The influence of anthropogenic regulation and evaporite dissolution on earthquake-triggered ground failure.

Remote sensing observations of Searles Lake following the 2019 moment magnitude 7.1 Ridgecrest, California, earthquake reveal an area where surface ejecta is arranged in a repeating hexagonal pattern that is collocated with a solution-mining operation. By analyzing geologic and geotechnical data, here we show that the hexagonal surface ejecta is likely not a result of liquefaction. Instead, we propose dissolution cavity collapse (DCC) as an alternative driving mechanism. We support this theory with pre-event Interferometric Synthetic Aperture Radar data, which reveals differential subsidence patterns and the creation of subsurface void space. We also find that DCC is likely triggered at a lower shaking threshold than classical liquefaction. This and other unknown mechanisms can masquerade as liquefaction, introducing bias into liquefaction prediction models that rely on liquefaction inventories. This paper also highlights the opportunities and drawbacks of using remote sensing data to disentangle the complex factors that influence earthquake-triggered ground failure.

Initiation of combined antiretroviral therapy confers suboptimal beneficial effects on neurovascular function in people with HIV.

Introduction: Due to advances in combined anti-retroviral treatment (cART), there is an increased burden of age-related cerebrovascular disease (CBVD), in people living with HIV (PWH). The underlying CNS injury can be assessed by measuring cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Methods: 35 treatment-naïve PWH and 53 HIV negative controls (HC) were enrolled in this study. Study participants underwent T1-weighted anatomical, pseudo-continuous arterial spin labeling, and resting-state functional MRI to obtain measures of CBF and CVR prior to starting cART treatment and at two-time points (12 weeks and 2 years) post-cART initiation. Controls were scanned at the baseline and 2-year visits. We also measured plasma levels of microparticles of endothelial and glial origin and well-known endothelial inflammation markers, ICAM-1 and VCAM-1, to assess HIV-associated endothelial inflammation and the interaction of these peripheral markers with brain neurovascular function. Results: HIV infection was found to be associated with reduced CVR and increased levels of endothelial and glial microparticles (MPs) prior to initiation of cART. Further, CVR correlated negatively with peripheral MP levels in PWH. Discussion: Our results suggest that while cART treatment has a beneficial effect on the neurovascular function after initiation, these benefits are suboptimal over time.

Brain iron imaging markers in the presence of white matter hyperintensities.

PURPOSE: To investigate the relationship between pathological brain iron deposition and white matter hyperintensities (WMHs) in cerebral small vessel disease (CSVD), via Monte Carlo simulations of magnetic susceptibility imaging and the development of a novel imaging marker called the Expected Iron Coefficient (EIC). METHODS: A synthetic pathological model of a different number of impenetrable spheres at random locations was employed to represent pathological iron deposition. The diffusion process was simulated with a Monte Carlo method with adjustable parameters to manipulate sphere size, distribution, and extracellular properties. Quantitative susceptibility mapping (QSM) was performed in a clinical dataset to study CSVD to derive and evaluate QSM, R2*, the iron microenvironment coefficient (IMC), and the EIC in the presence of WMHs. RESULTS: The simulations show that QSM signals increase in the presence of increased tissue iron, confirming that the EIC increases with pathology. Clinical results demonstrate that while QSM, R2*, and the IMC do not show significant differences in brain iron, the EIC does in the context of CSVD. CONCLUSION: The EIC is more sensitive to subtle changes in brain iron deposition caused by pathology, even when QSM, R2*, and the IMC fail.

Bypassing evolutionary dead ends and switching the rate-limiting step of a human immunotherapeutic enzyme.

