Jay S. Skyler
Feb 1, 2017; 66:241-255
Perspectives in Diabetes

Twenty-seven years after signing Barry Bonds to a then-record free-agent contract, the Giants are in the market for yet another superstar outfielder. San Francisco's interest in Bryce Harper remained a prominent topic of conversation during Saturday's FanFest at Oracle Park, with CEO Larry Baer weighing in on the potential franchise-altering benefits of landing a marquee player.

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.

30 April 2020

As editors, we feel like we’re spending a lot of time taking the superlatives out from articles - amazing, novel, important… But new research on BMJ.com suggests that we might not be doing that great a job, and that for some reason, papers authored by men tend to have more of them - because men put more in, or maybe a bias against woman writing in...

Miriam Cnop
Dec 1, 2005; 54:S97-S107
Section III: Inflammation and beta-Cell Death

Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein–coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1–dependent and serotonin-mediated mechanism.

Though some Reds fans were disappointed that Billy Hamilton wasn't brought back this season, it didn't take long for Cincinnati to find another dynamic player who also brings flash and unpredictability. That would be outfielder Yasiel Puig.

It wasn't just that there were new faces when Reds camp opened Tuesday with the reporting of pitchers and catchers for physicals, there was a different vibe that could be felt in the hallways and clubhouse.

In glioma patients, differentiation between tumor progression (TP) and treatment-related changes (TRCs) remains challenging. Difficulties in classifying imaging alterations may result in a delay or an unnecessary discontinuation of treatment. PET using O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) has been shown to be a useful tool for detecting TP and TRCs. Methods: We retrospectively evaluated 127 consecutive patients with World Health Organization grade II–IV glioma who underwent ¹⁸F-FET PET imaging to distinguish between TP and TRCs. ¹⁸F-FET PET findings were verified by neuropathology (40 patients) or clinicoradiologic follow-up (87 patients). Maximum tumor-to-brain ratios (TBR_max) of ¹⁸F-FET uptake and the slope of the time–activity curves (20–50 min after injection) were determined. The diagnostic accuracy of ¹⁸F-FET PET parameters was evaluated by receiver-operating-characteristic analysis and ² testing. The prognostic value of ¹⁸F-FET PET was estimated using the Kaplan–Meier method. Results: TP was diagnosed in 94 patients (74%) and TRCs in 33 (26%). For differentiating TP from TRCs, receiver-operating-characteristic analysis yielded an optimal ¹⁸F-FET TBR_max cutoff of 1.95 (sensitivity, 70%; specificity, 71%; accuracy, 70%; area under the curve, 0.75 ± 0.05). The highest accuracy was achieved by a combination of TBR_max and slope (sensitivity, 86%; specificity, 67%; accuracy, 81%). However, accuracy was poorer when tumors harbored isocitrate dehydrogenase (IDH) mutations (91% in IDH-wild-type tumors, 67% in IDH-mutant tumors, P < 0.001). ¹⁸F-FET PET results correlated with overall survival (P < 0.001). Conclusion: In our neurooncology department, the diagnostic performance of ¹⁸F-FET PET was convincing but slightly inferior to that of previous reports.

Posttreatment high-grade gliomas are usually monitored with contrast-enhanced MRI, but its diagnostic accuracy is limited as it cannot adequately distinguish between true tumor progression and treatment-related changes. According to recent Response Assessment in Neuro-Oncology recommendations, PET overcomes this limitation. However, it is currently unknown which tracer yields the best results. Therefore, a systematic review and metaanalysis were performed to compare the diagnostic accuracy of the different PET tracers in differentiating tumor progression from treatment-related changes in high-grade glioma patients. Methods: PubMed, Web of Science, and Embase were searched systematically. Study selection, data extraction, and quality assessment were performed independently by 2 authors. Metaanalysis was performed using a bivariate random-effects model when at least 5 studies were included. Results: The systematic review included 39 studies (11 tracers). ¹⁸F-FDG (12 studies, 171 lesions) showed a pooled sensitivity and specificity of 84% (95% confidence interval, 72%–92%) and 84% (95% confidence interval, 69%–93%), respectively. O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) (7 studies, 172 lesions) demonstrated a sensitivity of 90% (95% confidence interval, 81%–95%) and specificity of 85% (95% confidence interval, 71%–93%). For S-¹¹C-methyl)-l-methionine (¹¹C-MET) (8 studies, 151 lesions), sensitivity was 93% (95% confidence interval, 80%–98%) and specificity was 82% (95% confidence interval, 68%–91%). The numbers of included studies for the other tracers were too low to combine, but sensitivity and specificity ranged between 93%–100% and 0%–100%, respectively, for ¹⁸F-FLT; 85%–100% and 72%–100%, respectively, for 3,4-dihydroxy-6-¹⁸F-fluoro-l-phenylalanine (¹⁸F-FDOPA); and 100% and 70%–88%, respectively, for ¹¹C-choline. Conclusion: ¹⁸F-FET and ¹¹C-MET, both amino-acid tracers, showed a comparably higher sensitivity than ¹⁸F-FDG in the differentiation between tumor progression and treatment-related changes in high-grade glioma patients. The evidence for other tracers is limited; thus, ¹⁸F-FET and ¹¹C-MET are preferred when available. Our results support the incorporation of amino-acid PET tracers for the treatment evaluation of high-grade gliomas.

