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AIM This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB). METHODS A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM 7.4. The probability of target attainment (PTA, PK/PD target: unbound (f) area-under-the-concentration-time-curve (AUC)/minimal inhibitory concentration (MIC) of 119) as well as a region-specific cumulative fraction of response (CFR) were estimated for different dosing regimens. RESULTS A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (interindividual variability 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h-1 (interoccasion variability 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily. CONCLUSION This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

Dysregulations in autonomic and endocrine stress responses are linked to the emergence of psychopathology in adolescence. However, most studies fail to consider the interplay between these systems giving rise to conflicting findings and a gap in understanding adolescent stress response regulation. A multisystem framework-investigation of parasympathetic (PNS), sympathetic (SNS), and hypothalamic pituitary adrenal (HPA) axis components and their coordination-is necessary to understand individual differences in stress response coordination which contribute to stress vulnerabilities. As the first investigation to comprehensively evaluate these three systems in adolescence, the current study employed the Trier Social Stress Test in 72 typically developing adolescents (mean age = 13) to address how PNS, SNS, and HPA stress responses are coordinated in adolescence. Hypotheses tested key predictions of the Adaptive Calibration Model (ACM) of stress response coordination. PNS and SNS responses were assessed via heart rate variability (HRV) and salivary alpha amylase (sAA) respectively. HPA responses were indexed by salivary cortisol. Analyses utilized piecewise growth curve modeling to investigate these aims. Supporting the ACM theory, there was significant hierarchical coordination between the systems such that those with low HRV had higher sAA and cortisol reactivity and those with high HRV had low-to-moderate sAA and cortisol responsivity. Our novel results reveal the necessity of studying multisystem dynamics in an integrative fashion to uncover the true mechanisms of stress response and regulation during development. Additionally, our findings support the existence of characteristic stress response profiles as predicted by the ACM model.

The recent surge in telemedicine during the COVID-19 pandemic has highlighted how imperative it is to understand: 1) how liver transplant (LT) recipients use smartphone technology, and 2) what they need in terms of remote support to assist with post-transplant recovery. Smartphone applications (i.e. apps) have been used in other chronic medical conditions to improve coordination of care, patient education, and medication adherence (1).

Fluorophobic-driven assemblies of gold nanomaterials were stabilized into water-dispersible fluorous supraparticles by the film-forming protein hydrophobin II. The strategy makes use of fluorous nanomaterials of different dimensions to engineer size and inner functionalization of the resulting confined space. The inner fluorous compartments allow efficient encapsulation and transport of high loadings of partially fluorinated drug molecules in water.

From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV‐mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.

[Image: see text] COVER ILLUSTRATION The surfaces depicted are study averages from the current sample, and the top images reflect the group differences in connectivity during task while the reflection (bottom images) reflect group differences in connectivity at rest.

Understanding the molecular mechanisms governing nanoparticle–membrane interactions is of prime importance for drug delivery and biomedical applications. Neutron reflectometry (NR) experiments are combined with atomistic and coarse‐grained molecular dynamics (MD) simulations to study the interaction between cationic gold nanoparticles (AuNPs) and model lipid membranes composed of a mixture of zwitterionic di‐stearoyl‐phosphatidylcholine (DSPC) and anionic di‐stearoyl‐phosphatidylglycerol (DSPG). MD simulations show that the interaction between AuNPs and a pure DSPC lipid bilayer is modulated by a free energy barrier. This can be overcome by increasing temperature, which promotes an irreversible AuNP incorporation into the lipid bilayer. NR experiments confirm the encapsulation of the AuNPs within the lipid bilayer at temperatures around 55 °C. In contrast, the AuNP adsorption is weak and impaired by heating for a DSPC–DSPG (3:1) lipid bilayer. These results demonstrate that both the lipid charge and the temperature play pivotal roles in AuNP–membrane interactions. Furthermore, NR experiments indicate that the (negative) DSPG lipids are associated with lipid extraction upon AuNP adsorption, which is confirmed by coarse‐grained MD simulations as a lipid‐crawling effect driving further AuNP aggregation. Overall, the obtained detailed molecular view of the interaction mechanisms sheds light on AuNP incorporation and membrane destabilization. © 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Background and Aim: The magnitude of the risk of incident type 2 diabetes (T2D) and metabolic syndrome (MetS) among patients with nonalcoholic fatty liver disease (NAFLD) is poorly known. We gauged the risk of developing T2D and MetS in patients with NAFLD diagnosed by either serum liver enzymes (aminotransferases or gamma-glutamyltransferase [GGT]) or ultrasonography. Methods: Pertinent prospective studies were identified through extensive electronic database research, and studies fulfilling enrolment criteria were included in the meta-analysis. Results Overall, in a pooled population of 117020 patients (from 20 studies), who were followed-up for a median period of 5 years (range: 3–14.7 years), NAFLD was associated with an increased risk of incident T2D with a pooled relative risk of 1.97 (95% confidence interval [CI], 1.80–2.15) for alanine aminotransferase, 1.58 (95% CI, 1.43–1.74) for aspartate aminotransferase, 1.86 (95% CI, 1.71–2.03) for GGT (last vs first quartile or quintile), and 1.86 (95% CI, 1.76–1.95) for ultrasonography, respectively. Overall, in a pooled population of 81411 patients (from eight studies) who were followed-up for a median period of 4.5 years (range: 3–11 years), NAFLD was associated with an increased risk of incident MetS with a pooled relative risk of 1.80 (95% CI, 1.72–1.89) for alanine aminotransferase (last vs first quartile or quintile), 1.98 (95% CI, 1.89–2.07) for GGT, and 3.22 (95% CI, 3.05–3.41) for ultrasonography, respectively. Conclusions: Nonalcoholic fatty liver disease, as diagnosed by either liver enzymes or ultrasonography, significantly increases the risk of incident T2D and MetS over a median 5-year follow-up.

