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Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

Partial correlation coefficients are often used as effect sizes in the meta-analysis and systematic review of multiple regression analysis research results. There are two well-known formulas for the variance and thereby for the standard error (SE) of partial correlation coefficients (PCC). One is considered the "correct" variance in the sense that it better reflects the variation of the sampling distribution of partial correlation coefficients. The second is used to test whether the population PCC is zero, and it reproduces the test statistics and the p-values of the original multiple regression coefficient that PCC is meant to represent. Simulations show that the "correct" PCC variance causes random effects to be more biased than the alternative variance formula. Meta-analyses produced by this alternative formula statistically dominate those that use "correct" SEs. Meta-analysts should never use the "correct" formula for partial correlations' standard errors.

Publication bias is a ubiquitous threat to the validity of meta-analysis and the accumulation of scientific evidence. In order to estimate and counteract the impact of publication bias, multiple methods have been developed; however, recent simulation studies have shown the methods' performance to depend on the true data generating process, and no method consistently outperforms the others across a wide range of conditions. Unfortunately, when different methods lead to contradicting conclusions, researchers can choose those methods that lead to a desired outcome. To avoid the condition-dependent, all-or-none choice between competing methods and conflicting results, we extend robust Bayesian meta-analysis and model-average across two prominent approaches of adjusting for publication bias: (1) selection models of "p"-values and (2) models adjusting for small-study effects. The resulting model ensemble weights the estimates and the evidence for the absence/presence of the effect from the competing approaches with the support they receive from the data. Applications, simulations, and comparisons to preregistered, multi-lab replications demonstrate the benefits of Bayesian model-averaging of complementary publication bias adjustment methods.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

Single-stranded phosphorothioate oligonucleotides (PS-oligos) can activate TLR9, leading to an innate immune response. This can occur with PS-oligos containing unmethylated CpG sites, the canonical motif, or PS-oligos that do not contain those motifs (non-CpG). Structural evidence shows that TLR9 contains two PS-oligo binding sites, and recent data suggest that synergistic cooperative activation of TLR9 can be achieved by adding two separate PS-oligos to cells, each engaging with a separate site on TLR9 to enhance TLR9 activation as a pair. Here, we demonstrate and characterize this cooperativity phenomenon using PS-oligos in human cell lines, and we introduce several novel PS-oligo pairs (CpG and non-CpG pairs) that show cooperative activation. Indeed, we find that cooperative PS-oligos likely bind at different sites on TLR9. Interestingly, we find that PS-oligos that generate little TLR9 activation on their own can prime TLR9 to be activated by other PS-oligos. Finally, we determine that previous models of TLR9 activation cannot be used to fully explain data from systems using human TLR9 and PS-oligos. Overall, we reveal new details of TLR9 activation, but we also find that more work needs to be done to determine where certain PS-oligos are binding to TLR9.

Recent, high-profile, large-scale, preregistered failures to replicate uncover that many highly-regarded experiments are "false positives"; that is, statistically significant results of underlying null effects. Large surveys of research reveal that statistical power is often low and inadequate. When the research record includes selective reporting, publication bias and/or questionable research practices, conventional meta-analyses are also likely to be falsely positive. At the core of research credibility lies the relation of statistical power to the rate of false positives. This study finds that high (>50%-60%) median retrospective power (MRP) is associated with credible meta-analysis and large-scale, preregistered, multi-lab "successful" replications; that is, with replications that corroborate the effect in question. When median retrospective power is low (<50%), positive meta-analysis findings should be interpreted with great caution or discounted altogether.

The use of accelerated beams of electrons, protons or ions has furthered the development of nearly every scientific discipline. However, high-energy muon beams of equivalent quality have not yet been delivered. Muon beams can be created through the decay of pions produced by the interaction of a proton beam with a target. Such 'tertiary' beams have much lower brightness than those created by accelerating electrons, protons or ions. High-brightness muon beams comparable to those produced by state-of-the-art electron, proton and ion accelerators could facilitate the study of lepton-antilepton collisions at extremely high energies and provide well characterized neutrino beams1-6. Such muon beams could be realized using ionization cooling, which has been proposed to increase muon-beam brightness7,8. Here we report the realization of ionization cooling, which was confirmed by the observation of an increased number of low-amplitude muons after passage of the muon beam through an absorber, as well as an increase in the corresponding phase-space density. The simulated performance of the ionization cooling system is consistent with the measured data, validating designs of the ionization cooling channel in which the cooling process is repeated to produce a substantial cooling effect9-11. The results presented here are an important step towards achieving the muon-beam quality required to search for phenomena at energy scales beyond the reach of the Large Hadron Collider at a facility of equivalent or reduced footprint6.

