bluuebunny/crossref_metadata_2025 huggingface dataset:
P-A4 Multimodal theranostic tests for antiretroviral drug delivery
Authors: Kevadiya Bhavesh , Woldstad Christopher , Ottemann Brendan , Dash Prasanta , Sajja Balasrinivasa , Lamberty Benjamin , Morsey Brenda , Kocher Ted
Published: April 2018

Long acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections and facilitate drug entry into human immunodeficiency viral reservoirs. To speed LASER ART development “multimodal imaging theranostic nanoprobes” were created. These europium (Eu3+) doped cobalt ferrite (CF) dolutegravir (DTG) (EuCF-DTG) nanoparticles were used as platforms for drug-particle biodistribution. After parenteral injection of EuCF-DTG, to rats and rhesus macaques, measured drug and cobalt levels by florescence and magnetic resonance imaging tests were found to be coordinate to iron levels. Moreover, EuCF-DTG was found to be a log order-of-magnitude more sensitive than equivalent amounts of particle encased iron oxide. Folic acid decoration facilitated drug particle cell uptake. We posit that theranostic nanoprobes can facilitate LASER ART drug delivery and be used as part of a precision nanomedicine treatment strategy.
P-A6 A Possible Role for Retinoic Acid in the Functional cure of SIV Infections in ART/α4β7 mAb-treated Monkeys
Authors: Yu Jianshi , Jones Jace , Ansari Aftab , Sidell Neil , Kane Maureen
Published: April 2018

Our team of collaborators has recently reported that combining short term antiretroviral therapy (ART) with the in vivo administration of a primatized monoclonal antibody against the α4β7 integrin (α4β7 mAb) in SIV-infected macaques resulted in sustained control of viremia without need for continued therapy. We have determined that acute SIV infection caused a rapid and sustained drop in plasma retinoic acid (RA) levels that was not corrected upon ART-mediated control of viral replication, but was restored soon after start of α4β7 mAb treatment. This was followed by the rebound of certain CD8α+ NK lymphocytes, cells known to be regulated by RA. Depletion studies of the α4β7 mAb-treated “SIV controllers” with anti-CD8α and anti-CD8β Abs have indicated that rebound of viremia and return to suppression tracks most closely with the depletion and reappearance of NK and NKT cells. In parallel in vitro studies using a cell line model of latent SIV infection (Hut78 and SIV-Hut78), we determined that SIV infection inhibited RA production, while α4β7 mAb treatment can stimulate RA production. The data indicated that SIV-Hut78 cells showed a marked reduction in RALDH2 expression (the key regulatory enzyme in RA biosynthesis). The retinol chaperone protein RBP1 was also reduced in SIV-Hut78 cells. Together, these in vivo and in vitro studies indicate that an increase in RA levels is an early sign of the efficacy of α4β7 mAb treatment and suggests that ligation of the α4β7 integrin leads to intra-cellular signaling events that include the restoration of RA production by select RALDH-expressing cells, and signals that induce NK cell activation/re-distribution that may in concert play a fundamental role in sustained control of viremia.
Reliability of Rod Lengthening, Thoracic, and Spino-Pelvic Measurements on Biplanar Stereoradiography in Patients Treated With Magnetically Controlled Growing Rods
Authors: Obid Peter , Yiu Karen Kar Lum , Cheung Kenneth MC , Kwan Kenny , Ruf Michael , Cheung Jason Pui Yin
Published: April 2018

Study Design.

Cross-sectional study.

Objective.

To assess the inter- and intraobserver reliability of thoracic, spino-pelvic, and rod lengthening measurements made on biplanar spinal stereoradiography (EOS imaging) in children treated with magnetically controlled growing rod (MCGR).

Summary of Background Data.

MCGR treatment aims to gain spine length while gradually correcting the spinal deformity. Monitoring thoracic and spino-pelvic parameters is crucial for successful management. EOS imaging is widely used for diagnosis and monitoring of children with Early Onset Scoliosis. However, there is a paucity of literature on the reliability of thoracic and spino-pelvic parameters on EOS imaging in children treated with MCGR.

Methods.

