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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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Abstract

The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses — the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.

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... The enrichment of transcription factor binding motif in the flanking regions of genes in each cluster was determined by the one-tailed Fisher's exact test, and transcription factor binding motifs with q value ≤ 0.1 were defined as significantly enriched. The q values were calculated by the Benjamini-Hochberg procedure 52 . We used the genes analyzed in the hierarchical clustering as background. ...
... The overlap between the inferred genes and genes from ChIP data was determined by the one-tailed Fisher's exact test, and those with q value ≤ 0.1 were defined as significant. The q values were calculated by the Benjamini-Hochberg procedure 52 www.nature.com/scientificreports/ Insulin signaling pathway. ...
... Second, we selected two types of metabolic pathway nodes: one was a pathway that exhibited significant associations with any glucose-responsive metabolites or transcription factors; the other was a pathway whose percentage of regulated reactions was in the top 10% either by glucoseresponsive metabolites or by glucose-responsive genes encoding metabolic enzymes (Fig. S7A) www.nature.com/scientificreports/ between the metabolic reactions in a metabolic pathway and those regulated by a glucose-responsive molecule was determined by the one-tailed Fisher's exact test, and associations with a q value ≤ 0.01 were defined as significant. The q values were calculated by the Benjamini-Hochberg procedure 52 . We also selected glucose-responsive metabolites that exhibited significant associations with any metabolic pathway nodes and glucose-responsive transcription factors that regulate five or more metabolic enzymes. ...
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Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.
... To statistically test differences in processing pipelines, we performed a one-way repeated measures ANOVA (alpha = 0.05) on the dipolarity metric and ICLabel metric for each pipeline using the MATLAB (R2020A) function fitrm where the subject was the predictor variable, each metric was the response variable, and the pipeline was the withinsubjects variable. To account for Type I error, we adjusted our results using the false discovery rate correction with the Benjamini and Hochberg method [58]. ...
... The noise electrodes exhibited higher power in low frequencies and their slope was steeper than the other sensors. Scalp electrodes followed a common 1/f curve [58] but had an increase in power in the alpha and beta frequency range, most noticeable in the standing baseline condition. The mobile hitting conditions (i.e., hitting and competitive) had more power in higher frequencies than the standing baseline, stationary, and cooperative conditions. ...
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Researchers can improve the ecological validity of brain research by studying humans moving in real-world settings. Recent work shows that dual-layer EEG can improve the fidelity of electrocortical recordings during gait, but it is unclear whether these positive results extrapolate to non-locomotor paradigms. For our study, we recorded brain activity with dual-layer EEG while participants played table tennis, a whole-body, responsive sport that could help investigate visuomotor feedback, object interception, and performance monitoring. We characterized artifacts with time-frequency analyses and correlated scalp and reference noise data to determine how well different sensors captured artifacts. As expected, individual scalp channels correlated more with noise-matched channel time series than with head and body acceleration. We then compared artifact removal methods with and without the use of the dual-layer noise electrodes. Independent Component Analysis separated channels into components, and we counted the number of high-quality brain components based on the fit of a dipole model and using an automated labeling algorithm. We found that using noise electrodes for data processing provided cleaner brain components. These results advance technological approaches for recording high fidelity brain dynamics in human behaviors requiring whole body movement, which will be useful for brain science research.
... Outliers were identified based on exceeding 3 * IQR limits, and subsequently removed from analysis. Each analysis was corrected for multiple comparisons using false discovery rate (FDR; Benjamini and Hochberg, 1995). Supplementary Materials and Methods S1 provides detailed information. ...
... Potential associations between motion and the underlying functional connectivity matrix were assessed by (1) correlating average FD with connectivity strength of each edge in the functional connectivity matrix using Kendall's tau procedure. Statistical significance was set at P < 0.05 and the FDR was used to account for multiple comparisons (Benjamini andHochberg, 1995, identical to Ciric et al., 2017). The number of significant correlations was then summed and divided by the total number of edges. ...
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Introduction Trauma-focused psychotherapy for post-traumatic stress disorder (PTSD) is effective in about half of all patients. Investigating biological systems related to prospective treatment response is important to gain insight in mechanisms predisposing patients for successful intervention. We studied if spontaneous brain activity, brain network characteristics and head motion during the resting state are associated with future treatment success. Methods Functional magnetic resonance imaging scans were acquired from 46 veterans with PTSD around the start of treatment. Psychotherapy consisted of trauma-focused cognitive behavioral therapy (tf-CBT), eye movement desensitization and reprocessing (EMDR), or a combination thereof. After intervention, 24 patients were classified as treatment responders and 22 as treatment resistant. Differences between groups in spontaneous brain activity were evaluated using amplitude of low-frequency fluctuations (ALFF), while global and regional brain network characteristics were assessed using a minimum spanning tree (MST) approach. In addition, in-scanner head motion was assessed. Results No differences in spontaneous brain activity and global network characteristics were observed between the responder and non-responder group. The right inferior parietal lobule, right putamen and left superior parietal lobule had a more central position in the network in the responder group compared to the non-responder group, while the right dorsolateral prefrontal cortex (DLPFC), right inferior frontal gyrus and left inferior temporal gyrus had a less central position. In addition, responders showed less head motion. Discussion These results show that areas involved in executive functioning, attentional and action processes, learning, and visual-object processing, are related to prospective PTSD treatment response in veterans. In addition, these findings suggest that involuntary micromovements may be related to future treatment success.
... Due to the small sample size, non-parametric Quade tests (Quade, 1979) and corresponding post-hoc comparisons (Conover, 1980) with Benjamini-Hochberg α level adjustment (FDR = 0.1, Benjamini and Hochberg, 1995;cf. Weber et al., 2021) were performed on the same measures as in the previous studies. ...
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In a few years, manned space missions are planned in which the sensorimotor performance of humans will be of outstanding importance. However, research has repeatedly shown that human sensorimotor function can be impaired under conditions of microgravity. One way to compensate for these impairments is haptic feedback provided by the human-machine interface. In the current series of studies, sensorimotor performance was measured in basic aiming and tracking tasks. These tasks had to be performed using a force feedback joystick with different haptic settings (three spring stiffnesses, two dampings, two virtual masses, and no haptics). In two terrestrial studies, we investigated (1) the effects of cognitive load on performance in a dual-task paradigm ( N = 10) and (2) which learning effects can be expected in these tasks in a longitudinal study design ( N = 20). In the subsequent space study ( N = 3 astronauts), the influence of microgravity and haptic settings of the joystick were investigated. For this purpose, three mission sessions after 2, 4, and 6 weeks on board the International Space Station (ISS), as well as terrestrial pre- and post-flight sessions, were conducted. The results of the studies indicated that (1) additional cognitive load led to longer reaction times during aiming and increased tracking error while aiming precision was not affected. (2) Significant learning effects were evident for most measures in the study on time effects. (3) Contrary to the expected learning trend, microgravity impaired the aiming precision performance of all astronauts in the initial phase of adaptation (2 weeks in space). No other significant effects were found. Intriguingly, these performance decrements could be compensated for with low to medium spring stiffness and virtual mass. The general result pattern provides further evidence that distorted proprioception during early adaptation to microgravity conditions is one main mechanism underlying sensorimotor impairment.
... The adjustment methods included the Bonferroni correction ("Bonferroni") in which the p-values were multiplied by the number of comparisons. Less conservative corrections were also included by Holm ("holm") (Holm 1979), Hochberg ("hochberg") (Hochberg 1988), Hommel ("hommel") (Hommel 1988), Benjamini & Hochberg ("BH" or its alias "fdr") (Benjamini and Hochberg 1995), and Benjamini & Yekutieli ("BY") (Benjamini and Yekutieli 2001), respectively. The "BH" (aka "FDR") and "BY" methods of Benjamini, Hochberg, and Yekutieli control the false discovery rate, i.e., the expected proportion of false discoveries among the rejected hypotheses. ...