We introduce and evaluate three tests for publication selection bias based on excess statistical significance (ESS). The proposed tests incorporate heterogeneity explicitly in the formulas for expected and ESS. We calculate the expected proportion of statistically significant findings in the absence of selective reporting or publication bias based on each study's SE and meta-analysis estimates of the mean and variance of the true-effect distribution. A simple proportion of statistical significance test (PSST) compares the expected to the observed proportion of statistically significant findings. Alternatively, we propose a direct test of excess statistical significance (TESS). We also combine these two tests of excess statistical significance (TESSPSST). Simulations show that these ESS tests often outperform the conventional Egger test for publication selection bias and the three-parameter selection model (3PSM).

Test anxiety and academic stress were investigated as predictors of students’ academic progress in Physics in this study. A correlational research design was used. The study was guided by three research questions and three null hypotheses. The research was conducted in Education Zon C, Benue State, Nigeria. The study’s population consisted of 2692 SS II Physics students from public schools in the area. The study used a sample of 337 students drawn using simple random sampling. For data collection, the researchers employed the Physics Test Anxiety Inventory (PTAI) adapted from Spielberger (1980), the Physics Academic Stress Scale (PASS) adapted from Burge (2009), and the Physics Achievement Test (PAT) designed by the researchers. Four specialists faced validated the instruments. Using the Cronbach alpha approach, the reliability of the PTAI and PASS were estimated to be 0.73 and 0.84, respectively, while the reliability of the PAT was estimated to be 0.76 using the KR-20 formula. Regression analysis was utilized to answer the study questions, while ANOVA was employed to test the hypotheses made at the 0.05 level of significance. The result revealed that the proportion of variation students’ achievement in Physics that may be attributable to test anxiety and academic stress, is independently and jointly significant. Based on this conclusion, it was suggested that adequate learning resources, as well as a functioning and suitable learning environment, be made available in order for students to learn effectively. This will help them to be mentally ready for any form of testing or examinations.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N-acetylgalactosamine (GalNAc3) moiety to the extensively characterized phosphorothioate (PS)-modified 2'-O-methoxyethyl (2'MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes. In this study we report the integrated assessment of data available from randomized placebo-controlled dose-ranging studies of this chemical class of ASOs administered systemically to healthy human volunteers. First, we compare the pharmacokinetic and pharmacodynamic profiles of a subset of the GalNAc3-conjugated PS-modified 2'MOE ASOs to the parent PS-modified 2'MOE ASOs for which plasma analytes are available. We then evaluate the safety profile of the full set of GalNAc3-conjugated PS-modified 2'MOE ASO conjugates by the incidence of signals in standardized laboratory tests and by the mean laboratory test results as a function of dose level over time. With hepatocyte targeted delivery, the ED50 for the GalNAc3-conjugated PS-modified 2'MOE ASO subset ranges from 4 to 10 mg/week, up to 30-fold more potent than the parent PS-modified 2'MOE ASO. No GalNAc3-conjugated PS-modified 2'MOE ASO class effects were identified from the assessment of the integrated laboratory test data across all doses tested with either single or multidose regimens. The increase in potency supports an increase in the safety margin for this new chemical class of ASOs now under broad investigation in the clinic. Although the total exposure is limited in the initial phase 1 trials, ongoing and future investigations in patient populations will support evaluation of the effects of long-term exposure.

Phosphorothioate modified antisense oligonucleotides (PS-ASOs) can reduce gene expression through hybridization to target RNAs and subsequent cleavage by RNase H1. Target reduction through this mechanism is influenced by numerous features of the RNA, which modulate PS-ASO binding affinities to the RNA target, and how the PS-ASO-RNA hybrid is recognized by RNase H1 for RNA cleavage. Endogenous RNAs are frequently chemically modified, which can regulate intra- and intermolecular interactions of the RNA. The effects of PS-ASO modifications on antisense activity have been well studied; however, much less is known regarding the effects of RNA modifications on PS-ASO hybridization and RNase H1 cleavage activity. Here, we determine the effects of three different RNA modifications on PS-ASO binding and antisense activity in recombinant and cell-based systems. Some RNA modifications can reduce PS-ASO hybridization, the cleavage activity of RNase H1, or both, while other modifications had minimal effects on PS-ASO function. In addition to these direct effects, RNA modifications can also change the RNA structure, which may affect PS-ASO accessibility in a cellular context. Our results elucidate the effects of three prevalent RNA modifications on PS-ASO-mediated RNase H1 cleavage activity, and such findings will help improve PS-ASO target site selection.

