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Cluster-extent based thresholding is currently the most popular method for multiple comparisons correction of statistical maps in neuroimaging studies, due to its high sensitivity to weak and diffuse signals. However, cluster-extent based thresholding provides low spatial specificity; researchers can only infer that there is signal somewhere within a significant cluster and cannot make inferences about the statistical significance of specific locations within the cluster. This poses a particular problem when one uses a liberal cluster-defining primary threshold (i.e., higher p-values), which often produces large clusters spanning multiple anatomical regions. In such cases, it is impossible to reliably infer which anatomical regions show true effects. From a survey of 814 functional magnetic resonance imaging (fMRI) studies published in 2010 and 2011, we show that the use of liberal primary thresholds (e.g., p<.01) is endemic, and that the largest determinant of the primary threshold level is the default option in the software used. We illustrate the problems with liberal primary thresholds using an fMRI dataset from our laboratory (N=33), and present simulations demonstrating the detrimental effects of liberal primary thresholds on false positives, localization, and interpretation of fMRI findings. To avoid these pitfalls, we recommend several analysis and reporting procedures, including 1) setting primary p<.001 as a default lower limit; 2) using more stringent primary thresholds or voxel-wise correction methods for highly powered studies; and 3) adopting reporting practices that make the level of spatial precision transparent to readers. We also suggest alternative and supplementary analysis methods. •Cluster-extent based thresholding is popular because of its high sensitivity.•However, cluster-extent based thresholding has several important problems.•One pitfall is low spatial specificity when significant clusters are large.•Another pitfall is increased false positives when a liberal primary threshold is used.•We recommend using stringent primary thresholds and augmented reporting procedures.

Background: Taste, one of the five special senses, is the sensory impression of various substances on the tongue. There are five basic taste modalities such as sweet, salt, sour, bitter, and umami. The physiological taste threshold of the individual gets altered in hypothyroidism. Aims and Objectives: The present study was undertaken to test and compare the physiological taste threshold for the five primary taste modalities such as umami, salt, sweet, sour, and bitter in hypothyroid patients and the normal healthy controls. Materials and Methods: Thirty hypothyroid patients aged between 20 and 50 years and 30 age, sex, and anthropometrically matched apparently healthy individuals as control were included in the study. The tests for the threshold of all the five primary tastes were performed in both the groups and the results were compared. Results: The taste threshold for the sweet taste modality has been increased significantly (P < 0.05) in hypothyroid patients compared to controls. No difference could be observed in case of other taste modalities. Conclusion: The significant increase in the physiological taste threshold of sweet modality in hypothyroid patients compared to the controls suggests that hypothyroid patients may have a decreased sensitivity for the sweet taste. Thus, the taste dysfunction should be detected in them by proper screening. Timely management/treatment and counseling can help them to get back their normal taste threshold along with attaining the euthyroid status.

Objective: The main goal of the article is to assess the level of fiscal sustainability at the local government level in the Visegrad Group (V4) economies. Research Design Methods: Two different methods of fiscal sustainability measures were used in the article to verify whether the local government deficit is sustainable: estimations of the no-Ponzi conditions, and calculations of the threshold primary balance. The research period covered the years 2001-2016. Data were taken from the Eurostat database. Findings: Three out of four V4 countries met the initial no-Ponzi condition. The sums of discounted primary balances of their local governments were positive (Poland was the only exception). However, those sums were insufficient to cover the initial debt volume. It was possible in Hungary only. The Ponzi scheme was significantly reduced during the recovery time after the financial crisis of 2008-2009. Implications Recommendations: Generally, all the countries showed the potential to produce primary surpluses at the local level and they have been generally able to stabilise the local debt to GDP ratio. However, these surpluses in the Czech Republic, Slovakia and Poland were insufficient to cover the initial level of debt. Especially Poland should try to generate higher primary local surpluses to avoid the Ponzi scheme and increase the level of fiscal sustainability at the local government level in the future. Contribution Value Added: The originality of this work lies in using the Ponzi scheme and the values of the threshold primary gap to assess the fiscal sustainability of local government levels in the Visegrad Group Economies.