Objectives To investigate the prevalence of REM sleep behavior disorder (RBD) in patients with inflammatory arthritis (IA) to ascertain if RBD could be an internal red flag signaling a fluctuating state of inflammation based on the theory of “protoconsciousness”. Materials & Methods One hundred and three patients with a confirmed diagnosis of IA were consecutively recruited. The patients underwent general (IA activity, functional status, laboratory tests) and neurological evaluations. A neurologist investigated RBD and REM sleep parasomnias in a semi‐structured interview. Sleep quality was assessed with the Pittsburgh Sleep Quality Index, while the risk of obstructive sleep apnea syndrome (OSAS) was evaluated with the Berlin questionnaire. Beck Depression Inventory II and State‐Trait Anxiety Inventory investigated depression and anxiety. Results Patients had a mean age of 53.7 ± 14.6 years, 65% were women; 57.3% were in a clinically active phase of IA. Two women fulfilled ICSD‐3 criteria for RBD appearing 11 years after and 20 years before IA onset respectively. 31 patients scored positive for nightmare disorder (ND), 8 for recurrent isolated sleep paralysis. 65 (63.1%) patients reported poor sleep quality and 25 (24.3%) resulted at high risk for OSAS. 32 (31.0%) patients scored positively for depression or anxiety. Conclusions The prevalence of RBD in patients with IA did not differ from that in the general population, whereas ND presented a 2‐fold increased prevalence. Whether RBD can be considered a red flag signaling an internal danger remains an open question, while ND may be a new player in this intriguing relation.

Purpose The aim of this study was to evaluate whether upfront cellular enrichment via laser capture microdissection (LCM) is necessary for accurately quantifying predictive biomarkers in nonsmall cell lung cancer tumors. Experimental design Fifteen snap frozen surgical biopsies were analyzed. Whole tissue lysate and matched highly enriched tumor epithelium via LCM were obtained for each patient. The expression and activation/phosphorylation levels of 26 proteins were measured by reverse phase protein microarray. Differences in signaling architecture of dissected and undissected matched pairs were visualized using unsupervised clustering analysis, bar graphs, and scatter plots. Results Overall patient matched LCM and undissected material displayed very distinct and differing signaling architectures with 93% of the matched pairs clustering separately. These differences were seen regardless of the amount of starting tumor epithelial content present in the specimen. Conclusions and clinical relevance These results indicate that LCM driven upfront cellular enrichment is necessary to accurately determine the expression/activation levels of predictive protein signaling markers although results should be evaluated in larger clinical settings. Upfront cellular enrichment of the target cell appears to be an important part of the workflow needed for the accurate quantification of predictive protein signaling biomarkers. Larger independent studies are warranted.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations. Hum Brain Mapp 35:4064–4078, 2014. © 2014 Wiley Periodicals, Inc.

In eukaryotic cells, pre-mRNAs undergo several transformation steps to generate mature mRNAs ready to be exported to the cytoplasm. The molecular and structural apparatus for mRNA production is generally able to promptly respond to variations of metabolic demands. Hibernating mammals, which periodically enter a hypometabolic state, represent an interesting physiological model to investigate the adaptive morpho-functional modifications of the pre-mRNA transcriptional and processing machinery under extreme metabolic conditions. In this study, the subnuclear distribution of some transcriptional, splicing, and cleavage factors was investigated by ultrastructural immunocytochemistry in cell nuclei of the liver (a highly metabolizing organ involved in multiple regulatory functions) and the brown adipose tissue (responsible for nonshivering thermogenesis) from euthermic, hibernating, and arousing hazel dormice (Muscardinus avellanarius). Our observations demonstrate that, during hibernation, transcriptional activity significantly decreases and pre-mRNA processing factors undergo an intranuclear redistribution moving to domains usually devoid of such molecules; moreover, in hepatocytes, there is a preferential accumulation of pre-mRNAs at the splicing stage, whereas, in brown adipocytes, pre-mRNAs are mainly stored at the cleavage stage. Upon arousal, the pre-mRNAs at the cleavage stage are immediately utilized, while the maturation of pre-mRNAs at the splicing stage seems to be restored before transcription had taken place. Our data suggest a programmed intranuclear reorganization of the RNA maturation machinery aimed at efficiently and rapidly restoring the pre-mRNA processing, and, consequently, the specific cellular activities upon arousal. Once again natural hibernation appears as a highly programmed hypometabolic state rather than a simple fall of metabolic and physiological functions. Microsc. Res. Tech., 2008. © 2008 Wiley-Liss, Inc.