bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conditional power of antidepressant network meta-analysis
Authors: Holper Lisa 
Published: March 2021

Abstract
Background
Conditional power of network meta-analysis (NMA) can support the planning of randomized controlled trials (RCTs) assessing medical interventions. Conditional power is the probability that updating existing inconclusive evidence in NMA with additional trial(s) will result in conclusive evidence, given assumptions regarding trial design, anticipated effect sizes, or event probabilities.

Methods
The present work aimed to estimate conditional power for potential future trials on antidepressant treatments. Existing evidence was based on a published network of 502 RCTs conducted between 1979-2018 assessing acute antidepressant treatment in major depressive disorder (MDD). Primary outcomes were efficacy in terms of the symptom change on the Hamilton Depression Scale (HAMD) and tolerability in terms of the dropout rate due to adverse events. The network compares 21 antidepressants consisting of 231 relative treatment comparisons, 164 (efficacy) and 127 (tolerability) of which are currently assumed to have inconclusive evidence.

Results
Required sample sizes to achieve new conclusive evidence with at least 80% conditional power were estimated to range between N = 894 - 4190 (efficacy) and N = 521 - 1246 (tolerability). Otherwise, sample sizes ranging between N = 49 - 485 (efficacy) and N = 40 - 320 (tolerability) may require stopping for futility based on a boundary at 20% conditional power. Optimizing trial designs by considering multiple trials that contribute both direct and indirect evidence, anticipating alternative effect sizes or alternative event probabilities, may increase conditional power but required sample sizes remain high. Antidepressants having the greatest conditional power associated with smallest required sample sizes were identified as those on which current evidence is low, i.e., clomipramine, levomilnacipran, milnacipran, nefazodone, and vilazodone, with respect to both outcomes.

Conclusions
The present results suggest that conditional power to achieve new conclusive evidence in ongoing or future trials on antidepressant treatments is low. Limiting the use of the presented conditional power analysis are primarily due to the estimated large sample sizes which would be required in future trials as well as due to the well-known small effect sizes in antidepressant treatments. These findings may inform researchers and decision-makers regarding the clinical relevance and justification of research in ongoing or future antidepressant RCTs in MDD.
Resistance of strongylid nematodes to anthelmintic drugs and driving factors at Czech goat farms
Authors: Vadlejch Jaroslav , Kyriánová Iveta Angela , Várady Marián , Charlier Johannes 
Published: March 2021

Abstract
Background
Strongylid nematode infections may negatively affect both animal health and welfare, with deleterious consequences for livestock productivity. Many farmers in recent decades have relied on anthelmintics as the sole strategy of control, but the intensive use of these chemotherapeutics has led to the development of anthelmintic resistance (AR). Knowledge of both the efficacy of anthelmintics and factors promoting AR are essential to effectively control nematode infections, but no information on these topics for goats in the Czech Republic (CR) is available. This survey aimed to determine the occurrence of AR at Czech goat farms and to identify risk factors for the development of AR. A total of 24 herds of dairy goats across the CR were evaluated using in vitro tests for detecting AR, and a questionnaire survey was carried out to evaluate factors associated with AR.

Results
Resistance against benzimidazoles was confirmed at 18 (75%) farms, and the level of resistance was high in four (22%) of the affected herds based on the egg hatch test. Ivermectin-resistant nematodes were detected in 13 (54%) herds using the larval development test; Teladorsagia/Trichostrongylus and Haemonchus were the predominant types of resistant larvae. Eight (62%) of the affected herds were evaluated as highly resistant to ivermectin. Eleven (46%) of the herds were resistant to both benzimidazoles and ivermectin. This report is the first on dual AR in the CR. A univariate logistic regression analysis indicated that a high stocking rate and farmer inexperience were significantly associated with ivermectin and benzimidazole resistance, respectively.