We assess statistical power and excess statistical significance among 31 leading economics general interest and field journals using 22,281 parameter estimates from 368 distinct areas of economics research. Median statistical power in leading economics journals is very low (only 7%), and excess statistical significance is quite high (19%). Power this low and excess significance this high raise serious doubts about the credibility of economics research. We find that 26% of all reported results have undergone some process of selection for statistical significance and 56% of statistically significant results were selected to be statistically significant. Selection bias is greater at the top five journals, where 66% of statistically significant results were selected to be statistically significant. A large majority of empirical evidence reported in leading economics journals is potentially misleading. Results reported to be statistically significant are about as likely to be misleading as not (falsely positive) and statistically nonsignificant results are much more likely to be misleading (falsely negative). We also compare observational to experimental research and find that the quality of experimental economic evidence is notably higher. [ABSTRACT FROM AUTHOR]

This article provides concise, nontechnical, step‐by‐step guidelines on how to conduct a modern meta‐analysis, especially in social sciences. We treat publication bias, p‐hacking, and systematic heterogeneity as phenomena meta‐analysts must always confront. To this end, we provide concrete methodological recommendations. Meta‐analysis methods have advanced notably over the last few years. Yet many meta‐analyses still rely on outdated approaches, some ignoring publication bias and systematic heterogeneity. While limitations persist, recently developed techniques allow robust inference even in the face of formidable problems in the underlying empirical literature. The purpose of this paper is to summarize the state of the art in a way accessible to aspiring meta‐analysts in any field. We also discuss how meta‐analysts can use advances in artificial intelligence to work more efficiently. [ABSTRACT FROM AUTHOR]

Muon accelerators offer an attractive option for a range of future particle physics experiments. They can enable high energy (TeV+) high energy lepton colliders whilst mitigating the difficulty of synchrotron losses, and can provide intense beams of neutrinos for fundamental physics experiments investigating the physics of flavor. The method of production of muon beams results in high beam emittance which must be reduced for efficient acceleration. Conventional emittance control schemes take too long, given the very short (2.2 microsecond) rest lifetime of the muon. Ionisation cooling offers a much faster approach to reducing particle emittance, and the international MICE collaboration aims to demonstrate this technique for the first time. This paper will present the MICE RF system and its role in the context of the overall experiment.

Systemically administered 2'-O-methoxyethyl (2'MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2'MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2'MOE ASO-treated patients at doses >175 mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate. However, these changes were not clinically significant or progressive. No dose-related effects were observed in the incidence of abnormal renal test results in the total population of patients, or subpopulation of diabetic patients or patients with renal dysfunction at baseline. The incidence of acute kidney injury [serum creatinine ≥0.3 mg/dL (26.5 μM) increases from baseline or ≥1.5 × baseline] in 2'MOE ASO-treated patients (2.4%) was not statistically different from placebo (1.7%, P = 0.411). In conclusion, in this database, encompassing 32 clinical trials and 11 different 2'MOE ASOs, we found no evidence of clinically significant renal dysfunction up to 52 weeks of randomized-controlled treatment.

Muon beams of low emittance provide the basis for the intense, well-characterized neutrino beams necessary to elucidate the physics of flavor at a neutrino factory and to provide lepton-antilepton collisions at energies of up to several TeV at a muon collider. The international Muon Ionization Cooling Experiment (MICE) aims to demonstrate ionization cooling, the technique by which it is proposed to reduce the phase-space volume occupied by the muon beam at such facilities. In an ionization-cooling channel, the muon beam passes through a material in which it loses energy. The energy lost is then replaced using rf cavities. The combined effect of energy loss and reacceleration is to reduce the transverse emittance of the beam (transverse cooling). A major revision of the scope of the project was carried out over the summer of 2014. The revised experiment can deliver a demonstration of ionization cooling. The design of the cooling demonstration experiment will be described together with its predicted cooling performance.

Muon accelerators offer an attractive option for a range of future particle physics experiments. They can enable high energy (TeV+) high energy lepton colliders whilst mitigating the difficulty of synchrotron losses, and can provide intense beams of neutrinos for fundamental physics experiments investigating the physics of flavor. The method of production of muon beams results in high beam emittance which must be reduced for efficient acceleration. Conventional emittance control schemes take too long, given the very short (2.2 microsecond) rest lifetime of the muon. Ionisation cooling offers a much faster approach to reducing particle emittance, and the international MICE collaboration aims to demonstrate this technique for the first time. This paper will present the MICE RF system and its role in the context of the overall experiment.