bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updates on antiviral drugs for cytomegalovirus prevention and treatment
Authors: Kotton Camille N. 
Published: June 2019

Purpose of review
Cytomegalovirus (CMV) is the most common infection after organ transplant. In addition to causing a viral syndrome and infection, it also increases the risk for complications in the organ transplant, along with higher overall morbidity and mortality. Prevention and ideal treatment of CMV is paramount for optimal outcomes, both for individuals as well as for transplant programs. New guidelines and novel therapies are changing the way we manage disease.

Recent findings
Several new antiviral agents have emerged in recent times, including letermovir, maribavir, and brincidofovir, enhancing our ability to prevent and treat CMV. Recent data on novel agents will be reviewed, with an emphasis on recent guidelines and best practices.

Summary
Optimal treatment, influenced by recent advances in the field, including management of resistant virus, results in better outcomes with this significant and virulent virus.
Antimicrobials and Antiepileptics Are the Leading Causes of Idiosyncratic Drug‐induced Liver Injury in American Children
Authors: DiPaola Frank , Molleston Jean P. , Gu Jiezhun , Cirulli Elizabeth T. , Chalasani Naga , Barnhart Huiman , Kleiner David E. , Hoofnagle Jay H. , Fontana Robert J. ,   US Drug Induced Liver Injury Network
Published: June 2019

ABSTRACTObjectives:The aim of this study was to provide an overview of the presenting features, etiologies, and outcomes of children enrolled in the Drug‐induced Liver Injury Network (DILIN) prospective and retrospective studies.Methods:Consecutive definite, highly likely, or probable cases in children enrolled into the ongoing DILIN prospective and retrospective studies between September 2004 and February 2017 were reviewed.Results:Fifty‐seven cases were adjudicated as definite (14), highly likely (30), or probable (13) DILI. Median age was 14.3 years (1.7–17.9), 67% female, and 82% Caucasian. At DILI onset, 82% had hepatocellular injury with a median alanine aminotransferase of 411 U/L (33–4185), alkaline phosphatase 203 U/L (62–1177), and total bilirubin 3.3 mg/dL (0.2–33.9). The median duration of suspect medication use was 55 days (1–2789) and the most frequently implicated individual agents were minocycline (n = 11) and valproate (n = 6). Sixty‐three percent were hospitalized and 3 (5%) underwent liver transplant within 1 month of DILI onset. Among 46 children followed for at least 6 months, 8 (17%) met criteria for chronic DILI with 6 of them having persistent liver injury at 24 months of follow‐up. A genome‐wide association study in 39 Caucasian children focusing on regions associated with pediatric cholestatic liver disease failed to demonstrate any single nucleotide polymorphism associated with DILI susceptibility or outcome.Conclusions:Antimicrobials (51%) and antiepileptic drugs (21%) are the most frequently implicated agents in pediatric DILI patients. Although the majority of cases are self‐limited, there is potential for serious morbidity including acute liver failure, chronic liver injury, and death.
Changes in Anesthetic and Postoperative Sedation–Analgesia Practice Associated With Early Extubation Following Infant Cardiac Surgery: Experience From the Pediatric Heart Network Collaborative Learning Study*
Authors: Amula Venu , Vener David F. , Pribble Charles G. , Riegger Lori , Wilson Elizabeth C. , Shekerdemian Lara S. , Ou Zhining , Presson Angela P. , Witte Madolin K. , Nicolson Susan C. 
Published: June 2019

Objectives:
The Pediatric Heart Network sponsored the multicenter Collaborative Learning Study that implemented a clinical practice guideline to facilitate early extubation in infants after repair of isolated coarctation of the aorta and tetralogy of Fallot. We sought to compare the anesthetic practice in the operating room and sedation-analgesia management in the ICU before and after the implementation of the guideline that resulted in early extubation.

Design:
Secondary analysis of data from a multicenter study from January 2013 to April 2015. Predefined variables of anesthetic, sedative, and analgesia exposure were compared before and after guideline implementation. Propensity score weighted logistic regression analysis was used to determine the independent effect of intraoperative dexmedetomidine administration on early extubation.