The Trp metabolite kynurenine (KYN) accumulates in numerous solid tumours and mediates potent immunosuppression. Bacterial kynureninases (KYNases), which preferentially degrade kynurenine, can relieve immunosuppression in multiple cancer models, but immunogenicity concerns preclude their clinical use, while the human enzyme (HsKYNase) has very low activity for kynurenine and shows no therapeutic effect. Using fitness selections, we evolved a HsKYNase variant with 27-fold higher activity, beyond which exploration of >30 evolutionary trajectories involving the interrogation of >109 variants led to no further improvements. Introduction of two amino acid substitutions conserved in bacterial KYNases reduced enzyme fitness but potentiated rapid evolution of variants with ~500-fold improved activity and reversed substrate specificity, resulting in an enzyme capable of mediating strong anti-tumour effects in mice. Pre-steady-state kinetics revealed a switch in rate-determining step attributable to changes in both enzyme structure and conformational dynamics. Apart from its clinical significance, our work highlights how rationally designed substitutions can potentiate trajectories that overcome barriers in protein evolution.

Leveraging intrinsic flexibility to engineer enhanced enzyme catalytic activity.

Dynamic motions of enzymes occurring on a broad range of timescales play a pivotal role in all steps of the reaction pathway, including substrate binding, catalysis, and product release. However, it is unknown whether structural information related to conformational flexibility can be exploited for the directed evolution of enzymes with higher catalytic activity. Here, we show that mutagenesis of residues exclusively located at flexible regions distal to the active site of Homo sapiens kynureninase (HsKYNase) resulted in the isolation of a variant (BF-HsKYNase) in which the rate of the chemical step toward kynurenine was increased by 45-fold. Mechanistic pre­steady-state kinetic analysis of the wild type and the evolved enzyme shed light on the underlying effects of distal mutations (>10 Å from the active site) on the rate-limiting step of the catalytic cycle. Hydrogen-deuterium exchange coupled to mass spectrometry and molecular dynamics simulations revealed that the amino acid substitutions in BF-HsKYNase allosterically affect the flexibility of the pyridoxal-5'-phosphate (PLP) binding pocket, thereby impacting the rate of chemistry, presumably by altering the conformational ensemble and sampling states more favorable to the catalyzed reaction.

Risk Mitigation of Pacemaker Pocket Erosion in Thin Patients.

The aging population, particularly the thin and frail, has an increased risk of long-term cardiac implantable electronic device complications. This case is that of an elderly, thin-skinned patient who presented with a pacemaker pocket erosion 4 years after elective generator change, potentiated by a small pocket size with a superficial suture fixating the generator in the subcutaneous pocket. The risk for device erosion may have been mitigated during the generator change by increasing the size of the pocket, using a submuscular pocket, and potentially an absorbable antibacterial envelope. Fixation of the generator is considered optional.

Le risque de complications liées aux dispositifs électroniques cardiaques implantables est plus grand à long terme au sein de la population vieillissante, particulièrement chez les personnes minces et fragiles. Nous présentons ici le cas d'un patient âgé, à la peau fine, qui, quatre ans après le remplacement non urgent du générateur de son stimulateur cardiaque, a présenté une érosion de la loge du boîtier aggravée par la petite taille de celle-ci. Une suture superficielle fixait le générateur dans la loge sous-cutanée. Le risque d'érosion de la loge du boîtier aurait pu être atténué par l'augmentation de la taille de la loge lors du remplacement du générateur, par le recours à une loge sous-musculaire, et peut-être par l'utilisation d'une enveloppe antibactérienne résorbable. La fixation du générateur est jugée facultative.

Clinical electrophysiology of the aging heart.

INTRODUCTION: Advancements in medical and consumer-grade technologies have made it easier than ever to monitor a patient's heart rhythm and to diagnose arrhythmias. Octogenarians with symptomatic arrhythmias have unique management challenges due to their frailty, complex drug interactions, cognitive impairment, and competing comorbidities. The management decisions are further complicated by the lack of randomized evidence to guide treatment. AREAS COVERED: A comprehensive literature review was undertaken to outline various tachyarrhythmias and bradyarrhythmias and their management, the role of cardiac implantable electronic devices, cardiac ablations, and specific geriatric arrhythmia considerations as recommended in international guidelines. EXPERT OPINION: Atrial fibrillation (AF) is arguably the most important arrhythmia in the elderly and is associated with significant morbidity and mortality. Early diagnosis of AF, potentially with smart devices (wearables), has the potential to reduce the incidence of stroke, systemic emboli, and the risk of dementia. Bradyarrhythmias have a high incidence in the elderly as well, often requiring implantation of a permanent pacemaker. Leadless pacemakers implanted directly into the right ventricle are great options for gaining traction in elderly patients.