Conclusions
The results of our survey suggest that AR is widespread amongst herds of dairy goats in the CR, likely due to inappropriate practices of pasture and health management. AR may be an issue for expanding dairy-goat production in the CR in the near future unless both veterinary practitioners and farmers widely adopt strategies to prevent the development of AR.
Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis
Authors: Su Wenliang , Cui Huan , Wu Danning , Yu Jiawen , Ma Lulu , Zhang Xiuhua , Huang Yuguang , Ma Chao 
Published: March 2021

Abstract
Background
As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure.

Methods
The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain.

Results
Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH.

Conclusions
HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.
The hidden fluctuation-dissipation theorem for growth
(a)
Authors: Gomes-Filho Márcio S. , Oliveira Fernando A. 
Published: March 2021

Abstract
In a stochastic process, where noise is always present, the fluctuation-dissipation theorem (FDT) becomes one of the most important tools in statistical mechanics and, consequently, it appears everywhere. Its major utility is to provide a simple response to study certain processes in solids and fluids. However, in many situations we are not talking about a FDT, but about the noise intensity. For example, noise has enormous importance in diffusion and growth phenomena. Although we have an explicit FDT for diffusion phenomena, we do not have one for growth processes where we have a noise intensity. We show that there is a hidden FDT for the growth phenomenon, similar to the diffusive one. Moreover, we show that growth with correlated noise presents as well a similar form of FDT. We also call attention to the hierarchy within the theorems of statistical mechanics and how this explains the violation of the FDT in some phenomena.
Depressive symptoms, HIV-related stigma and ART adherence among caregivers of children in vulnerable households in rural southern Malawi
Authors: Spielman Kathryn L. , Soler-Hampejsek Erica , Muula Adamson S. , Tenthani Lyson , Hewett Paul C. 
Published: March 2021

Background
Few studies have explored the association between depressive symptoms, HIV infection and stigma in vulnerable populations. The objective of this study is to examine factors associated with depressive symptoms among caregivers living in vulnerable households in Malawi and assess how reported depressive symptoms and other factors affect ART adherence among caregivers who report testing positive for HIV and currently on ART.

Methods
We interviewed 818 adult caregivers of children aged 0–17 years living in vulnerable households in 24 health facility catchment areas in five districts in rural southern Malawi in 2016–2017. Vulnerable households had either economic and food insecurity, or chronic illness. Questions on five depressive symptoms were used. ART adherence was self-report of not forgetting to take ART medication in the last week. Perceived and anticipated measures of stigma were used. Multivariable linear and logistic regressions documented relationships between depressive symptoms, self-reported HIV status, HIV-related stigma, and ART adherence.

Results
Most caregivers were women (86.2%); about one third had no spouse or live-in partner. Fifty-seven percent of caregivers reported having three or more depressive symptoms. Forty-one percent of caregivers reported testing positive for HIV. Self-reported HIV positive status was associated with depressive symptoms (adjusted coeff = 0.355, p-value <0.001), which were in turn associated with poorer ART adherence among caregivers (aOR 0.639, p-value = 0.023). HIV-related stigma was also associated with depressive symptoms for caregivers who reported having HIV (coeff = 0.302, p-value = 0.028) and those who reported testing negative for HIV (coeff = 0.187, p-value <0.001). Having social support was associated with lower depressive symptoms (coeff = -0.115, p = 0.007). HIV-related stigma, having social support, and other socio-demographic characteristics were not found to be associated with ART adherence.

Conclusions
Addressing mental health among caregivers in vulnerable households may be an important step toward achieving viral suppression among vulnerable populations living with HIV in Malawi. Integrating depression screening into HIV care and treatment protocols could be a promising intervention to improve longer-term outcomes.
“Doctor, my back hurts and I cannot sleep.” Depression in primary care patients: Reasons for consultation and perceived depression stigma
Authors: Heinz Ines , Baldofski Sabrina , Beesdo-Baum Katja , Knappe Susanne , Kohls Elisabeth , Rummel-Kluge Christine 
Published: March 2021

Background
General practitioners (GPs) play a significant role in depression care. Recognition of depression is crucial for adequate treatment but is impeded by a high portion of depressed patients only reporting physical symptoms to their GP. Among the many reasons for this phenomenon is mental health stigma. We investigated how patients with depression differed from patients without depression regarding the types and number of complaints presented to their GP, as well as their depression stigma. For the subgroup of patients with depression, potential associations between perceived depression stigma and number and types of presented complaints were investigated to see if these might reflect the patient’s intention to conceal mental health symptoms due to fear of being stigmatized by others. Further, we investigated if perceived depression stigma is related to depression treatment.

