (N = 24) 10 Hz rTMS over the bilateral M1. Patients were evaluated at baseline (T0), after the last session of treatment (T1) and 30 days after the last session (T2). The primary outcomes were Freezing of Gait Questionnaire (FOGQ) scores, with Timed Up and Go Test (TUG) time, Standing-Start 180° Turn (SS-180) time, SS-180 steps, United Parkinson Disease Rating Scales (UPDRS) III, Hamilton Depression scale (HAMD)-24 and Hamilton Anxiety scale (HAMA)-14 as secondary outcomes.ResultsTwo patients in each group dropped out at T2 and no serious adverse events were reported by any subject. Two-way repeated ANOVAs revealed significant group × time interactions in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14. Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14 at T1 and T2. No significant improvement was found in the sham group. The Spearman correlation analysis revealed a significantly positive association between the changes in HAMD-24 and HAMA-14 scores and FOGQ scores at T1.ConclusionHigh-frequency rTMS over bilateral M1 can improve FOG and reduce depression and anxiety in patients with PD