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Objectives: Curcuma longa (CL) and Boswellia serrata (BS) extracts are used to relieve osteoarthritis symptoms. The aim of this in vitro study was to investigate their mechanisms of action at therapeutic plasmatic concentrations on primary human osteoarthritic (OA) chondrocytes. Methods: BS (10–50 μg/ml) and CL (0.4–2 μg/ml corresponding to 1–5 µM of curcumin) were evaluated separately or in combination on primary chondrocytes isolated from 17 OA patients and cultured in alginate beads. Ten patients were used for RNA-sequencing analysis. Proteomic confirmation was performed either by immunoassays in the culture supernatant or by flow cytometry for cell surface markers after 72 h of treatment. Results: Significant gene expression modifications were already observed after 6 h of treatment at the highest dose of CL (2 μg/ml) while BS was significantly effective only after 24 h of treatment irrespective of the concentration tested. The most over-expressed genes by CL were anti-oxidative, detoxifying, and cytoprotective genes involved in the Nrf2 pathway. Down-regulated genes were principally pro-inflammatory cytokines and chemokines. Inversely, BS anti-oxidant/detoxifying activities were related to the activation of Nrf1 and PPARα pathways. BS anti-inflammatory effects were associated with the increase in GDF15, decrease in cholesterol cell intake and fatty acid metabolism-involved genes, and down-regulation of Toll-like receptors (TLRs) activation. Similar to CL, BS down-regulated ADAMTS1, 5, and MMP3, 13 genes expression. The combination of both CL and BS was significantly more effective than CL or BS alone on many genes such as IL-6, CCL2, ADAMTS1, and 5. Conclusion: BS and CL have anti-oxidative, anti-inflammatory, and anti-catabolic activities, suggesting a protective effect of these extracts on cartilage. Even if they share some mechanism of action, the two extracts act mainly on distinct pathways, and with different time courses, justifying their association to treat osteoarthritis.
... All P values were two-sided with the level of statistical significance set at < 0.05. The Benjamini-Hochberg procedure was used to control false discovery rate (FDR) for multiple comparisons, and the FDR adjusted P values < 0.05 were considered statistically significant (11,12). All analyses were carried out using SPSS version 25 (IBM Corp. ...
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Cervical cancer with nodal involvement beyond the pelvis was considered as distant nodal metastasis in the previous International Federation of Gynecology and Obstetrics staging system. With the improvement of cancer-directed therapies, some of these patients can receive curative treatment. Classifying them as distant metastasis may result in underestimation of their prognosis as well as undertreatment. However, limited research has been conducted on the survival and treatment pattern in distant lymphatic metastatic cervical cancer. To investigate the survival, treatment pattern, and treatment outcome of patients with cervical cancer metastasized to distant lymph nodes (DLN) beyond the pelvis. Patients with stage III-IV cervical cancer from 1988 to 2016 were identified using the Surveillance, Epidemiology, and End Results program. The cancer cause-specific survival (CSS) was analyzed using the Kaplan-Meier method, log-rank test, multivariable Cox proportional hazard regression, subgroup analysis, and propensity score-matched analysis. Of 17783 patients with stage III-IV cervical cancer, patients with distant nodal disease beyond the pelvis (n=1883; included para-aortic lymph nodes metastasis) had superior survival compared to those with pelvic organ invasion or with distant organ(s) metastasis (5-year CSS, 32.3%, 26.3%, and 11.5%, respectively; adjusted P<0.001). The T stage significantly affected the survival of patients with positive DLN (5-year CSS for T1, T2, and T3: 47.3%, 37.0%, and 19.8%, respectively, adjusted P<0.01). For patients with positive DLN, combination radiotherapy (external beam radiotherapy [EBRT] with brachytherapy) prolonged CSS compared to EBRT alone (5-year CSS, 38.0% vs 21.7%; propensity score-adjusted HR, 0.60; 95% CI 0.51-0.72; P<0.001). Despite the superiority of combination radiotherapy, EBRT was the most frequently used treatment after 2004 (483/1214, 39.8%), while the utilization of combination radiotherapy declined from 37.8% (253/669) during 1988 through 2003 to 25.2% (306/1214) during 2004 through 2016. Patients with cervical cancer metastasized to DLN have favorable survival compared to those with pelvic organ invasion or with distant organ(s) metastasis. Their prognosis is significantly affected by local tumor burden and local treatment. Adequate and aggressive local radiotherapy, such as image-guided brachytherapy, can be considered for these patients to achieve better outcomes.
... In so doing, it is necessary to consider that multiple tests are performed. The simplest approach to deal with multiple testing is to apply a Bonferroni correction to the critical value used in the z-statistics (1), but more accurate procedures are preferable (Benjamini & Hochberg, 1995;Thissen et al., 2002) . ...
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The goodness of fit of a statistical model refers to the extent to which it captures the data generating mechanism. When more than one model is involved, model selection is necessary, which involves assessing the discrepancy between two models. We provide an introduction to goodness of fit and model selection with continuous outcomes (e.g. structural equation modeling) as well as with discrete outcomes (e.g. item response theory). We show how poor model fit predicts parameter bias and leads to biased conclusions, and how fit statistics can be used to improve the model. We illustrate the goodness of fit vs. model selection distinction using a simple regression model, arguing that R2 is a model selection (not goodness of fit) statistic, and we provide numerical examples illustrating model fit, model selection, and item selection using factor analysis and item response theory models.
... We only plot stations with data over the entire period, but the results are qualitatively the same if we allow stations to have up to 15 years of missing data, as Lebassi et al. (2009) did. In evaluating significance using a p-value threshold, we stress the importance of controlling for the false discovery rate (FDR) (Benjamini & Hochberg, 1995;Wilks, 2016). We limit the fraction of false negatives to 0.05, which leads to a value p FDR ≤ 0.05 that a p-value must be smaller than in order to be deemed significant. ...
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Plain Language Summary Downscaling methods and models yield climate projections on local scales relevant to entities such as cities and individual facilities. Weighted averages of future projections are needed so that the huge amount of existing climate model data is curated to a set that is compact enough to be widely‐accessible to end users. Observations are used to judge which models most faithfully represent historical climate. In California, previous work has ostensibly observed coastal cooling and inland warming over the later part of the 20th century. Upon closer inspection, we determine that this California coastal cooling finding is likely an artifact due to historical changes in observing practices at weather stations. We then evaluate and weight downscaled models using temperature records that show California coastal cooling and separately develop weights using temperature records that do not show such cooling. When we carefully consider the information in the observational data, we find that the two approaches to weighting produce about the same results. However, the weights can significantly differ when observational uncertainty is not considered. Together, these results highlight the importance, even over a heavily‐instrumented area like California, of carefully evaluating historical climate model simulations when producing future, localized climate projections for end users.
... The area under the curve (AUC) of dialysate IL-6 AR for incident UF insufficiency was calculated by receiver operating characteristic (ROC) analysis. Given the large number of statistical tests performed, P-values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control in multivariate regression analysis (30,31). Data analysis was carried out using the SPSS software package (version 22.0, Chicago, IL, USA) and R software (version 3.6.1, ...