Three independent reviewers independently read a random assortment of 20 whole spine posteroanterior and lateral radiographs from patients treated with MCGR. The measurements were repeated 4 weeks after the initial read. The following radiological parameters were measured: Cobb angle of the main and compensatory curves, coronal balance, coronal T1-S1 and T1-T12 length, chest width and depth at T6, pelvic inlet width, MCGR distracted lengths, global kyphosis, proximal and distal junctional angle, lordosis, sagittal balance, pelvic incidence, pelvic tilt and sacral slope. Statistical analysis was performed with paired t test and Cronbach alpha for inter- and intraobserver reliability.

Results.

All measurements had good or excellent intra- and interobserver reliability (α>0.8; P < 0.05), except measurements of the proximal junctional angle which showed only poor intra- and interobserver reliability for patients with an upper instrumented vertebra cranial to T4.

Conclusion.

EOS imaging is reliable for diagnosis and monitoring of children with Early Onset Scoliosis treated with MCGR. EOS imaging is particularly excellent for assessment of MCGR lengthening. Diagnosis and interpretation of early proximal junctional kyphosis within the cervicothoracic junction should be made with caution.

Level of Evidence: 3
Alterations in Intramedullary T2-weighted Increased Signal Intensity following Laminoplasty in Cervical Spondylotic Myelopathy Patients
Authors: Machino Masaaki , Ando Kei , Kobayashi Kazuyoshi , Ito Kenyu , Tsushima Mikito , Morozumi Masayoshi , Tanaka Satoshi , Ota Kyotaro , Ito Keigo , Kato Fumihiko , Ishiguro Naoki , Imagama Shiro
Published: April 2018

Study Design.

A prospective comparative imaging study.

Objective.

This study investigated whether the postoperative classification of and alterations in increased signal intensity (ISI) of the spinal cord reflected the postoperative severity of symptoms and surgical outcomes in cervical spondylotic myelopathy (CSM) patients.

Summary of Background Data.

Although ISI on performing magnetic resonance imaging (MRI) is observed in CSM patients, alterations in ISI have not been investigated. The association of postoperative ISI with surgical outcomes in CSM patients remains controversial.

Methods.

Totally, 505 consecutive CSM patients (311 males) with a mean age of 66.6 (range, 41–91) years were enrolled. All were treated with laminoplasty and underwent MRI scans: preoperatively and after an average of 26.5 months postoperatively (range 12–66 months). ISI was classified pre- and postoperatively into three groups based on sagittal T2-weighted magnetic resonance images: Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). The patients’ pre- and postoperative neurological statuses were evaluated using the Japanese Orthopaedic Association scoring system for cervical myelopathy (JOA score) and other quantifiable tests, including the 10-s grip and release (10-s G&R) test and 10-s step test.

Results.

Preoperatively, 168 patients had Grade 0 ISI, 169 had Grade 1, and 168 had Grade 2; postoperatively, 210 patients had Grade 0 ISI, 94 had Grade 1, and 201 had Grade 2. Patients with postoperative Grade 0 ISI had a better postoperative JOA score, recovery rate, and 10-s G&R and 10-s step test scores than those with other grades. The postoperative ISI grade improved in 66 patients (13.1%), worsened in 57 (11.3%), and remained unchanged in 382 (75.6%).

Conclusion.

Postoperative ISI partially reflects postoperative symptoms and surgical outcomes. Alterations in ISI were observed postoperatively in 123 patients (24.4%) and were not correlated with surgical outcomes.

Level of Evidence: 2
Flexible Versus Restrictive Visiting Policies in ICUs: A Systematic Review and Meta-Analysis*
Authors: Nassar Junior Antonio Paulo , Besen Bruno Adler Maccagnan Pinheiro , Robinson Caroline Cabral , Falavigna Maicon , Teixeira Cassiano , Rosa Regis Goulart
Published: April 2018

Objectives:

To synthesize data on outcomes related to patients, family members, and ICU professionals by comparing flexible versus restrictive visiting policies in ICUs.

Data Sources:

Medline, Scopus, and Web of Science.

Study Selection:

Observational and randomized studies comparing flexible versus restrictive visiting policies in the ICU and evaluating at least one patient-, family member–, or ICU staff–related outcome.

Data Extraction:

Duplicate independent review and data abstraction.

