APOL1-Mediated Kidney Disease.

This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening and management.

Quantifying motional dynamics in nuclear magnetic resonance logging.

The motional dynamics of nuclear magnetic resonance (NMR) logging tools can significantly influence the measurement performance of such tools. NMR logging is used for geophysical evaluation in geological environments, primarily quantifying formation porosity and fluid volumes, as well as providing a qualitative estimation of permeability. NMR logging tools are conveyed via two main mechanisms; wireline logging and logging while drilling (LWD). We conduct detailed simulations to quantify the impact of tool motion on NMR measurements during logging. This involves conducting electromagnetic simulations which quantify the magnetic fields generated by a logging tool, and subsequently introducing motion profiles within the relevant spin dynamic calculations. This enables tool motional dynamics to be imposed on the signal acquisition. Several movement profiles are considered: linear axial movement to replicate wireline logging tool motion, as well as axial harmonic and lateral harmonic movement to simulate the shocks and vibrations experienced during logging while drilling. Lateral motion is observed to cause a greater degree of signal attenuation relative to axial motion due to the cylindrical shape of the excited volume. The magnitude of motion (e.g. the velocity of linear motion or the amplitude of harmonic motion) is demonstrated to increase the severity of signal attenuation, as expected. However, the frequency of harmonic motion demonstrates a more complex effect on the measured signal. The harmonic interaction between the motion frequency and measurement frequency (determined by the echo spacing) can cause wave interference which results in enhanced or diminished signal attenuation. Finally, we demonstrate that reducing both the magnetic field gradient as well as the echo spacing reduce the degree of signal attenuation observed during measurement. The results presented in this work demonstrate how the optimisation of key design parameters can be used to control the sensitivity of NMR logging tools towards motion.

Observational Study of Noninvasive Venous Waveform Analysis to Assess Intracardiac Filling Pressures During Right Heart Catheterization.

BACKGROUND: Outpatient monitoring and management of patients with heart failure (HF) reduces hospitalizations and health care costs. However, the availability of noninvasive approaches to assess congestion is limited. Noninvasive venous waveform analysis (NIVA) uses a unique physiologic signal, the morphology of the venous waveform, to assess intracardiac filling pressures. This study is a proof of concept analysis of the correlation between NIVA value and pulmonary capillary wedge pressure (PCWP) and the ability of the NIVA value to predict PCWP > 18 mmHg in subjects undergoing elective right heart catheterization (RHC). PCWP was also compared across common clinical correlates of congestion. METHODS AND RESULTS: A prototype NIVA device, which consists of a piezoelectric sensor placed over the skin on the volar aspect of the wrist, connected to a data-capture control box, was used to collect venous waveforms in 96 patients during RHC. PCWP was collected at end-expiration by an experienced cardiologist. The venous waveform signal was transformed to the frequency domain (Fourier transform), where a ratiometric algorithm of the frequencies of the pulse rate and its harmonics was used to derive a NIVA value. NIVA values were successfully captured in 83 of 96 enrolled patients. PCWP ranged from 4-40 mmHg with a median of 13 mmHg. NIVA values demonstrated a linear correlation with PCWP (r = 0.69, P < 0.05). CONCLUSIONS: This observational proof-of-concept study using a prototype NIVA device demonstrates a moderate correlation between NIVA value and PCWP in patients undergoing RHC. NIVA, thus, represents a promising developing technology for noninvasive assessment of congestion in spontaneously breathing patients.

Analyzing Learned Molecular Representations for Property Prediction.

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial data sets spanning a wide variety of chemical end points. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary data sets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.

Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.

Using Twitter Data to Gain Insights into E-cigarette Marketing and Locations of Use: An Infoveillance Study.

BACKGROUND: Marketing and use of electronic cigarettes (e-cigarettes) and other electronic nicotine delivery devices have increased exponentially in recent years fueled, in part, by marketing and word-of-mouth communications via social media platforms, such as Twitter. OBJECTIVE: This study examines Twitter posts about e-cigarettes between 2008 and 2013 to gain insights into (1) marketing trends for selling and promoting e-cigarettes and (2) locations where people use e-cigarettes. METHODS: We used keywords to gather tweets about e-cigarettes between July 1, 2008 and February 28, 2013. A randomly selected subset of tweets was manually coded as advertising (eg, marketing, advertising, sales, promotion) or nonadvertising (eg, individual users, consumers), and classification algorithms were trained to code the remaining data into these 2 categories. A combination of manual coding and natural language processing methods was used to indicate locations where people used e-cigarettes. Additional metadata were used to generate insights about users who tweeted most frequently about e-cigarettes. RESULTS: We identified approximately 1.7 million tweets about e-cigarettes between 2008 and 2013, with the majority of these tweets being advertising (93.43%, 1,559,508/1,669,123). Tweets about e-cigarettes increased more than tenfold between 2009 and 2010, suggesting a rapid increase in the popularity of e-cigarettes and marketing efforts. The Twitter handles tweeting most frequently about e-cigarettes were a mixture of e-cigarette brands, affiliate marketers, and resellers of e-cigarette products. Of the 471 e-cigarette tweets mentioning a specific place, most mentioned e-cigarette use in class (39.1%, 184/471) followed by home/room/bed (12.5%, 59/471), school (12.1%, 57/471), in public (8.7%, 41/471), the bathroom (5.7%, 27/471), and at work (4.5%, 21/471). CONCLUSIONS: Twitter is being used to promote e-cigarettes by different types of entities and the online marketplace is more diverse than offline product offerings and advertising strategies. E-cigarettes are also being used in public places, such as schools, underscoring the need for education and enforcement of policies banning e-cigarette use in public places. Twitter data can provide new insights on e-cigarettes to help inform future research, regulations, surveillance, and enforcement efforts.

In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo.

The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)- and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10(-7) M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy.

Low-frequency NMR with a non-resonant circuit.

Nuclear magnetic resonance typically utilizes a tuned resonance circuit with impedance matching to transmit power and receive signal. The efficiency of such a tuned coil is often described in terms of the coil quality factor, Q. However, in field experiments such as in well-logging, the circuit Q can vary dramatically throughout the depth of the wellbore due to temperature or fluid salinity variations. Such variance can result in erroneous setting of NMR circuit parameters (tuning and matching) and subsequent errors in measurements. This paper investigates the use of a non-resonant transmitter to reduce the circuit sensitivity on Q and demonstrates that such circuits can be efficient in delivering power and current to the coil. We also describe a tuned receiver circuit whose resonant frequency can be controlled digitally. Experimental results show that a range of common NMR experiments can be performed with our circuits.

The best of the best discourse on health: poetic insights on how professional sport socializes a family of men into hegemonic masculinity and physical inactivity.

This study examines how 4 men from the same family, representing different generations, construct health from their perceptions of professional athletes. Many men are socialized and participate in sport discourses that promote certain truths about being a man that often have detrimental effects to their health. The capacity of research to inform men's construction of health is limited. In an attempt to engage male participants within the research process and cause a form of catalytic validity, transcripts from interviews with the men were analyzed, and thematic findings were represented in a poetic form and shared with the participants for discussion and refinement. The findings revealed how the male participants reiterated messages that the media promotes, such as the importance of physical and mental strength for a man. More significantly, the men became aware that they assumed a narrow definition of health portrayed by professional athletics that perpetuated a hegemonic masculinity. Reflections on changes in the men's lifestyle choices after engaging in the research process are offered in the conclusion.