OBJECTIVE

To evaluate and compare the efficacy of long-term use of low-dose aspirin for the prevention of dementia in men and women.

Joseph Largay
Jan 1, 2012; 30:25-26
Case Studies

Ideological differences in the Democratic Party over immigration that were once masked by unity against President Trump’s border wall and immigration agenda are now being exposed as Democratic presidential candidates seek to stand out in a crowded field and amid controversy over an emergency border spending bill. As the 2020 electoral calendar accelerates, how the party navigates the gulf between its most liberal and conservative wings will become a greater challenge for its leaders.

Two of the authors of the American Dental Association's antibiotics guideline will discuss C. diff infections and antibiotic stewardship in dentistry April 21 as part of a free, online conference organized by the Peggy Lillis Foundation.

OBJECTIVE

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A_1c (HbA_1c) at baseline.

With the Trump administration having announced the end of the DACA program, Congress is facing growing calls to protect unauthorized immigrants who came to the U.S. as children. This fact sheet examines DREAM Act bills introduced in Congress as of mid-2017, offering estimates of who might earn conditional legal status—and ultimately legal permanent residence—based on educational, professional, and other requirements in the legislation.

2017 saw the introduction of several bills—two of them by Senate Republicans in the weeks following the Trump administration’s announcement that it would terminate the Deferred Action for Childhood Arrivals (DACA) program—that would provide a pathway to conditional and then legal permanent residence to unauthorized immigrants brought to the United States as children, if they meet a range of educational, professional, and other criteria.

When the Rev. Martin Luther King Jr. called on America to open the doors of opportunity to people of color, the civil rights leader was making a moral argument.

WASHINGTON – Four years since the Every Student Succeeds Act (ESSA) was signed into law, all 50 states, the District of Columbia and Puerto Rico have developed accountability plans that include blueprints for serving English Learners (ELs), as well as measuring these students’ progress and being accountable for their outcomes. This marked a significant development, as EL performance was previously not well integrated with factors that determined whether a school was performing well or poorly.

Experts share how states have approached Every Student Succeeds Act (ESSA) implementation, and areas where the law and state efforts to support English Learners can be improved.

OBJECTIVE

Prevalence and prognostic impact of cardiovascular disease differ between patients with or without diabetes. We aimed to explore differences in the prevalence and prognosis of myocardial ischemia by automated quantification of total perfusion deficit (TPD) among patients with and without diabetes.

Experts share how states have approached Every Student Succeeds Act (ESSA) implementation, areas where the law and state efforts to support English Learners can be improved, and findings from the compendium, The Patchy Landscape of State English Learner Policies under ESSA. 

The Difficulties Of South American Football

Dementia.

Paris : E. Leroux, 1874.

London : Walton & Maberly, 1866.

Berlin : G. Reimer, 1879.

Berlin : G. Reimer, 1899.

London : J. Murray, 1877.

Manchester : J. Heywood, 1888.

London : Adlard, 1904.

London : Cassell, 1901.

London : Cassell, 1894.

Paris : G. Steinheil, 1888.

South Dakota lawmakers have rejected a bill that would have allowed science teachers to discuss strengths and weaknesses of evolutionary and climate change theories.

An Alaskan high school exchange program works to promote understanding between the state's urban centers and its remote Native Villages and communities.

Gregor Pasemann, Wilhelm Stannat.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 547--579.

Abstract:
A parameter estimation problem for a class of semilinear stochastic evolution equations is considered. Conditions for consistency and asymptotic normality are given in terms of growth and continuity properties of the nonlinear part. Emphasis is put on the case of stochastic reaction-diffusion systems. Robustness results for statistical inference under model uncertainty are provided.