Methods
Data on depressive symptoms (assessed by the Depression Screening Questionnaire; DSQ), depression stigma (assessed by the Depressions Stigma Scale; DSS), type of complaints reported to the GP and treatment-related factors were collected from 3,563 unselected primary care patients of 253 GPs in a cross-sectional epidemiological study (“VERA study”) in six different German regions. Data of a total of 3,069 patients was used for analysis on complaints reported to the GP (subsample of the VERA study), and for 2,682 out of 3,069 patients data on a stigma questionnaire was available.

Results
Nearly half of the primary care patients with depression (42.2%) reported only physical complaints to their GP. Compared to patients without a depression diagnosis, patients with depression reported twice as many complaints to their GP with a mean of 2.02 (1.33) vs. 1.2 (0.69), including a more frequent combination of physical and mental symptoms (28.8% vs. 3.5%). Patients with depression showed higher total stigma compared to patients without depression, Mdn = 48 (IQR 40–54) vs. Mdn = 46.3 (IQR 29–53), due to higher perceived stigma, Mdn = 27 (IQR 21–32) vs. Mdn = 25.9 (IQR 20–29). Perceived stigma was associated with male gender (beta -.14, p = .005) and a lack of pharmacological treatment (beta -.14, p = .021) in patients with a depression diagnosis.

Conclusion
The number of complaints presented to the GP might function as a marker to actively explore depression in primary care patients, in particular when both physical and mental symptoms are reported. Perceived depression stigma should also be addressed especially in male patients. Further research should clarify the role of perceived stigma as a potential inhibitor of pharmacological treatment of depression in primary care.
Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice
Authors: McGuirt Avery F. , Post Michael R. , Pigulevskiy Irena , Sulzer David , Lieberman Ori J. 
Published: March 2021

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih, and INaP. We demonstrated that the developmental increase in INaPdrives increased ChI firing rates during the postnatal period and can be reversed by the INaPinhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced INaPand identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENTMotor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.
Synaptophysin Regulates Fusion Pores and Exocytosis Mode in Chromaffin Cells
Authors: Chang Che-Wei , Hsiao Yu-Tien , Jackson Meyer B. 
Published: March 2021

Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Previous work has demonstrated functions for syp in synaptic vesicle cycling, endocytosis, and synaptic plasticity, but the role of syp in the process of membrane fusion during Ca2+-triggered exocytosis remains poorly understood. Furthermore, although syp resides on both large dense-core and small synaptic vesicles, its role in dense-core vesicle function has received less attention compared with synaptic vesicle function. To explore the role of syp in membrane fusion and dense-core vesicle function, we used amperometry to measure catecholamine release from single vesicles in male and female mouse chromaffin cells with altered levels of syp and the related tetraspanner protein synaptogyrin (syg). Knocking out syp slightly reduced the frequency of vesicle fusion events below wild-type (WT) levels, but knocking out both syp and syg reduced the frequency 2-fold. Knocking out both proteins stabilized initial fusion pores, promoted fusion pore closure (kiss-and-run), and reduced late-stage fusion pore expansion. Introduction of a syp construct lacking its C-terminal dynamin-binding domain in syp knock-outs (KOs) increased the duration and fraction of kiss-and-run events, increased total catecholamine release per event, and reduced late-stage fusion pore expansion. These results demonstrated that syp and syg regulate dense-core vesicle function at multiple stages to initiate fusion, control the choice of mode between full-fusion and kiss-and-run, and influence the dynamics of both initial and late-stage fusion pores. The transmembrane domain (TMD) influences small initial fusion pores, and the C-terminal domain influences large late-stage fusion pores, possibly through an interaction with dynamin.SIGNIFICANCE STATEMENTThe secretory vesicle protein synaptophysin (syp) is known to function in synaptic vesicle cycling, but its roles in dense-core vesicle functions, and in controlling membrane fusion during Ca2+-triggered exocytosis remain unclear. The present study used amperometry recording of catecholamine release from endocrine cells to assess the impact of syp and related proteins on membrane fusion. A detailed analysis of amperometric spikes arising from the exocytosis of single vesicles showed that these proteins influence fusion pores at multiple stages and control the choice between kiss-and-run and full-fusion. Experiments with a syp construct lacking its C terminus indicated that the transmembrane domain (TMD) influences the initial fusion pore, while the C-terminal domain influences later stages after fusion pore expansion.
Effect of COVID-19 on the clinical course of diabetic ketoacidosis (DKA) in people with type 1 and type 2 diabetes
Authors: Kempegowda Punith , Melson Eka , Johnson Agnes , Wallett Lucy , Thomas Lucretia , Zhou Dengyi , Holmes Catherine , Juszczak Agata , Karamat Mohammed Ali , Ghosh Sandip , Hanif Wasim , Narendran Parth , Bellary Srikanth 
Published: March 2021