Increased risk for cerebral small vessel disease is associated with quantitative susceptibility mapping in HIV infected and uninfected individuals.

The aim of this study was to assess, in the context of cerebral small vessel disease (CSVD), whether cardiovascular risk factors and white matter hyperintensities (WMHs) were associated with brain tissue susceptibility as measured by quantitative susceptibility mapping (QSM). Given that CSVD is diagnosed by the presence of lacunar strokes, periventricular and deep WMHs, increased perivascular spaces, and microbleeds, we expected that QSM could capture changes in brain tissue due to underlying CSVD pathology. We compared a cohort of 101 HIV-infected individuals (mean age ± SD = 53.2 ± 10.9 years) with mild to moderate cardiovascular risk scores, as measured by the Reynolds risk score, to 102 age-matched controls (mean age (SD) = 50.3 (15.7) years) with similar Reynolds scores. We performed brain MRI to assess CSVD burden by acquiring 3D T1-MPRAGE, 3D FLAIR, 2D T2-TSE, and mGRE for QSM. We found that signs of CSVD are significantly higher in individuals with HIV-infection compared to controls and that WMH volumes are significantly correlated with age and cardiovascular risk scores. Regional QSM was associated with cardiovascular risk factors, age, sex, and WMH volumes but not HIV status. These results suggest that QSM may be an early imaging marker reflective of alterations in brain microcirculation.

Surface-Based Connectivity Integration: An atlas-free approach to jointly study functional and structural connectivity.

There has been increasing interest in jointly studying structural connectivity (SC) and functional connectivity (FC) derived from diffusion and functional MRI. Previous connectome integration studies almost exclusively required predefined atlases. However, there are many potential atlases to choose from and this choice heavily affects all subsequent analyses. To avoid such an arbitrary choice, we propose a novel atlas-free approach, named Surface-Based Connectivity Integration (SBCI), to more accurately study the relationships between SC and FC throughout the intra-cortical gray matter. SBCI represents both SC and FC in a continuous manner on the white surface, avoiding the need for prespecified atlases. The continuous SC is represented as a probability density function and is smoothed for better facilitation of its integration with FC. To infer the relationship between SC and FC, three novel sets of SC-FC coupling (SFC) measures are derived. Using data from the Human Connectome Project, we introduce the high-quality SFC measures produced by SBCI and demonstrate the use of these measures to study sex differences in a cohort of young adults. Compared with atlas-based methods, this atlas-free framework produces more reproducible SFC features and shows greater predictive power in distinguishing biological sex. This opens promising new directions for all connectomics studies.

Mitochondrial toxicity before and after combination antiretroviral therapy, a Magnetic Resonance Spectroscopy study.

The aim of this study was to quantify, via Magnetic Resonance Spectroscopy (MRS), the effect of combination antiretroviral therapy (cART) on brain metabolites and characterize any possible associations between changes in metabolites, age, blood biomarkers of neuronal damage, functional connectivity and cognitive performance. As cART has dramatically increased the life expectancy of HIV-infected (HIV + ) individuals and unmasked an increase in HIV-associated neurocognitive disorders, it is still not clear whether cART neurotoxicity contributes to these disorders. We hypothesized a bimodal effect, with early cART treatment of HIV infection decreasing inflammation as measured by MRS metabolites and improving cognitive performance, and chronic exposure to cART contributing to persistence of cognitive impairment via its effect on mitochondrial function. Basal ganglia metabolites, functional connectivity, cognitive scores, as well as plasma levels of neurofilament light chain (NfL) and tau protein were measured before and after 12 weeks, 1 year and 2 years of cART in a cohort of 50 cART-naïve HIV + subjects and 72 age matched HIV- healthy controls. Glutamate (Glu) levels were lower in the cART naïve patients than in healthy controls and were inversely correlated with plasma levels of NfL. There were no other significant metabolite differences between HIV + and uninfected individuals. Treatment improved Glu levels in HIV+, however, no associations were found between Glu, functional connectivity and cognitive performance. Stable brain metabolites and plasma levels of NfL and Tau over two-years of follow-ups suggest there are no signs of cART neurotoxicity in this relatively young cohort of HIV + individuals.