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Introduction UF insufficiency is a major limitation in PD efficiency and sustainability. Our study object to investigate the efficacy of intraperitoneal inflammation marker, IL-6 level as a predictor of UF insufficiency in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods Stable prevalent CAPD patients were enrolled in this prospective study. IL-6 concentration in the overnight effluent was determined and expressed as the IL-6 appearance rate (IL-6 AR). Patients were divided into two groups according to the median of IL-6 AR and prospectively followed up until death, transfer to permanent HD, recovery of renal function, kidney transplantation, transfer to other centers, lost to follow-up or to the end of study (January 31, 2021). Factors associated with UF capacity as well as dialysate IL-6 AR were assessed by multivariable linear regression. Cox proportional hazards model was used to examine the association between dialysate IL-6 AR and UF insufficiency. Results A total of 291 PD patients were enrolled, including 148 males (51%) with a mean age of 56.6 ± 14.1 years and a median PD duration of 33.4 (12.7–57.5) months. No correlation was found between dialysate IL-6 AR and UF capacity at baseline. PD duration was found positively correlated with baseline dialysate IL-6 AR, while 24h urine volume was negatively correlated with baseline dialysate IL-6 AR ( P < 0.05). By the end of study, UF insufficiency was observed in 56 (19.2%) patients. Patients in the high IL-6 AR group showed a significantly inferior UF insufficiency-free survival when compared with their counterparts in the low IL-6 AR group ( P = 0.001). In the multivariate Cox regression analysis, after adjusting for DM, previous peritonitis episode and 24h urine volume, higher baseline dialysate IL-6 AR (HR 3.639, 95% CI 1.776–7.456, P = 0.002) were associated with an increased risk of UF insufficiency. The area under the ROC curve (AUC) for baseline IL-6 AR to predict UF insufficiency was 0.663 (95% CI, 0.580–0.746; P < 0.001). Conclusion Our study suggested that the dialysate IL-6 AR could be a potential predictor of UF insufficiency in patients undergoing PD.
... Benjamini-Hochberg method [21] was used to control the false discovery rate (FDR), and the P-value was adjusted by using the sequential modified correction for the multiple hypothesis testing. Furthermore, the intra-observer reliability was tested for 25% of the patients using the inter-class correlation coefficient (ICC). ...
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Objectives This study aimed to find out the correlation between different anatomical parameters of the mandible and the occurrence of a bad split in patients who had undergone bilateral split sagittal ramus osteotomy (BSSRO). Materials and method At both the distal roots of the first molar (1) and the retromolar area (2), we measured the distance from the buccal margin of the inferior dental canal (IDC) to the buccal margin of the cortical bone (MCBC), the thickness of both buccal cortical (WBCB) and cancellous bone (WBCA), distance from the superior border of IDC to the alveolar crest (MCAC), buccolingual thickness (BLT), and thickness of cancellous bone (WCA). At the ramus, the distances between the sigmoid notch to the upper part of the lingula (SL) and the inferior border of the mandible (SIBM), the thickness of the ramus at the level of the lingula (BLTR), and the anteroposterior width of the ramus (APWR) were measured. The paired and independent t-tests were used when applicable, and a P-value < 0.05 was considered significant. Results MCBC1 showed a significant difference between bad and non-bad split sides (P = 0.037). Both WBCA1 and WBCA2 show the same significant difference (P = 0.023, 0.024). Similarly, WCA1 and WCA2 showed a statistical difference between the bad and non-bad split sides (P = 0.027, 0.036). There were no statistically significant differences between the compared sides of WBCB1, WBCB2, MCAC1, MCAC2, SIBM, APWR, SL, and BLTR. Conclusion Narrow space between IDC and the buccal cortical margin, along with the decrease in the thickness of both buccal cancellous bone and total cancellous bone at the inferior border of the mandible along the course of SSRO, has been implicated in the occurrence of bad split intraoperatively.
... One-way ANOVA between the A375R and A375 sample pair and between A375R + N and A375R was performed using the R programming language linear model function lm(). p-values were adjusted for multiple testing by the Benjamini-Hocheberg method to calculate false discovery rates (Benjamini and Hochberg, 1995). A false discovery rate not greater than 0.05 was used to determine statistical significance of changed metabolites. ...
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Melanoma is the most aggressive type of skin cancer with a high incidence and low survival rate. More than half of melanomas present the activating BRAF mutations, along which V600E mutant represents 70%–90%. Vemurafenib (Vem) is an FDA-approved small-molecule kinase inhibitor that selectively targets activated BRAF V600E and inhibits its activity. However, the majority of patients treated with Vem develop acquired resistance. Hence, this study aims to explore a new treatment strategy to overcome the Vem resistance. Here, we found that a potential anticancer drug norcantharidin (NCTD) displayed a more significant proliferation inhibitory effect against Vem-resistant melanoma cells (A375R) than the parental melanoma cells (A375), which promised to be a therapeutic agent against BRAF V600E-mutated and acquired Vem-resistant melanoma. The metabolomics analysis showed that NCTD could, especially reverse the upregulation of pentose phosphate pathway and lipogenesis resulting from the Vem resistance. In addition, the transcriptomic analysis showed a dramatical downregulation in genes related to lipid metabolism and mammalian target of the rapamycin (mTOR) signaling pathway in A375R cells, but not in A375 cells, upon NCTD treatment. Moreover, NCTD upregulated butyrophilin (BTN) family genes, which played important roles in modulating T-cell response. Consistently, we found that Vem resistance led to an obvious elevation of the p-mTOR expression, which could be remarkably reduced by NCTD treatment. Taken together, NCTD may serve as a promising therapeutic option to resolve the problem of Vem resistance and to improve patient outcomes by combining with immunomodulatory therapy.
... The test was also performed to evaluate differences between input GW and outflow samples for on-site parameters. Finally, p-values were corrected with the false discovery rate approach of (Benjamini and Hochberg, 1995) when multiple comparisons were performed. ...
Article
The use of green walls for greywater treatment represents a great opportunity to reduce potable water consumption and achieve multiple benefits. This study aims to analyse the efficiency of a pilot scale open-air green wall and evaluate its durability over time. The green wall consists of two modular panels (P1 set up in 2020, and P2 in 2018), each including nine pots organised in three independent columns. Coconut coir (80%) and perlite (20%) were used as filter media for three ornamental plant species (Carex morrowi, Hedera helix, Lonicera nitida). Each column was individually fed in batch mode with 24 Lday⁻¹ (hydraulic loading rate - HLR 740.8 Lm⁻² day⁻¹) of greywater from January to March 2021. 190 water samples were analysed for 13 physical-chemical parameters. Both panels exhibited very good removal efficiencies for TSS (P1: 97.4 ± 4.6%, P2: 89.1 ± 13.8%), BOD5 (P1: 98.8 ± 2.4%, P2: 94.5 ± 9.2%), COD (P1: 78.5 ± 5.2%, P2: 80.1 ± 4.2%), TN (P1: 49.2 ± 30.4%, P2: 48.0 ± 23.31%), MBAS (P1: 92.7 ± 3.8%, P2: 75.3 ± 8.0%). P1 reached satisfying pollutants removal after two levels, while P2 showed higher variability and frequent clogging phenomena, needing three levels (e.g., cumulative BOD5 removal along the three levels in P1: 45.2 ± 36.2% | 86.5 ± 14.8% | 98.8 ± 2.4%; in P2: 16.5 ± 20.8% | 51.8 ± 32.3% | 94.5 ± 9.2%). This highlighted that the third level of P2 was necessary to guarantee good performances after over 2 years of operation. This study confirmed that green walls have high potential in greywater treatment also in challenging conditions (i.e. winter climate, high HLR and operating times), opening to further studies devoted to extending their lifetime.
... Mixed-effects linear regression models were applied to assess differences between 2020 and 2019, with respect to comparable months (March to December of each year) and the origin of the data (i.e., the specific medical center from which data were retrieved), which were modeled as random factors. We conducted a series of univariate linear regressions, each time with the factor of interest as the dependent variable and adjusted for multiple comparisons with Bejamini and Hochberg's false discovery rate correction [29]. In cases where observations significantly deviated from a normal distribution (tested with Kolmogorov Smirnov test and an α of <0.01), the non-parametric Wilcoxon test was applied instead. ...