Data Synthesis:

Of 16 studies identified for inclusion, seven were meta-analyzed. Most studies were rated as having a moderate risk of bias. Among patients, flexible visiting policies were associated with reduced frequency of delirium (odds ratio, 0.39; 95% CI, 0.22–0.69; I
2 = 0%) and lower severity of anxiety symptoms (mean difference, –2.20; 95% CI, –3.80 to –0.61; I
2 = 71%). Flexible visiting policies were not associated with increased risk of ICU mortality (odds ratio, 0.71; 95% CI, 0.38–1.36; I
2 = 86%), ICU-acquired infections (odds ratio, 0.98; 95% CI, 0.68–1.42; I
2 = 11%), or longer ICU stay (mean difference, –0.26 d; 95% CI, –0.57 to 0.05; I
2 = 54%). Among family members, flexible visiting policies were associated with greater satisfaction. Among ICU professionals, flexible visiting policies were associated with higher burnout levels.

Conclusions:

Flexible ICU visiting hours have the potential to reduce delirium and anxiety symptoms among patients and to improve family members’ satisfaction. However, they may be associated with an increased risk of burnout among ICU professionals. These conclusions are based on few studies, with small samples and moderate risk of bias.
Socioeconomic and Tobacco Mediation of Ethnic Inequalities in Mortality over Time
Authors: Blakely Tony , Disney George , Valeri Linda , Atkinson June , Teng Andrea , Wilson Nick , Gurrin Lyle
Published: April 2018

Background:

Racial/ethnic inequalities in mortality may be reducible by addressing socioeconomic factors and smoking. To our knowledge, this is the first study to estimate trends over multiple decades in (1) mediation of racial/ethnic inequalities in mortality (between Māori and Europeans in New Zealand) by socioeconomic factors, (2) additional mediation through smoking, and (3) inequalities had there never been smoking.

Methods:

We estimated natural (1 and 2 above) and controlled mediation effects (3 above) in census-mortality cohorts for 1981–1984 (1.1 million people), 1996–1999 (1.5 million), and 2006–2011 (1.5 million) for 25- to 74-year-olds in New Zealand, using a weighting of regression predicted outcomes.

Results:

Socioeconomic factors explained 46% of male inequalities in all three cohorts and made an increasing contribution over time among females from 30.4% (95% confidence interval = 18.1%, 42.7%) in 1981–1984 to 41.9% (36.0%, 48.0%). Including smoking with socioeconomic factors only modestly altered the percentage mediated for males, but more substantially increased it for females, for example, 7.7% (5.5%, 10.0%) in 2006–2011. A counterfactual scenario of having eradicated tobacco in the past (but unchanged socioeconomic distribution) lowered mortality for all sex-by-ethnic groups and resulted in a 12.2% (2.9%, 20.8%) and 21.2% (11.6%, 31.0%) reduction in the absolute mortality gap between Māori and Europeans in 2006–2011, for males and females, respectively.

Conclusions:

Our study predicts that, in this high-income country, reducing socioeconomic disparities between ethnic groups would greatly reduce ethnic inequalities in mortality over the long run. Eradicating tobacco would notably reduce ethnic inequalities in absolute but not relative mortality.
Retaining nurses in a changing health care environment: The role of job embeddedness and self-efficacy
Authors: Vardaman James M. , Rogers Bryan L. , Marler Laura E.
Published: April 2018

Background:

Because nurses are on the front lines of care delivery, they are subject to frequent changes to their work practices. This change-laden environment puts nurses at higher risk for turnover. Given the frequent disruption to the way nurses perform their jobs, change-related self-efficacy (CSE), or confidence that one can handle change, may be vital to their retention.

Purpose:

The purpose of this article is to examine the roles of CSE and job embeddedness in reducing turnover intentions among nurses. Specifically, this article tests a model in which CSE is the intervening mechanism through which job embeddedness influences turnover intentions.

Methods:

Drawing on a sample of 207 nurses working in the medical/surgical unit of a major metropolitan hospital in the United States, this study employs OLS regression to test for direct effects of job embeddedness and CSE on turnover intentions and bias-corrected bootstrapping to test for the indirect effects of job embeddedness on turnover intentions through CSE.

Findings:

Results show that CSE is directly linked to turnover intentions, and the effects of job embeddedness on turnover intentions become fully manifest through CSE.