China is currently undergoing an important stage wherein it is adjusting its development mode and upgrading its industrial structure. Green investment has become a major driving force through which China can achieve green and sustainable development. Based on the panel data of 30 Chinese provinces for the 2006–2017 period, this paper uses a spatial Durbin model and a dynamic threshold model to empirically analyze the impact of green investment and institutional quality on environmental pollution. The research results show that China’s environmental pollution is significantly characterized by spatial dependence. Local environmental pollution is negatively impacted by green investment, but it is not affected by green investment in neighboring areas; this conclusion remains valid after a series of robustness tests. Green investment can reduce environmental pollution by improving efficiency of energy conservation and emission reduction, expanding technological innovation capabilities and upgrading the industrial structure. The regression results of the dynamic threshold model show that green investment has a nonlinear impact on environmental pollution that is dependent on institutional quality. A higher degree of regional corruption can lead to a gradual decrease in the role of green investment in reducing environmental pollution. However, improvements in marketization and intellectual property protection can increase the positive influence of green investment in reducing environmental pollution. Significant regional heterogeneity is also found in the impact of green investment on environmental pollution, and this impact gradually decreases from the eastern coast to the western region.

Background Pediatric headache is an increasing medical problem that has adverse effects on children’s quality of life, academic performance, and social functioning. Children with primary headaches exhibit enhanced sensory sensitivity compared to their healthy peers. However, comprehensive investigations including multimodal sensory sensitivity assessment are lacking. This study aimed to compare sensory sensitivity of children with primary headaches with their healthy peers across multiple sensory domains. Methods The study included 172 participants aged 6 to 17 years (M = 13.09, SD = 3.02 years; 120 girls). Of these 80 participants were patients with migraine, 23 were patients with tension-type headache, and 69 were healthy controls. The following sensory measures were obtained: Mechanical Detection Threshold (MDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), detection and pain threshold for Transcutaneous Electrical Nerve Stimulation (TENS), olfactory and intranasal trigeminal detection threshold, and odor identification ability. Sensory sensitivity was compared between groups with a series of Kruskal-Wallis tests. Binomial regression models were used to compare the relative utility of sensory sensitivity measures in classifying participants into patients and healthy controls, as well as into patients with migraine and tension-type headache. Results Patients with migraine had lower MPT measured at the forearm than patients with tension-type headaches and healthy controls. MPS was higher in patients with migraine than in healthy controls. All patients with headaches had lower detection threshold of TENS and higher olfactory sensitivity. Healthy controls showed increased intranasal trigeminal sensitivity. Scores in MPS, TENS, and olfactory and trigeminal thresholds were significantly predicting presence of primary headaches. Additionally, scores in MPT, olfactory and trigeminal threshold were positive predictors of type of headache. Conclusions Children with primary headaches exhibit different sensory profiles than healthy controls. The obtained results suggest presence of increased overall, multimodal sensitivity in children with primary headaches, what may negatively impact daily functioning and contribute to further pain chronification. Trial registration The study was registered in the German Registry of Clinical Trials (DRKS) DRKS00021062.

The authors identify programmed cell death ligand-1 (PD-L1), an immunity suppressor produced by cancer cells, as a new pain inhibitor and a neuromodulator. They report that PD-L1 is produced by melanoma and normal neural tissues and that it inhibits acute and chronic pain. Via activation of PD-1, its receptor, PD-L1 decreases the excitability of nociceptive neurons in mouse and human dorsal root ganglia. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 ( Pdcd1 ) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K + channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.