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During the COVID-19 pandemic there have been numerous reports of increases in psychiatric morbidity and a deterioration of status among existing patients. There is little information about how this increase has affected youth and rates of adolescent psychiatric hospitalization. Our study was aimed at examining trends in youth psychiatric hospitalization during the first year of the COVID-19 pandemic. Method: We used medical records to compare trends in hospitalization rates from 2019 to 2020, among psychiatric youth wards from five different centers in Israel. Results: The number of patients that were hospitalized in youth psychiatric wards decreased significantly from 2019 (Mean ± SD=52.2 ± 28.6 per month) to 2020 (M ± SD = 40.8 ± 22.0; unstandardized B = −11.4, 95% CI = −14.4 to −8.3, p < 0.0001). There was a significant decrease in the number of patients that were hospitalized due to internalizing disorders from 2019 (M ± SD = 22.3 ± 9.3 per month) to 2020 (M ± SD = 16.8 ± 7.7; B = −5.5, 95% CI = −8.0 to −3.0, p = 0.0002) and a marginally significant increase in the number of restraints per month (2019: M ± SD = 2.8 ± 6.8, 2020: M ± SD = 9.0 ± 14.5; Z = −1.96, Rosenthal’s r= 0.36, p = 0.07).Conclusions: There was a significant decline in psychiatric hospitalizations during the pandemic, specifically among patients suffering from internalizing disorders. The reasons for this decline, and the future impact these changes had on hospitalizations during the pandemic demand further research. Study limitations: This is a retrospective multicenter study from five medical centers in Israel, therefore generalizability of our findings is limited.
... We assessed the overall significance of this relationship using a global Monte Carlo test with 49,999 random permutations of both model 2 (H1: assuming no relationship between R and L) and model 4 (H2: assuming no relationship between L and Q). Since the global test could not test the bivariate relationship between individual environmental variables and functional traits, we used fourth-corner analysis with an adjusted p value (i.e., p-values were corrected using the false discovery rate adjustment method to limit bias due to multiple-test comparisons) to test their relationships (function fourthcorner in R package ade4, Benjamini and Hochberg, 1995;Dong et al., 2021). Furthermore, we used a combination of RLQ and fourth-corner analyses to evaluate the significance of the associations between environmental variables (or functional traits) and the RLQ axes (Dray et al., 2014). ...
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Macrobenthos taxonomic and functional diversity are key indicators of ecosystem health. River–lake ecotones are key macrobenthos habitats. However, we don’t fully understand macrobenthos biodiversity patterns in these ecotones. We studied water environment, sediment heavy metal contents, and macrobenthos community, which we sampled simultaneously from 29 sampling sites along the Fu River–Baiyangdian Lake gradient in Northern China with five field surveys from 2018 to 2019. Six trait classes resolved into 25 categories were allocated to macrobenthos through a binary coding system. We used the RLQ framework (R, environmental variables; L, species of taxa; Q, traits) and fourth-corner analyses to evaluate the relationship between environmental variables and macrobenthos traits. Finally, we carried out variance partitioning to assess the contributions of environmental variables to variation of macrobenthos diversities. As the results, TN and TP contents in the river and lake mouths were lower than those in the adjacent river and lake, indicating that the river–lake ecotones played a role in purifying the water and buffering pollution. High taxonomic diversity of macrobenthos in the lake mouth and the presence of unique taxa in the two ecotones revealed edge effects, but the macrobenthos abundance and biomass were extremely low compared with those in the adjacent river and lake. We found no significant correlation between the taxonomic and functional diversity indices in the river and lake mouths. Water depth, water transparency, TN, and TP were the main water environmental drivers of macrobenthos taxonomic and functional diversity, explaining up to 45.5% and 56.2% of the variation, respectively. Sediment Cd, Cr, Cu, Pb, and Zn contents explained 15.1% and 32.8%, respectively, of macrobenthos taxonomic and functional diversity. Our results suggest that functional diversity approaches based on biological traits can complement taxonomic approaches in river–lake ecotones. Furthermore, improving water depth, transparency, eutrophication, and heavy metal pollution will improve macrobenthos diversity in these ecotones and maintain ecosystem health.
... Using PICRUSt2 (Douglas et al., 2020), we predicted the functional difference in relative abundance on Kyoto Encyclopedia of Genes and Genomes (KEGG) level 3 pathways that were present in at least 15% of samples, and with a minimum mean relative abundance of 0.01%. The Wilcoxon rank-sum test was employed and then followed by Benjamini-Hochberg false discovery rate (FDR) correction (Yoav and Yosef, 1995). The Spearman correlation analysis was performed to demonstrate the relationship between skin microbiota and clinical characteristics. ...
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Psoriasis can be provoked or exacerbated by environmental exposures such as certain microbiomes. The distinction between plaque psoriasis (PP) and guttate psoriasis (GP) in the skin or pharyngeal microbiota is not yet clear. High-throughput sequencing using Illumina MiSeq was used in this study to characterize skin and pharyngeal microbial composition in patients with PP [large PP (LPP, n = 62), small PP (SPP, n = 41)] and GP (n = 14). The alpha- and beta-diversity of skin microbiota LPP was similar to that of the SPP group, but different from the GP group. There were no differences in pharyngeal microbiota among the groups. According to linear discriminant analysis effect size (LEfSe) analysis, Staphylococcus, Stenotrophomonas, Enhydrobacter, Brevundimonas, and Allorhizobium–Neorhizobium–Pararhizobium–Rhizobium were the dominant genera of skin microbiota in PP. Diversity of skin microbiota correlated with Psoriasis Area and Severity Index (PASI). Moderate-to-severe psoriasis and mild psoriasis have different microbiota compositions. The skin microbiota may be related to the pharyngeal microbiota. Furthermore, two microbiota-based models could distinguish psoriasis subtypes with area under the receiver-operating characteristic curve (AUC-ROC) of 0.935 and 0.836, respectively. In conclusion, the skin microbiota in patients with LPP is similar to that in patients with SPP, but displays variations compared to that of GP, no differences are noted between subtypes in pharyngeal microbiota. Skin microbiota diversity correlated with PASI.
... (c) An example of missing reference points due to incorrect subject placement during image capture (one occurrence) was used for simplicity. As sample measures were repeated and paired, and the population distributions were not normal, pair-wise testing of manual measures and image-based measures was conducted in R (R Core Team, 2021) using Wilcox rank sum tests with p value adjustments as in Benjamini and Hochberg (1995). To allow this testing, predicted weight and girth were calculated from the fish body side area and body height at the mid-point of fork length measurements extracted from the digital images using the OLS regression equations. ...
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Two cross-sectional survey studies were conducted to examine the relationships between minority stressors, protective factors and mental health outcomes in lesbian, gay and bisexual people (LGB) in the United Kingdom (UK). A convenience sample of 156 LGB people in the UK participated in Study 1. Multiple regression analyses showed that victimization and sexuality-related identity threat were positively associated with anxiety and that identity resilience, social support and degree of outness were negative correlates; and that rejection was negatively associated with depression while identity resilience and social support were negative correlates. In Study 2, based on a convenience sample of 333 gay men, our structural equation model showed that ethnic minority status, lower identity resilience and higher identity threat were associated with greater distress; ethnic minority status was associated with less social support and more internalized homonegativity; being single was associated with less social support and more internalized homonegativity; identity resilience was positively associated with social support and negatively associated with internalized homonegativity; identity threat was associated with less social support and more internalized homonegativity; internalized homonegativity was negatively associated with social support; and social support was negatively associated with distress while internalized homonegativity was positively associated with distress. Findings show differential effects of particular stressors on particular mental health outcomes in LGB people and the significance of promoting identity resilience, social support and degree of outness as protective factors.