A longitudinal analysis of brain extracellular free water in HIV infected individuals.

Initiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to HIV-uninfected (HIV-) individuals at baseline. These increased FW values positively correlated with neurofilament light chain (NfL) and negatively correlated with CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV- cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL, and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections.

INTRODUCTION: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs. METHODS: This was a retrospective cohort study of adult patients treated with ≥72 hours of VAN for MRSA cSSTI from 2008 to 2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as (1) resolution of signs and symptoms of infection within 72 hours, (2) stabilization and/or reduction in lesion size, (3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome. RESULTS: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group versus 52.5% in the below-target AUC group, (P = .013). Target-AUC attainment was independently associated with increased odds of TCS (adjusted odds ratio [aOR], 2.208; 95% confidence interval [CI], 1.047-4.659). CONCLUSIONS: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warranted for patients at high risk of VAN failure or VAN-associated toxicity.

Conformational Dynamics Contribute to Substrate Selectivity and Catalysis in Human Kynureninase.

Kynureninases (KYNases) are enzymes that play a key role in tryptophan catabolism through the degradation of intermediate kynurenine and 3'-hydroxy-kynurenine metabolites (KYN and OH-KYN, respectively). Bacterial KYNases exhibit high catalytic efficiency toward KYN and moderate activity toward OH-KYN, whereas animal KYNases are highly selective for OH-KYN, exhibiting only minimal activity toward the smaller KYN substrate. These differences reflect divergent pathways for KYN and OH-KYN utilization in the respective kingdoms. We examined the Homo sapiens and Pseudomonas fluorescens KYNases (HsKYNase and PfKYNase respectively) using pre-steady-state and hydrogen-deuterium exchange mass spectrometry (HDX-MS) methodologies. We discovered that the activity of HsKYNase critically depends on formation of hydrogen bonds with the hydroxyl group of OH-KYN to stabilize the entire active site and allow productive substrate turnover. With the preferred OH-KYN substrate, stabilization is observed at the substrate-binding site and the region surrounding the PLP cofactor. With the nonpreferred KYN substrate, less stabilization occurs, revealing a direct correlation with activity. This correlation holds true for PfKYNases; however there is only a modest stabilization at the substrate-binding site, suggesting that substrate discrimination is simply achieved by steric hindrance. We speculate that eukaryotic KYNases use dynamic mobility as a mechanism of substrate specificity to commit OH-KYN to nicotinamide synthesis and avoid futile hydrolysis of KYN. These findings have important ramifications for the engineering of HsKynase with high KYN activity as required for clinical applications in cancer immunotherapy. Our study shows how homologous enzymes with conserved active sites can use dynamics to discriminate between two highly similar substrates.

Bioenergy from biofuel residues and waste.

This article is a review of the scientific literature published in 2019 on topics relating to bioenergy from biofuel residues and waste. This literature review is divided into the following sections: Feedstocks, Biodiesel, Bioethanol, Hydrogen, Biohydrogen, Biofuel Residues, Microalgae, and Lignocelluloses.

Distributed treatment systems.

This section presents a review of the scientific literature published in 2019 on topics relating to distributed treatment systems. This review is divided into the following sections: constituent removal, treatment technologies, planning and treatment management, and other topics. PRACTITIONER POINTS: Highlights changes and innovation in removal techniques and technologies in water treatment. Reviews management systems of distributed treatment systems. Discusses point-of-use treatment systems.