Setting:
Five children’s hospitals.

Patients:
A total of 240 study subjects who underwent repair of coarctation of the aorta or tetralogy of Fallot (119 preguideline implementation and 121 postguideline implementation).

Interventions:
None.

Measurements and Main Results:
Clinical practice guideline implementation was accompanied by a decrease in the median total intraoperative dose of opioids (49.7 vs 24.0 µg/kg of fentanyl equivalents, p < 0.001) and benzodiazepines (1.0 vs 0.4 mg/kg of midazolam equivalents, p < 0.001), but no change in median volatile anesthetic agent exposure (1.3 vs 1.5 minimum alveolar concentration hr, p = 0.25). Intraoperative dexmedetomidine administration was associated with early extubation (odds ratio 2.5, 95% CI, 1.02–5.99, p = 0.04) when adjusted for other covariates. In the ICU, more patients received dexmedetomidine (43% vs 75%), but concomitant benzodiazepine exposure decreased in both the frequency (66% vs 57%, p < 0.001) and cumulative median dose (0.5 vs 0.3 mg/kg of ME, p = 0.003) postguideline implementation.

Conclusions:
The implementation of an early extubation clinical practice guideline resulted in a reduction in the dose of opioids and benzodiazepines without a change in volatile anesthetic agent used in the operating room. Intraoperative dexmedetomidine administration was independently associated with early extubation. The total benzodiazepine exposure decreased in the early postoperative period.
Detrimental Effects of Psychotropic Medications Differ by Sex in Aging People With HIV
Authors: Mathur Swati , Roberts-Toler Carla , Tassiopoulos Katherine , Goodkin Karl , McLaughlin Milena , Bares Sara , Koletar Susan L. , Erlandson Kristine M. ,   for the ACTG A5322 Study Team
Published: June 2019

Background:
Mental health conditions are common among persons with HIV (PWH). An understanding of factors associated with prescription medication use for these conditions and clinical impact of the prescription medications may improve care of mental health disorders in PWH.

Methods:
Psychotropic medication use was examined among PWH within the AIDS Clinical Trials Group A5322 (HAILO) study. Multivariable logistic models and Cox regression models estimated the association between psychotropic medications (any/none) with baseline and incident slow gait (>1 s/m) and neurocognitive impairment (NCI) for more than 4 years.

Results:
Of 1035 participants, the median age was 51 years.81% were men, 30% black, non-Hispanic, and 20% Hispanic. Psychotropic medication use was similar between men (34%) and women (38%; P = 0.19). PWH using psychotropic medications had greater odds of baseline slow gait {odds ratio 1.61, [95% confidence interval (CI): 1.23 to 2.10]; P < 0.001}. Men but not women using psychotropic medications had an increased risk of developing slow gait [hazard ratio 1.85; (1.29 to 2.65) vs 0.77; (CI: 0.35 to 1.68), P interaction = 0.045]. The sex-specific odds ratios for medication use and NCI were qualitatively but not statistically different [men: 1.79; (1.14–2.80); women: 1.27; (0.56–2.90); P interaction = 0.47]. Psychotropic medication use was associated with an increased risk of incident NCI [hazard ratio 2.18; (95% CI: 1.23 to 3.84), P = 0.007] in both men and women.

Conclusions:
Psychotropic medications are associated with impairment in functional outcomes of aging, with a greater risk of baseline NCI and incident slow gait among men. Further investigation is needed to optimize outcomes in PWH and prescription of psychotropic medications among both men and women.
Is a Postvoid Residual Necessary? A Randomized Trial of Two Postoperative Voiding Protocols
Authors: Willis-Gray Marcella G. , Wu Jennifer M. , Field Christine , Pulliam Samantha , Husk Katherine E. , Brueseke Taylor J. , Geller Elizabeth J. , Connolly AnnaMarie , Dieter Alexis A. 
Published: June 2019

Objectives
This study aimed to compare a backfill-assisted voiding trial (VT) with and without a postvoid residual (PVR) after pelvic reconstructive surgery.