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Egg production is a pivotal indicator for evaluating the fertility of poultry, and the ovary is an essential organ for egg production and plays an indispensable role in poultry production and reproduction. In order to investigate different aspects of egg production mechanisms in different poultry, in this study we performed a metabolomic analysis of the transcriptomic combination of the ovaries of two chicken breeds, the high-production Ninghai indigenous chickens and the low-production Wuliangshan black-boned chickens, to analyze the biosynthesis and potential key genes and metabolic pathways in the ovaries during egg production. We predicted four genes in the transcriptomic that are associated with egg production, namely P2RX1, INHBB, VIPR2, and FABP3, and identified three important pathways during egg production, “Calcium signaling pathway”, “Neuroactive ligand–receptor interaction” and “Cytokine–cytokine receptor interaction”, respectively. In the metabolomic 149 significantly differential metabolites were identified, 99 in the negative model and 50 in the positive model, of which 17α-hydroxyprogesterone, iloprost, spermidine, and adenosine are important metabolites involved in reproduction. By integrating transcriptomics and metabolomics, the correlation between specific differential genes and differential metabolites identified important gene-metabolite pairs “VIPR2-Spermidine” and “P2RX1-Spermidine” in egg production. In conclusion, these data provide a better understanding of the molecular differences between the ovaries of low- and high-production hens and provide a theoretical basis for further studies on the mechanics of poultry egg production.
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Introduction Hemorrhagic early death (HED) remains a major cause of treatment failure among patients with acute promyelocytic leukemia (APL). We aimed to investigate the prognostic potential of rotational thromboelastometry (ROTEM) for bleeding in patients with APL. Materials and Methods 31 newly-diagnosed APL patients (median age of 40 years; 14 female/17 male) that underwent treatment at the Clinic of Hematology UCCS from 2016-2020 with all-trans retinoic acid and anthracyclines were recruited. CBCs (complete blood count), conventional coagulation tests (CCTs), and ROTEM parameters obtained before treatment initiation were evaluated. Results All patients demonstrated at least one ROTEM parameter out of the reference range. ROTEM parameters associated with significant hemorrhage were EXTEM clotting time (CT) (P = 0.041) and INTEM amplitude 10 (A10) (P = 0.039), however, only EXTEM CT (P = 0.036) was associated with HED. Among CBCs and CCTs, only platelets were associated with significant bleeding (P = 0.015), while D-dimer was associated with both bleeding and HED (P = 0.001 and P = 0.002, respectively). Conclusion Our results indicate that ROTEM parameters may reveal hypocoagulability in APL patients and have the potential to improve current hemorrhage prognostic methods. Additionally, these results suggest the combination of ROTEM and CCTs might be useful in identifying patients at risk for HED.
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The ability to understand speech in complex environments depends on the brain's ability to preserve the precise timing characteristics of the speech signal. Age-related declines in temporal processing may contribute to the older adult's experience of communication difficulty in challenging listening conditions. This study's purpose was to evaluate the effects of rate discrimination training on auditory temporal processing. A double-blind, rand-omized control design assigned 77 young normal-hearing, older normal-hearing, and older hearing-impaired listeners to one of two treatment groups: experimental (rate discrimination for 100-and 300-Hz pulse trains) and active control (tone detection in noise). All listeners were evaluated during pre-and post-training sessions using perceptual rate discrimination of 100-, 200-, 300-, and 400-Hz band-limited pulse trains and auditory steady-state responses (ASSRs) to the same stimuli. Training generalization was evaluated using several temporal processing measures and sentence recognition tests that included time-compressed and reverberant speech stimuli. Results demonstrated a session × training group interaction for perceptual and ASSR testing to the trained frequencies (100 and 300 Hz), driven by greater improvements in the training group than in the active control group. Further, post-test rate discrimination of the older listeners reached levels that were equivalent to those of the younger listeners at pre-test. Generalization was observed in significant improvement in rate discrimination of untrained frequencies (200 and 400 Hz) and in correlations between performance changes in rate discrimination and sentence recognition of reverberant speech. Further, non-auditory inhibition/attention performance predicted training-related improvement in rate discrimination. Overall, the results demonstrate the potential for auditory training to partially restore temporal processing in older listeners and highlight the role of cognitive function in these gains.
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Purpose The primary aim of this study was to compare decoding and literacy-related skills of children with suspected childhood apraxia of speech (sCAS) to children with reading disorders (RD) and no history of speech sound disorder (RD-no SSD) to determine if the groups differ in decoding and the endophenotypes that contribute to RD. We also explored the association between language impairment (LI) and decoding and literacy-related skills within the participant group with sCAS. Method Participants were school-age children and adolescents, 8–14 years of age, with a diagnosis of sCAS ( n = 13) or RD-no SSD ( n = 16). The sCAS and RD-no SSD groups were compared on measures of single-word decoding, oral language, motor-speech skills, phonological processing, and speech-in-noise perception, employing t tests and analysis of covariance. The sCAS + LI and sCAS-only groups were compared on similar measures using t tests. Results Compared to the RD-no SSD group, the sCAS group performed significantly worse on measures of phonological processing, multisyllable word repetition, diadochokinetic rate, and speech-in-noise perception. The groups did not differ on measures of single-word decoding, with mean scores for both groups falling below average. All participants with sCAS + LI demonstrated deficits in literacy and literacy-related skills compared to a smaller percentage of the sCAS-only group. Conclusions Children with sCAS and children with RD-no SSD demonstrate similar impairments in literacy. However, the endophenotypes underlying these difficulties can differ between the groups. Deficits in skills needed for literacy may require specifically tailored interventions to address reading difficulties for children with sCAS, especially for those with comorbid LI.
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Several recent studies investigated the rhythmic nature of cognitive processes that lead to perception and behavioral report. These studies used different methods, and there has not yet been an agreement on a general standard. Here, we present a way to test and quantitatively compare these methods. We simulated behavioral data from a typical experiment and analyzed these data with several methods. We applied the main methods found in the literature, namely sine-wave fitting, the discrete Fourier transform (DFT) and the least square spectrum (LSS). DFT and LSS can be applied both on the average accuracy time course and on single trials. LSS is mathematically equivalent to DFT in the case of regular, but not irregular sampling - which is more common. LSS additionally offers the possibility to take into account a weighting factor which affects the strength of the rhythm, such as arousal. Statistical inferences were done either on the investigated sample (fixed-effect) or on the population (random-effect) of simulated participants. Multiple comparisons across frequencies were corrected using False Discovery Rate, Bonferroni, or the Max-Based approach. To perform a quantitative comparison, we calculated sensitivity, specificity and d-prime of the investigated analysis methods and statistical approaches. Within the investigated parameter range, single-trial methods had higher sensitivity and d-prime than the methods based on the average accuracy time course. This effect was further increased for a simulated rhythm of higher frequency. If an additional (observable) factor influenced detection performance, adding this factor as weight in the LSS further improved sensitivity and d-prime. For multiple comparison correction, the Max-Based approach provided the highest specificity and d-prime, closely followed by the Bonferroni approach. Given a fixed total amount of trials, the random-effect approach had higher d-prime when trials were distributed over a larger number of participants, even though this gave less trials per participant. Finally, we present the idea of using a dampened sinusoidal oscillator instead of a simple sinusoidal function, to further improve the fit to behavioral rhythmicity observed after a reset event.