A Multicenter Evaluation of Vancomycin-Associated Acute Kidney Injury in Hospitalized Patients with Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: We sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI). METHODS: Retrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria. RESULTS: In total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929-11.499), no medical insurance (aOR 3.451, 95% CI 1.310-9.090), ICU residence (aOR 4.398, 95% CI 1.676-11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158-7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037-1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days, p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%, p < 0.001) and increased all-cause 30-day mortality (5.1 vs. 0.3%, p = 0.024) CONCLUSIONS: V-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy.

Pathomechanisms of HIV-Associated Cerebral Small Vessel Disease: A Comprehensive Clinical and Neuroimaging Protocol and Analysis Pipeline.

Rationale: We provide an in-depth description of a comprehensive clinical, immunological, and neuroimaging study that includes a full image processing pipeline. This approach, although implemented in HIV infected individuals, can be used in the general population to assess cerebrovascular health. Aims: In this longitudinal study, we seek to determine the effects of neuroinflammation due to HIV-1 infection on the pathomechanisms of cerebral small vessel disease (CSVD). The study focuses on the interaction of activated platelets, pro-inflammatory monocytes and endothelial cells and their impact on the neurovascular unit. The effects on the neurovascular unit are evaluated by a novel combination of imaging biomarkers. Sample Size: We will enroll 110 HIV-infected individuals on stable combination anti-retroviral therapy for at least three months and an equal number of age-matched controls. We anticipate a drop-out rate of 20%. Methods and Design: Subjects are followed for three years and evaluated by flow cytometric analysis of whole blood (to measure platelet activation, platelet monocyte complexes, and markers of monocyte activation), neuropsychological testing, and brain MRI at the baseline, 18- and 36-month time points. MRI imaging follows the recommended clinical small vessel imaging standards and adds several advanced sequences to obtain quantitative assessments of brain tissues including white matter microstructure, tissue susceptibility, and blood perfusion. Discussion: The study provides further understanding of the underlying mechanisms of CSVD in chronic inflammatory disorders such as HIV infection. The longitudinal study design and comprehensive approach allows the investigation of quantitative changes in imaging metrics and their impact on cognitive performance.

The impact of chemically enhanced primary treatment on the downstream liquid and solid train processes.

The use of chemical coagulants and flocculants to supplement chemically enhanced primary treatment (CEPT) processes is increasing in popularity as it has been demonstrated to improve carbon redirection and suspended solids and phosphorus removal. Dosing 15 mg ferric chloride/L of wastewater and poly aluminum chloride (PACl; 0.5 mg/L) to the influent of a primary clarifier successfully achieved improved carbon redirection and suspended solids removal at a full-scale WWTP. In this study, the impacts of PACl on the downstream liquid and solid train processes of the same WWTP were investigated. Compared to FeCl3 addition, a combined PACl and FeCl3 addition to the primary influent reduced the TSS and TP concentrations of the secondary clarifier effluent by 20% and 33%, respectively. Effluent BOD5 and ammonia-nitrogen concentrations of the downstream activated sludge process were not affected by the addition of a combined FeCl3 and PACl in the primary clarifier. PACl addition affects the bioavailability of carbon and hence reduced the methane production efficiency of the primary sludge by 20%-30%. However, the significant amount of carbon concentrated in the CEPT sludge would enhance the amount of energy recovered through incineration. PRACTITIONER POINTS: The chemically enhanced primary treatment process is an attractive method for carbon redirection and energy recovery. The combined FeCl3 and PACl addition in the primary clarifier improves the full scale activated sludge process effluent quality. PACl has a negative effect on methane production.

Distributed treatment systems.

This section presents a review of the scientific literature published in 2018 on topics relating to distributed treatment systems. This review is divided into the following sections: constituent removal, treatment technologies, planning and treatment management, and other topics.