Objective
COVID-19 in people with diabetes is associated with a disproportionately worse prognosis. DKA is an acute complication of diabetes with a mortality rate of approximately 0.67%. Little is known about the natural history of DKA in the presence of COVID-19. This study aimed to explore the effects of COVID-19 on presentation, clinical course and outcome in patients presenting with DKA.

Design
Retrospective cohort study.

Methods
All patients treated for DKA between 1 March 2020 and 30 May 2020 were included. Patients were categorised as COVID-positive or COVID-negative based on the swab test. A pre-COVID group was established using data from 01 March 2019 to 30 May 2019 as external control. Data regarding demographics, diabetes type, pH, bicarbonate, lactate, glucose, DKA duration, complications and outcome were collected.

Results
A total of 88 DKA episodes were included in this study. There was no significant difference in the severity or duration of DKA between the three groups. COVID-positive T1DM were more hyperglycaemic on admission compared to COVID-negative and pre-COVID patients. There was an over representation of T2DM in COVID-positive patients with DKA than in pre-COVID or COVID-negative groups.

Conclusion
COVID-19 appears to influence the natural history of DKA differently in T1DM and T2DM. Patients with T1DM and COVID-19 presented with more hyperglycaemia (60 mmol/L (35.9–60.0) vs 31.4 mmol/L (28.0–39.1) vs 24 mmol/L (20.2–33.75), respectively). Patients with T2DM were unusually presenting in DKA when infected with COVID-19 with greater ICU need and higher mortality rates. A collaborative, multi-centre study is needed to provide more definitive results.
RILEM TC 277-LHS report: a review on the mechanisms of setting and hardening of lime-based binding systems
Authors: Alvarez J. I. , Veiga R. , Martínez-Ramírez S. , Secco M. , Faria P. , Maravelaki P. N. , Ramesh M. , Papayianni I. , Válek J. 
Published: March 2021

AbstractThe main objective of RILEM TC LHS-277 “Specifications for testing and evaluation of lime-based repair materials for historic Structures” is the revision, adaption and, when necessary proposal, of the test methods to accurately study lime-based binding systems and mixtures, such as mortars and grouts. The empiric use of the lime-based composites and the predominant employ of cement in the field of Civil Engineering have led to the widespread application of test methods developed for cement-based composites to test the former. However, the clear differences in composition and performance between modern cement binders and lime-based materials would advise to explore specific test methods for the latter. To undertake this task the previous knowledge on the mechanisms of setting and hardening of these binders must be revised, arranged and synthesized. Processes such as drying, carbonation, hydration and pozzolanic reaction may occur during the setting and hardening of lime-based mortars and competition between them cannot be underestimated. With the aim of underpinning the revision and proposal of test methods for lime-based systems, this review paper reports a comprehensive study of the mechanisms of setting and hardening of these binders, considering the variability of the composition, which includes pure air lime as well as lime with hydraulic properties, lime-cement and lime-pozzolan systems.