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Many disordered proteins conserve essential functions in the face of extensive sequence variation, making it challenging to identify the mechanisms responsible for functional selection. Here we identify the molecular mechanism of functional selection for the disordered adenovirus early gene 1A (E1A) protein. E1A competes with host factors to bind the retinoblastoma (Rb) protein, subverting cell cycle regulation. We show that two binding motifs tethered by a hypervariable disordered linker drive picomolar affinity Rb binding and host factor displacement. Compensatory changes in amino acid sequence composition and sequence length lead to conservation of optimal tethering across a large family of E1A linkers. We refer to this compensatory mechanism as conformational buffering. We also detect coevolution of the motifs and linker, which can preserve or eliminate the tethering mechanism. Conformational buffering and motif–linker coevolution explain robust functional encoding within hypervariable disordered linkers and could underlie functional selection of many disordered protein regions. Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.
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Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA‐DRB5*01:01:01‐DRB1*15:01:01‐DQA1*01:02:01‐DQB1*06:02:01 haplotype. Here, high‐resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls. The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA‐DR‐DQ genotypes were found. Three extended HLA‐DR‐DQ genotypes were found to be correlated to MS; HLA‐DRB5*01:01:01‐DRB1*15:01:01‐DQA1*01:02:01‐DQB1*06:02:01 haplotype together with (A) HLA‐DRB4*01:01:01//DRB4*01:01:01:01‐DRB1*07:01:01‐DQA1*02:01//02:01:01‐DQB1*02:02:01, (B) HLA‐DRBX*null‐DRB1*08:01:01‐DQA1*04:01:01‐DQB1*04:02:01, and (C) HLA‐DRB3*01:01:02‐DRB1*03:01:01‐DQA1*05:01:01‐DQB1*02:01:01. At the allelic level, HLA‐DRB3*01:01:02 was considered protective against MS. However, when combined with HLA‐DRB3*01:01:02‐DRB1*03:01:01‐DQA1*05:01:01‐DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes. In conclusion, with 69 genotypes presented among 100 patients, high‐resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA‐DRB5*01:01:01‐DRB1*15:01:01‐DQA1*01:02:01‐DQB1*06:02:01.
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The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll-like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL-infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell-extrinsic mechanisms of drug resistance and disease progression.
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Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ ( n = 26; M/F: 21/5) and HC ( n = 28; 20/8) (22–64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1β, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.
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We aimed to investigate the alpha (α) activity in operators experiencing boredom while performing prolonged monitoring and prospective memory tasks using different processing mechanisms. Fifty-four participants underwent electroencephalography (EEG) and were found to have poorer prospective memory performance under top-down conditions. Further, α power and synchronization were higher during bottom-up than in top-down processes, revealing an inhibition effect of the former. Significant differences in brain regions and hemispheres were identified to distinguish different cognitive processes in both information-processing mechanisms. Thus, people are likely to cope with boredom differently in terms of top-down and bottom-up processes. Specifically, a higher attention level was reported during top-down processing, to mitigate the negative influences of boredom. Overall, this study provides EEG evidence which suggests that prospective memory can be enhanced in top-down processing during prolonged monitoring tasks by increasing the salience of cues.
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Possession of flowers that trap fly pollinators is a conservative trait within the genus Ceropegia, in which pollination systems can be generalized or highly specialized. However, little is known about the role of plant–pollinator interactions in the maintenance of species boundaries. This study examined the degree of plant–pollinator specialization and identified the parameters responsible for specificity among four co-occurring Ceropegia species with overlapping flowering times. All investigated plant species were functionally specialized on pollination by Chloropidae and/or Milichiidae flies and each Ceropegia species was, in turn, ecologically highly specialized on only two pollinating fly morphospecies, though one plant species appeared more generalist. Species-specific fly attraction was due to the differences between plant species in floral scents, floral morphology, colour patterns, and presence of other functional structures, e.g., vibratile trichomes, which were shown to contribute to pollinator attraction in one study species. The combination of these olfactory and visual cues differentially influenced pollinator preferences and thus hindered heterospecific visitation. Furthermore, a pollinator exchange experiment also highlighted that species integrity is maintained through efficient ethological isolation (pollinator attraction). The mechanical isolation mediated by the fit between floral morphology and size and/or shape of fly pollinators appears less pronounced here, but whether or not the morphological match between male (pollinium) and female (guide rails) reproductive organs can impede hybridization remains to be investigated.
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Research indicates that teachers’ theories of intelligence (incremental vs. entity) are likely to affect their teaching practices, and some teachers hold lower expectations for students with learning disabilities. This study explored the relationships between college instructors’ theories of intelligence and the feedback they provided based on a student’s writing sample under two conditions: the student’s dyslexia was mentioned versus not mentioned. One hundred and one college instructors completed a survey. Results of path analysis indicated the instructors who endorsed the incremental theory of intelligence gave significantly more encouraging comments than those who endorsed the entity theory. Instructors’ theories of intelligence did not predict the grade assigned, the number of weaknesses pointed out, and the number of suggestions provided. The instructors informed of the student’s dyslexia gave significantly higher grades than those not informed, but the instructors’ feedback did not differ. No significant interaction between instructors’ theories of intelligence and awareness of student dyslexia was found.
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We extend the study of behavioural types in voluntary contribution games, adapting the elicitation method of Fischbacher et al. (2001) to a broader range of economic and strategic incentives. Our results in the standard VCM game align with previous findings in many respects; in particular, we identify one-quarter of participants as a distinctive group of “strong” conditional cooperators. We provide an explanation for the behaviour of this group by tracking their contribution strategies as the financial incentives of the game vary. We find that conditional cooperators follow a sophisticated rule, matching contributions only when doing so leads to an overall welfare improvement. This favours an account of conditional cooperation based on social norm compliance, rather than confusion, inequity aversion, or warm-glow giving.
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Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon ( GCG , 56%), amylin ( IAPP , 52%), insulin ( INS , 44%), and somatostatin ( SST , 24%). Inhibition of two DEGs, UNC5D and SERPINE2 , impaired glucose-stimulated insulin secretion and impacted cell survival in a human β-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
Article
Background The Victorian Institute of Sport Assessment–Achilles (VISA-A) questionnaire is validated and widely used in Achilles tendinopathy. How well it can evaluate treatment outcomes is not well understood. Purpose To evaluate the responsiveness of the VISA-A in midportion Achilles tendinopathy and compare it with other patient-reported outcome measures. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods Enrolled were 97 participants with clinically diagnosed Achilles tendinopathy (median age, 50 years [interquartile range, 18 years]; symptom duration, 10 months [interquartile range, 28.7 months). The participants underwent a baseline evaluation and completed between 1 and 6 follow-up evaluations at 8, 16, 24, 32, 40, and/or 48 weeks. Participants completed the VISA-A, the Patient Reported Outcomes Measurement Information System short form Version 2.0 (PROMIS) Physical Function and Pain Interference subscales, and the Tampa Scale for Kinesiophobia (TSK). Three thresholds were evaluated with a receiver operating characteristic analysis (minimal clinically important difference [MCID], substantial benefit [SB], and complete recovery [CR]) using an 11-point global rating of change scale as an anchor. Thresholds were evaluated on raw scores as well as changes from baseline. Results The VISA-A was able to detect all 3 thresholds for changes over time, with raw scores >70.5, >77.5, and >89.5 representing the MCID, SB, and CR, respectively; thresholds for changes from baseline on the VISA-A were increases of 23.5, 19.5, and 37.5 points from baseline, respectively. The PROMIS subscale raw scores had identical thresholds for SB and CR (52.45 for Physical Function and 45.6 for Pain Interference). A score <34.5 on the TSK was the threshold for SB. Conclusion The VISA-A was the most responsive outcome measure evaluated. Raw scores had increasingly higher thresholds for the MCID, SB, and CR, which were therefore logically consistent.