Methods
This was a nonblinded randomized controlled trial of women undergoing pelvic organ prolapse and/or stress incontinence surgery. Participants were randomized immediately after surgery to either a PVR VT or a PVR-free VT. Our primary outcome was the rate of VT failure at discharge. Secondary outcomes included days of catheterization, urinary tract infection (UTI), and prolonged voiding dysfunction. With a power of 80% and an α of 0.05, we needed 126 participants to detect a 25% difference in VT failure (60% in PVR VT vs 35% in PVR-free VT).

Results
Participants were enrolled from March 2017 to October 2017. Of the 150 participants, mean age was 59 years, and 33% underwent vaginal hysterectomy, 48% underwent anterior repair, and 75% underwent midurethral sling. Seventy-five (50%) were randomized to PVR VT and 75 (50%) to PVR-free VT, with no differences in baseline demographic or intraoperative characteristics between the 2 groups. Our primary outcome, VT failure, was not significantly different (53% PVR VT vs 53% PVR-free VT, P = 1.0). There were no significant differences in days of postoperative catheterization (1 [0, 4] in PVR VT vs 1 [0, 4] in PVR-free VT, P = 0.90), UTI (20% PVR VT vs 20% PVR-free VT, P = 1.0), or postoperative voiding dysfunction (4% PVR VT vs 5% PVR-free VT, P = 1.0).

Conclusions
When performing a backfill-assisted VT, checking a PVR does not affect VT failure, postoperative duration of catheterization, UTI, or voiding dysfunction.
Gabapentin and Memantine for Treatment of Acquired Pendular Nystagmus: Effects on Visual Outcomes
Authors: Nerrant Elodie , Abouaf Lucie , Pollet-Villard Frédéric , Vie Anne-Laure , Vukusic Sandra , Berthiller Julien , Colombet Bettina , Vighetto Alain , Tilikete Caroline 
Published: June 2019

Background:The most common causes of acquired pendular nystagmus (APN) are multiple sclerosis (MS) and oculopalatal tremor (OPT), both of which result in poor visual quality of life. The objective of our study was to evaluate the effects of memantine and gabapentin treatments on visual function. We also sought to correlate visual outcomes with ocular motor measures and to describe the side effects of our treatments.Methods:This study was single-center cross-over trial. A total of 16 patients with chronic pendular nystagmus, 10 with MS and 6 with OPT were enrolled. Visual acuity (in logarithm of the minimum angle of resolution [LogMAR]), oscillopsia amplitude and direction, eye movement recordings, and visual function questionnaires (25-Item National Eye Institute Visual Functioning Questionnaire [NEI-VFQ-25]) were performed before and during the treatments (gabapentin: 300 mg 4 times a day and memantine: 10 mg 4 times a day).Results:A total of 29 eyes with nystagmus were evaluated. Median near monocular visual acuity improved in both treatment arms, by 0.18 LogMAR on memantine and 0.12 LogMAR on gabapentin. Distance oscillopsia improved on memantine and on gabapentin. Median near oscillopsia did not significantly change on memantine or gabapentin. Significant improvement in ocular motor parameters was observed on both treatments. Because of side effects, 18.8% of patients discontinued memantine treatment—one of them for a serious adverse event. Only 6.7% of patients discontinued gabapentin. Baseline near oscillopsia was greater among those with higher nystagmus amplitude and velocity.Conclusions:This study demonstrated that both memantine and gabapentin reduce APN, improving functional visual outcomes. Gabapentin showed a better tolerability, suggesting that this agent should be used as a first-line agent for APN. Data from our investigation emphasize the importance of visual functional outcome evaluations in clinical trials for APN.
Discovering precise temporal patterns in large-scale neural recordings through robust and interpretable time warping
Authors: Williams Alex H. , Poole Ben , Maheswaranathan Niru , Dhawale Ashesh K. , Fisher Tucker , Wilson Christopher D. , Brann David H. , Trautmann Eric , Ryu Stephen , Shusterman Roman , Rinberg Dmitry , Ölveczky Bence P. , Shenoy Krishna V. , Ganguli Surya 
Published: June 2019