Yichong Wu, Tiejun Li, Xiaoping Liu, Luonan Chen.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1269--1301.

Abstract:
Detecting the change of biological interaction networks is of great importance in biological and medical research. We proposed a simple loss function, named as CrossFDTL, to identify the network change or differential network by estimating the difference between two precision matrices under Gaussian assumption. The CrossFDTL is a natural fusion of the D-trace loss for the considered two networks by imposing the $ell _{1}$ penalty to the differential matrix to ensure sparsity. The key point of our method is to utilize the cross variables, which correspond to the sum and difference of two precision matrices instead of using their original forms. Moreover, we developed an efficient minimization algorithm for the proposed loss function and further rigorously proved its convergence. Numerical results showed that our method outperforms the existing methods in both accuracy and convergence speed for the simulated and real data.

Fabien Panloup, Samy Tindel, Maylis Varvenne.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1075--1136.

Abstract:
In this paper we consider the drift estimation problem for a general differential equation driven by an additive multidimensional fractional Brownian motion, under ergodic assumptions on the drift coefficient. Our estimation procedure is based on the identification of the invariant measure, and we provide consistency results as well as some information about the convergence rate. We also give some examples of coefficients for which the identifiability assumption for the invariant measure is satisfied.

Derivatives play an important role in bandwidth selection methods (e.g., plug-ins), data analysis and bias-corrected confidence intervals. Therefore, obtaining accurate derivative information is crucial. Although many derivative estimation methods exist, the majority require a fixed design assumption. In this paper, we propose an effective and fully data-driven framework to estimate the first and second order derivative in random design. We establish the asymptotic properties of the proposed derivative estimator, and also propose a fast selection method for the tuning parameters. The performance and flexibility of the method is illustrated via an extensive simulation study.

Abbas Pak, M. E. Ghitany, Mohammad Reza Mahmoudi.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 4, 894--914.

Abstract:
This paper focuses on Bayesian estimation of the parameters and reliability function of the power Lindley distribution by using various symmetric and asymmetric loss functions. Assuming suitable priors on the parameters, Bayes estimates are derived by using squared error, linear exponential (linex) and general entropy loss functions. Since, under these loss functions, Bayes estimates of the parameters do not have closed forms we use lindley’s approximation technique to calculate the Bayes estimates. Moreover, we obtain the Bayes estimates of the parameters using a Markov Chain Monte Carlo (MCMC) method. Simulation studies are conducted in order to evaluate the performances of the proposed estimators under the considered loss functions. Finally, analysis of a real data set is presented for illustrative purposes.

Christian Olivera, Ciprian Tudor.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 3, 520--531.

Abstract:
Via a special transform and by using the techniques of the Malliavin calculus, we analyze the density of the solution to a stochastic differential equation with unbounded drift.

Rodrigo Citton P. dos Reis, Enrico A. Colosimo, Gustavo L. Gilardoni.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 2, 374--396.

Abstract:
In the data analysis from multiple repairable systems, it is usual to observe both different truncation times and heterogeneity among the systems. Among other reasons, the latter is caused by different manufacturing lines and maintenance teams of the systems. In this paper, a hierarchical model is proposed for the statistical analysis of multiple repairable systems under different truncation times. A reparameterization of the power law process is proposed in order to obtain a quasi-conjugate bayesian analysis. An empirical Bayes approach is used to estimate model hyperparameters. The uncertainty in the estimate of these quantities are corrected by using a parametric bootstrap approach. The results are illustrated in a real data set of failure times of power transformers from an electric company in Brazil.

A deep neural network has relieved the burden of feature engineering by human experts, but comparable efforts are instead required to determine an effective architecture. On the other hands, as the size of a network has over-grown, a lot of resources are also invested to reduce its size. These problems can be addressed by sparsification of an over-complete model, which removes redundant parameters or connections by pruning them away after training or encouraging them to become zero during training. In general, however, these approaches are not fully differentiable and interrupt an end-to-end training process with the stochastic gradient descent in that they require either a parameter selection or a soft-thresholding step. In this paper, we propose a fully differentiable sparsification method for deep neural networks, which allows parameters to be exactly zero during training, and thus can learn the sparsified structure and the weights of networks simultaneously using the stochastic gradient descent. We apply the proposed method to various popular models in order to show its effectiveness.