Article
This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (VO2R) reserve either 1:1 or more accurate. Cycle ergometer data of the maximal incremental exercise tests performed by 450 healthy and sedentary participants (17-66 years) of the HERITAGE Family Study, grouped for sex, ethnicity, age, body fat, resting HR, and VO2max, were used to calculate the individual linear regressions between %HRR and %VO2R. The mean slope and intercept of the individual linear regressions of each subgroup were compared with 1 and 0 (identity line), respectively, using Hotelling tests followed by post-hoc one-sample t-tests. Two multiple linear regressions were also performed, using either the slopes or intercepts of the individual linear regressions as dependent variables and sex, age, resting HR, and VO2max as independent variables. The mean %HRR-%VO2R relationships of all subgroups differed from the identity line. Moreover, individual linear regression intercepts (8.9±16.0) and slopes (0.971±0.190) changed (p<0.001) after 20 weeks of aerobic training (13.1±11.1 and 0.891±0.122). The multiple linear regressions could explain only 3.8% and 1.3% of the variance in the intercepts and slopes, whose variability remained high (standard error of estimate of 15.8 and 0.189). In conclusion, the %HRR-%VO2R relationship differs from the identity line regardless of individual characteristics and their difference increased after aerobic training. Moreover, due to the high interindividual variability, using a single equation for the whole population seems not suitable for representing the %HRR-%VO2R relationship of a given subject, even when several individual characteristics are considered.
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Food insecurity continues to be a problem in the U.S., especially in Arkansas, which ranked second in the nation in food-insecure households in 2020 (Arkansas Food Bank, n.d.). To help address this, community-based food pantries make food avail­able directly to area residents. Food pantry demand has increased during COVID-19, which has exacer­bated food insecurity, particularly in the southern U.S. In Arkansas, the Arkansas Food Bank (AFB) serves as the state’s largest nongovernmental food aid provider, working with 310 pantries. Pantries typically distribute food to clients in one of two ways: by using a prefilled bag or box of items (the traditional model), or by allowing clients to select items (the client-choice model). Although research has shown that the client-choice model has a variety of benefits for client health and well­being, pantries using the traditional model remain the norm in Arkansas, accounting for 87% of total pantries. Currently, there is limited research that identifies perceived barriers to converting to a client-choice model among pantry managers, and that identifies whether perceived barriers and local­ized concerns contribute to different operation styles among pantries. To address this, we exam­ined perceived barriers to client-choice conversion using a mixed-method survey conducted with 187 Arkansas food pantry managers. We used common factor analysis to identify four barriers perceived by pantries to converting their traditional pantry to a client-choice pantry: (1) food supply concerns, (2) having limited non­food resources, (3) food waste concerns, and (4) confu­sion from clients and nutritional concerns. A cluster analysis of pantry respondents was also used, based on their level of concern for the four identified perceived barriers. Clusters we identified are Potential Converters (18.2%), Confusion Concerned pantries (56.7%), and pantries who are Skeptics (25.1%). Our findings suggest that food pantry stakeholders may need additional outreach and education concerning the various ways that client choice can be implemented. Our results pro­vide valuable information for those involved in dis­tributing food aid to food-insecure households.
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We provide the first systematic research into the origins of subjective freedom of speech in Germany. Relying on the GLES 2021 Cross-Section Pre-Election Survey, which includes a newly designed survey item on subjective freedom of speech, we evaluate a whole range of plausible candidate hypotheses. First, we contribute to cumulative research by testing the explanatory factors in Gibson (1993)—citizens’ social class, their political involvement and political preferences, and their personality dispositions—for the German case. Second, we move beyond the state of the art and test three new hypotheses that reflect more recent political developments and arguments in the free speech debate: the role of social media, increasing political and social polarization, and the rise of populism. Importantly, all hypothesis tests reported in this paper have been preregistered prior to data collection. Our results reveal that three explanatory factors are significantly, consistently, and substantively related to subjective free speech in Germany: political preferences, populist attitudes, and identification with the Alternative for Germany party.
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Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer’s disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer’s disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer’s disease clinical trials. A comprehensive comparison of Alzheimer’s disease blood biomarkers in cognitively unimpaired individuals reveals that plasma p-tau231 and p-tau217 capture very early Aβ changes, showing promise as markers to enrich a preclinical population for Alzheimer’s disease clinical trials
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The fermentation of medicinal plants has been studied very little, as compared to the fermentation of food and beverages. One approach applies fermentation by single bacterial or fungal strains and targets the production of specific compounds or preservation of the fermented material. Spontaneous fermentation by an autochthonous starter community may lead to a more diverse blend of fermentation products because co-occurring microbes may activate the biosynthetic potentials and formation of compounds not produced in single strain approaches. We applied the community approach and studied the fermentation of four medicinal plants (Achillea millefolium, Taraxacum officinale, Mercurialis perennis, and Euphrasia officinalis), according to a standardized pharmaceutical fermentation method. It is based on the spontaneous fermentation by plant-specific bacterial and fungal communities under a distinct temperature regime, with a recurrent cooling during the first week and further fermentation for at least six months. The results revealed both general and plant-specific patterns in the composition and succession of microbial communities during fermentation. Lactic acid bacteria increasingly dominated in all preparations, whereas the fungal communities retained more plant-specific features. Three distinct fermentation phases with characteristic bacterial communities were identified, i.e., early, middle, and late phases. Co-occurrence network analyses revealed the plant-specific features of the microbial communities.
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Introduction: The density of tobacco retailers varies by community characteristics such as poverty levels or racial and ethnic composition. However, few studies have investigated how specific types of tobacco retailers vary by community characteristics. Our objective was to assess how the types of tobacco retailers in Ohio varied by the characteristics of the communities in which they were located. Results: For all US Census tracts, convenience stores were the most common type of retailer selling tobacco. Yet, the prevalence of convenience stores was higher in high-poverty urban tracts than in low-poverty urban tracts. Discount stores were the second-most common type of tobacco retailer and were most prevalent in rural tracts and high-racial and ethnic minority urban tracts. Grocery stores, pharmacies, and vape or hookah shops typically had the highest prevalence in more advantaged tracts. Conclusion: Our findings demonstrate that the distribution of specific retailer types varies by community characteristics. The distribution of these retailer types has implications for product availability and price, which may subsequently affect tobacco use and cessation. To create equitable outcomes, policies should focus on retailers such as convenience and discount stores, which are heavily located in communities experiencing tobacco-related health disparities.
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The relationship between the gut microbiota and brain function are receiving increasing research attention. Studies investigating gut microbiota and early childhood neurocognition are limited, particularly in longitudinal measurements. We examined cross‐sectional relationships between gut microbiota of a cohort of otherwise healthy children using 16S rRNA sequencing and their cognitive development measured with Bayley's Scales of Infant Development III at 24 months of age (n = 43), and longitudinal relationships between gut microbiota composition at 12 months (n = 41) of age and neurodevelopment at 24 months of age. Associations between gut microbiota characteristics and cognitive development were observed both cross‐sectionally and longitudinally, notably with butyrate producing bacteria among some children. Bacterial diversity varied between cross‐sectional and longitudinal observations, where the gut microbiota community of children with lower cognitive scores had a trend toward higher alpha diversity, whereas, in the longitudinal observation, a trend toward reduced alpha diversity was observed. This study is limited by a small sample size and its exploratory nature. Yet, the study contributes to knowledge in the gut microbiota characteristics and early life neurodevelopment, a field of study which is underexplored, presenting opportunities for future larger specific studies.
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The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4 ⁺ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation.
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A modification of the Bonferroni procedure for testing multiple hypotheses is presented. The method, based on the ordered p-values of the individual tests, is less conservative than the classical Bonferroni procedure but is still simple to apply. A simulation study shows that the probability of a type I error of the procedure does not exceed the nominal significance level, α, for a variety of multivariate normal and multivariate gamma test statistics. For independent tests the procedure has type I error probability equal to α. The method appears particularly advantageous over the classical Bonferroni procedure when several highly-correlated test statistics are involved.