AbstractThough the temporal precision of neural computation has been studied intensively, a data-driven determination of this precision remains a fundamental challenge. Reproducible spike time patterns may be obscured on single trials by uncontrolled temporal variability in behavior and cognition, or may not even be time locked to measurable signatures in either behavior or local field potentials (LFP). To overcome these challenges, we describe a general-purpose time warping framework that reveals precise spike-time patterns in an unsupervised manner, even when spiking is decoupled from behavior or is temporally stretched across single trials. We demonstrate this method across diverse systems: cued reaching in nonhuman primates, motor sequence production in rats, and olfaction in mice. This approach flexibly uncovers diverse dynamical firing patterns, including pulsatile responses to behavioral events, LFP-aligned oscillatory spiking, and even unanticipated patterns, like 7 Hz oscillations in rat motor cortex that are not time-locked to measured behaviors or LFP.
High-yield fabrication of DNA and RNA scaffolds for single molecule force and torque spectroscopy experiments
Authors: Papini Flávia Stal , Seifert Mona , Dulin David 
Published: June 2019

AbstractSingle molecule biophysics experiments have enabled the observation of biomolecules with a great deal of precision in space and time, e.g. nucleic acids mechanical properties and protein-nucleic acids interactions using force and torque spectroscopy techniques. The success of these experiments strongly depends on the capacity of the researcher to design and fabricate complex nucleic acid scaffolds, as the pertinence and the yield of the experiment strongly depend on the high quality and purity of the final scaffold. Though the molecular biology techniques involved are well known, the fabrication of nucleic acids scaffold for single molecule experiments still remains a difficult task. Here, we present new protocols to generate high quality coilable double-stranded DNA and RNA, as well as DNA and RNA hairpins with ~500-1000 bp long stems. Importantly, we present a new approach based on single-stranded DNA’s annealing and show, using magnetic tweezers, that it is more efficient to generate complex nucleic acid scaffolds in larger amount and at higher purity than a standard PCR-digestion-ligation approach. The protocols we describe here enable the design of any sort of complex nucleic acid scaffold for single molecule biophysics experiments and will therefore be extremely valuable to the community.
Improving detection capabilities of a critically endangered freshwater invertebrate with environmental DNA using digital droplet PCR
Authors: Mauvisseau Quentin , Davy-Bowker John , Bulling Mark , Brys Rein , Neyrinck Sabrina , Troth Christopher , Sweet Michael 
Published: June 2019

AbstractIsogenus nubeculais a critically endangered Plecoptera species. Considered extinct in the UK, the species was recently rediscovered in one location of the river Dee in Wales after 22 years of absence. As many species belonging to the Perlodidae, this species can be a bio-indicator, utilised for assessing water quality and health status of a given freshwater system. However, conventional monitoring of invertebrates via kick-sampling for example, is an invasive and expensive (time consuming). Further, such methods require a high level of taxonomic expertise. Here, we compared the traditional kick-sampling method with the use of eDNA detection using qPCR and ddPCR-analyses. In spring 2018, we sampled eDNA from twelve locations on the river Dee.I. nubeculawas detected using kick-sampling in five of these locations, three locations using both eDNA detection and kick-sampling and one location using eDNA detection alone – resulting in a total of six known and distinct populations of this critically endangered species. Interestingly, despite the eDNA assay being validated in vitro and in silico, and results indicating high sensitivity, qPCR analysis of the eDNA samples proved to be ineffective. In contrast, ddPCR analyses resulted in a clear detection ofI. nubeculaat four locations suggesting that inhibition most likely explains the big discrepancy between the obtained qPCR and ddPCR results. It is therefore important to explore inhibition effects on any new eDNA assay. We also highlight that ddPCR may well be the best option for the detection of aquatic organisms which are either rare or likely to shed low levels of eDNA into their environment.
Using structural analysis in silico to assess the impact of missense variants in MEN1
Authors: Caswell Richard C. , Owens Martina M. , Gunning Adam C. , Ellard Sian , Wright Caroline F. 
Published: June 2019