Livestock grazing has been shown to alter the structure and functions of grassland ecosystems. It is well acknowledged that grazing pressure is one of the strongest drivers of ecosystem‐level effects of grazing, but few studies have assessed how grazing pressure impacts grassland biodiversity and ecosystem multifunctionality (EMF). Here, we assessed how different metrics of biodiversity (i.e., plants and soil microbes) and EMF responded to seven different grazing treatments based on an 11‐year field experiment in semi‐arid Inner Mongolian steppe. We found that soil organic carbon, plant‐available nitrogen and plant functional diversity all decreased even at low grazing pressure, while above‐ground primary production and bacterial abundance decreased only at high levels of grazing pressure. Structural equation models revealed that EMF was driven by direct effects of grazing, rather than the effects of grazing on plant or microbial community composition. Grazing effects on plant functional diversity and soil microbial abundance did have moderate effects on EMF, while plant richness did not. Synthesis. Our results showed ecosystem functions differ in their sensitivity to grazing pressure, requiring a low grazing threshold to achieve multiple goals in the Eurasian steppe. A plain language summary is available for this article. Plain Language Summary

1. Overgrazing has resulted in widespread decline in biodiversity and ecosystem functioning in grasslands world-wide in recent decades. However, few studies have examined the patterns and thresholds of grazing-induced changes in community structure and ecosystem functioning along a grazing gradient and based on species-level responses and plant functional traits. 2. To identify the thresholds of grazing intensity (GI) at both species and community levels, we conducted a grazing manipulation experiment with seven levels of GI (0-9 sheep ha⁻¹) and two topographies (flat vs. slope) in a typical steppe. Four plant functional traits were measured, including specific leaf area (SLA), plant height, leaf nitrogen content (LNC) and stem: leaf ratio. 3. The threshold of GI that significantly altered community composition was at 3-75 sheep ha⁻¹ for the flat system and 3.0 sheep ha⁻¹ for the slope system. For both flat and slope systems, the threshold GI for changes in primary productivity was at 3.0 sheep ha⁻¹, beyond which the productivity decreased substantially. 4. At the species level, the abundances of common species, most of which are perennial grasses, declined at moderate grazing intensities (3.0-4.5 sheep ha⁻¹). The abundances of most rare species, which are perennial forbs, declined at low grazing intensities (1.5-3.0 sheep ha⁻¹). SLA and LNC are good predictors of species-level responses to grazing. Low SLA and high LNC species are negatively affected by high GI, while high SLA and low LNC species are little affected by grazing. The negative effect of GI on species' abundance was greater in the slope system than in the flat system. 5. Synthesis and applications. Our results indicate that the structural and functioning thresholds of grazing intensity depend on plant traits and species composition, which is mediated by topographic location. These findings, integrating plant functional traits and threshold approaches, have important implications for determining sustainable grazing intensity in grassland management and biodiversity conservation in semi-arid regions.

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N ​= ​50) and a large sample of cLBP patients (N ​= ​102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P ​= ​0.01) over the low back, but not finger (P ​= ​0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P ​< ​0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ ​= ​0.27, P ​= ​0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ ​= ​0.52, P ​= ​0.03) and increased S1-back adjacent white matter FA (ρ ​= ​−0.56, P ​= ​0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.

Traditional Thai massage (TTM) is a unique form of whole body massage practiced to promote health and well-being in Thailand since ancient times. The goal of the present study was to create a standardised TTM protocol to treat office syndrome (OS) diagnosed based on the identification of the palpation of at least one so-called myofascial trigger point (MTrP) in the upper trapezius muscle. The new 90 min TTM protocol, which was developed following appropriate review of the literature and in consultation with relevant experts, has 25 distinct steps (20 pressing steps, 2 artery occlusion steps, and 3 stretching steps). Eleven TTM therapists treated three patients each using the new 90 min TTM protocol. All of the therapists reported scores greater than 80% in respect to their satisfaction and confidence to deliver the protocol, and all of the patients gave the treatment a satisfaction score of greater than 80%. The treatment produced a significant reduction in pain intensity measured on a Visual Analogue Scale (VAS), with minimum and maximum values of 0 and 10 cm, of 2.33 cm (95% CI (1.76, 2.89 cm), p < 0.001) and significant increase in pain pressure threshold (PPT) of 0.37 kg/cm2 (95% CI (0.10, 0.64 kg/cm2), p < 0.05). The protocol was revised based on the feedback and the results obtained, and the new standardised TTM protocol will be applied in a randomised control trial (RCT) to compare the efficacy of TTM and conventional physical therapy (PT) for treating OS.