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Current methods of statistical inference are correct but incomplete. Small probability (α) of wrong null-hypothesis rejections can be misunderstood. Definitive rejections of null hypotheses, as well as interval assessments of effect sizes, are impossible in single cases with significance probabilities like .05. Sufficiently large sets of independent experiments and attained significance levels (p-values) should be registered. From such data it is possible to calculate least upper bounds for proportions of fallacies in sets of null-hypothesis rejections or effect-size assessments. A provisional rejection of a null hypothesis in a one-tailed test, or a one-sided confidence interval showing a nonzero effect, is here called a discovery. Consider a large number n of independent experiments with r discoveries. For r rejections of null hypotheses the proportion of fallacies Q has least upper bound Qmax = (n/r — 1)α/(1 — α) < 1. For r confidence intervals, the proportion of fallacies is E = αn/r (assuming that no alternative is in the “wrong” direction).
Article
A sharper Bonferroni procedure for multiple tests of significance is derived. This procedure is an improvement of Hochberg's (1988) procedure which contrasts the individual P-values with corresponding critical points. It is shown that Hochberg's original procedure is conservative, and can be made more powerful by enlarging the rejection region so that the type-one error is exactly at the nominal level. It is also shown that the modified procedure retains all the desired properties of the original procedure.
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Simes (1986) has proposed a modified Bonferroni procedure for the test of an overall hypothesis which is the combination of n individual hypotheses. In contrast to the classical Bonferroni procedure, it is not obvious how statements about individual hypotheses are to be made for this procedure. In the present paper a multiple test procedure allowing statements on individual hypotheses is proposed. It is based on the principle of closed test procedures (Marcus, Peritz & Gabriel, 1976) and controls the multiple level α.
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A practicing statistician looks at the multiple comparison controversy and related issues through the eyes of the users. The concept of consistency is introduced and discussed in relation to five of the more common multiple comparison procedures. All of the procedures are found to be inconsistent except the simplest procedure, the unrestricted least significant difference (LSD) procedure (or multiple t test). For this and other reasons the unrestricted LSD procedure is recommended for general use, with the proviso that it should be viewed as a hypothesis generator rather than as a method for simultaneous hypothesis generation and testing. The implications for Scheffé's test for general contrasts are also discussed, and a new recommendation is made.
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A simple procedure for multiple tests of significance based on individual p-values is derived. This simple procedure is sharper than Holm's (1979) sequentially rejective procedure. Both procedures contrast the ordered p- values with the same set of critical values. Holm's procedure rejects an hypothesis only if its p-value and each of the smaller p-values are less than their corresponding critical-values. The new procedure rejects all hypotheses with smaller or equal p-values to that of any one found less than its critical value.
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This paper presents a simple and widely ap- plicable multiple test procedure of the sequentially rejective type, i.e. hypotheses are rejected one at a tine until no further rejections can be done. It is shown that the test has a prescribed level of significance protection against error of the first kind for any combination of true hypotheses. The power properties of the test and a number of possible applications are also discussed.
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Optimality criteria formulated in terms of the power functions of the individual tests are given for problems where several hypotheses are tested simultaneously. Subject to the constraint that the expected number of false rejections is less than a given constant $\gamma$ when all null hypotheses are true, tests are found which maximize the minimum average power and the minimum power of the individual tests over certain alternatives. In the common situations in the analysis of variance this leads to application of multiple $t$-tests. In that case the resulting procedure is to use Fisher's "least significant difference," but without a preliminary $F$-test and with a smaller level of significance. Recommendations for choosing the value of $\gamma$ are given by relating $\gamma$ to the probability of no false rejections if all hypotheses are true. Based upon the optimality of the tests, a similar optimality property of joint confidence sets is also derived.
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Simes (1986) has proposed a modified Bonferroni procedure for the test of an overall hypothesis which is the combination of n individual hypotheses. In contrast to the classical Bonferroni procedure, it is not obvious how statements about individual hypotheses are to be made for this procedure. In the present paper a multiple test procedure allowing statements on individual hypotheses is proposed. It is based on the principle of closed test procedures (Marcus, Peritz & Gabriel, 1976) and controls the multiple level α.
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Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and anisoylated plasminogen streptokinase activator (APSAC) in myocardial infarction has been proved to reduce mortality. A new front-loaded infusion regimen of 100 mg of rt-PA with an initial bolus dose of 15 mg followed by an infusion of 50 mg over 30 min and 35 mg over 60 min has been reported to yield higher patency rates than those achieved with standard regimens of thrombolytic treatment. The effects of this front-loaded administration of rt-PA versus those obtained with APSAC on early patency and reocclusion of infarct-related coronary arteries were investigated in a randomized multicenter trial in 421 patients with acute myocardial infarction. Coronary angiography 90 min after the start of treatment revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) in 84.4% of 199 patients given rt-PA versus 70.3% of 202 patients given APSAC (p = 0.0007). Early reocclusion within 24 to 48 h was documented in 10.3% of 174 patients given rt-PA versus 2.5% of 163 patients given APSAC. Late reocclusion within 21 days was observed in 2.6% of 152 patients given rt-PA versus 6.3% of 159 patients given APSAC. There were 5 in-hospital deaths (2.4%) in the rt-PA group and 17 deaths (8.1%) in the APSAC group (p = 0.0095). The reinfarction rate was 3.8% and 4.8%, respectively. Peak serum creatine kinase and left ventricular ejection fraction at follow-up angiography were essentially identical in both treatment groups. There were more bleeding complications after APSAC (45% vs. 31%, p = 0.0019).(ABSTRACT TRUNCATED AT 250 WORDS)
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The problem of multiple comparisons is discussed in the context of medical research. The need for more powerful procedures than classical multiple comparison procedures is indicated. To this end some new, general and simple procedures are discussed and demonstrated by two examples from the medical literature: the neuropsychologic effects of unidentified childhood exposure to lead, and the sleep patterns of sober chronic alcoholics.
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The randomized clinical trial is the preferred research design for evaluating competing diagnostic and therapeutic alternatives, but confidence in the conclusions from a randomized clinical trial depends on the authors' attention to acknowledged methodologic and statistical standards. This survey assessed the level of attention to the problem of multiple comparisons in the analyses of contemporary randomized clinical trials. Of the 67 trials surveyed, 66 (99 percent) performed multiple comparisons with a mean of 30 therapeutic comparisons per trial. When criteria for statistical impairment were applied, 50 trials (75 percent) had the statistical significance of at least one comparison impaired by the problem of multiple comparisons, and 15 (22 percent) had the statistical significance of all comparisons impaired by the problem of multiple comparisons. Although some statistical techniques are available, there still exists a great need for future work to clarify further the problem of multiple comparisons and determine how the impact of this problem can best be minimized in subsequent research.
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This article discusses statistical methods for comparing the means of several groups and focuses on examples from 50 Original Articles published in the Journal in 1978 and 1979. Although medical authors often present comparisons of the means of several groups, the most common method of analysis, multiple t-tests, is usually a poor choice. Which method of analysis is appropriate depends on what questions the investigators wish to ask. If the investigators want to identify which of the groups under study are different from the rest, they will need a different method from the one required if they wish simply to decide whether or not the groups share a common mean. More complicated questions about the group means call for more sophisticated techniques. Of the 50 Journal articles examined, 27 (54 per cent) used inappropriate statistical methods to analyze the differences between group means. Investigators need to become better acquainted with statistical techniques for making multiple comparisons between group means.
  • Hochberg
Statistical problems in reporting of clinical trials
  • S. J. Pocock
  • M. D. Hughes
  • R. J. Lee