ABSTRACTDespite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variation, the interpretation of novel missense variants can remain challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease-associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analysed the predicted effect of 338 known missense variants on the structure of Menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability providing a strong indicator of pathogenicity. Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise Menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease.
Gq-mediated calcium dynamics and membrane tension modulate neurite plasticity
Authors: Pearce Katherine M. , Bell Miriam , Linthicum Will H. , Wen Qi , Srinivasan Jagan , Rangamani Padmini , Scarlata Suzanne 
Published: June 2019

AbstractThe formation and disruption of synaptic connections during development is a fundamental step in neural circuit formation. Subneuronal structures such as neurites are known to be sensitive to the level of spontaneous neuronal activity but the specifics of how neurotransmitter-induced calcium activity regulates neurite homeostasis are not yet fully understood. In response to stimulation by neurotransmitters such as acetylcholine, calcium responses in cells are mediated the Gαq/phospholipase Cβ (PLCβ)/ phosphatidylinositol 4,5 bisphosphate (PI(4, 5)P2) signaling pathway. Here, we show that prolonged Gαq stimulation results in the retraction of neurites in PC12 cells and rupture of neuronal synapses by modulating membrane tension. To understand the underlying cause, we dissected the behavior of individual components of the Gαq/PLCβ/PI(4, 5)P2pathway during retraction, and correlated these to the retraction of the membrane and cytoskeletal elements impacted by calcium signaling. We developed a mathematical model that combines biochemical signaling with membrane tension and cytoskeletal mechanics, to show how signaling events are coupled to retraction velocity, membrane tension and actin dynamics. The coupling between calcium and neurite retraction is shown to be operative in theC. elegansnervous system. This study uncovers a novel mechanochemical connection between the Gαq/PLCβ/(PI(4, 5)P2pathway that couples calcium responses with neural plasticity.
Agricultural impacts on streams near Nitrate Vulnerable Zones: a case study in the Ebro basin, northern Spain
Authors: Ladrera Rubén , Belmar Oscar , Tomás Rafael , Prat Narcís , Cañedo-Argüelles Miguel 
Published: June 2019

AbstractAgricultural intensification during the last century has produced river degradation across Europe. From the wide range of pressures derived from agricultural activities that impact rivers, diffuse agricultural pollution has received most of the attention from managers and scientists. The aim of this study was to determine the main pressures exerted by intensive agriculture around Nitrate Vulnerable Zones (NVZs), which are areas of land that drain into waters polluted by nitrates according to the European Nitrate Directive (91/676/EEC). The study area was located in the NW of La Rioja (Northern Spain), which has the highest levels of nitrate concentrations within the Ebro basin. The relationships between forty environmental variables and the taxonomic and functional characteristics of macroinvertebrate assemblages (which are good indicators of water quality) were analyzed in 11 stream reaches differentially affected by upstream agricultural activity. The streams affected by a high percentage of agricultural area had significantly greater nitrate concentrations and distinct macroinvertebrate assemblages dominated by pollution tolerant taxa. Hydromorphological alteration (i.e. channel simplification, riparian forest degradation and sediment inputs), which is closely linked to agricultural practices, was the main factor affecting macroinvertebrate assemblages. Good agricultural practices should be implemented in streams affected by NVZs to reverse stream degradation, in consonance with the European Water Framework Directive (WFD). Management actions in these areas should not focus exclusively on nitrate reduction, but also on restoring riparian and aquatic habitats.
Functional analyses ofSTIM1mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome
Authors: Peche Georges Arielle , Spiegelhalter Coralie , Silva-Rojas Roberto , Laporte Jocelyn , Böhm Johann 
Published: June 2019

ABSTRACTTubular aggregate myopathy (TAM) is a progressive disorder essentially involving muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), associating TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and Stormorken syndrome arise from gain-of-function mutations inSTIM1orORAI1, both encoding key regulators of Ca2+homeostasis, and mutations in either gene results in excessive Ca2+entry. The pathomechanistic similarities and differences of TAM and Stormorken syndrome are only partially understood. Here we provide functionalin celluloexperiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, induce major nuclear import of the Ca2+-dependent transcription factor NFAT, and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca2+entry, highlighting that TAM and Stormorken syndrome involve a common pathomechanism.