Practice Implications:

Improved nurse retention may lead to stable patient care and less disruption in service delivery. Improved retention also benefits health care organizations financially, as costs of replacing a nurse can exceed 100% of the salary for the position. Given the shortage of nurses in some geographic areas, retention remains an important goal.
Holistic in the Hectic
Authors: Landis Philip
Published: April 2018

Despite public knowledge of advanced directives and end-of-life wishes, desire for control over destiny often conflicts with the reality of end-of-life presentation. Recognized as best practice by both the Emergency Nurses Association and the American College of Emergency Physicians, family presence during resuscitation can actually prevent unintended harm to patients and their families.
ASSOCIATION BETWEEN GENOTYPE AND DISEASE PROGRESSION IN ITALIAN STARGARDT PATIENTS
Authors: Di Iorio Valentina , Orrico Ada , Esposito Gabriella , Melillo Paolo , Rossi Settimio , Sbordone Sandro , Auricchio Alberto , Testa Francesco , Simonelli Francesca
Published: April 2018

Purpose:

To investigate the natural history of Stargardt disease over a multiyear follow-up.

Methods:

We reviewed medical records of Stargardt disease patients, with clinical diagnosis of Stargardt disease at a single institution, which was also supported by molecular diagnosis. All patients underwent best-corrected visual acuity, fundus photography, optical coherence tomography, and full-field electroretinography.

Results:

The study cohort consisted of 157 Stargardt disease patients aged 30.4 ± 1.1 years. Longitudinal analysis (mean follow-up: 3 years) showed a significant worsening of best-corrected visual acuity at an average rate of 1.5 Early Treatment Diabetic Retinopathy Study letters/year (P < 0.001), an enlargement of retinal pigment epithelium lesion area by optical coherence tomography at an average linear rate of 0.10 mm2/year (P < 0.001), and a thinning of central macular thickness at a mean rate of −1.42 μm/year (P < 0.001). Survival analysis showed that patients with 2 alleles harboring likely-null variants, on average, reached most severe disease stage, i.e., legal blindness, alteration in both dark-adapted and light-adapted electroretinographic responses, and retinal pigment epithelium lesion area larger than 2.5 mm2 significantly earlier than patients with at least one allele harboring a missense variant.

Conclusion:

The current longitudinal study showed a significant genotype–phenotype correlation characterization, because patients harboring 2 likely-null alleles reach a severe disease stage about 10 years earlier than patients with at least one missense allele.
MULTILEVEL ISCHEMIA IN DISORGANIZATION OF THE RETINAL INNER LAYERS ON PROJECTION-RESOLVED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Onishi Alex C. , Ashraf Mohammed , Soetikno Brian T. , Fawzi Amani A.
Published: April 2018

Purpose:

To examine the relationship between ischemia and disorganization of the retinal inner layers (DRIL).

Methods:

Cross-sectional retrospective study of 20 patients (22 eyes) with diabetic retinopathy presenting to a tertiary academic referral center, who had DRIL on structural optical coherence tomography (OCT) using Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) and OCT angiography with XR Avanti (Optovue Inc, Fremont, CA) on the same day. Optical coherence tomography angiography images were further processed to remove flow signal projection artifacts using a software algorithm adapted from recent studies. Retinal capillary perfusion in the superficial capillary plexuses, middle capillary plexuses, and deep capillary plexuses, as well as integrity of the photoreceptor lines on OCT was compared in areas with DRIL to control areas without DRIL in the same eye.

Results:

Qualitative assessment of projection-resolved OCT angiography of eyes with DRIL on structural OCT demonstrated significant perfusion deficits compared with adjacent control areas (P < 0.001). Most lesions (85.7%) showed superimposed superficial capillary plexus and/or middle capillary plexus nonperfusion in addition to deep capillary plexus nonflow. Areas of DRIL were significantly associated with photoreceptor disruption (P = 0.035) compared with adjacent DRIL-free areas.

Conclusion:

We found that DRIL is associated with multilevel retinal capillary nonperfusion, suggesting an important role for ischemia in this OCT phenotype.
Barriers to Rehabilitation Care in Pediatric Cochlear Implant Recipients
Authors: Noblitt Bryce , Alfonso Kristan P. , Adkins Margaret , Bush Matthew L.
Published: April 2018

Objective:

The purpose of this study was to assess barriers to rehabilitation care for pediatric cochlear implant (CI) recipients.

Study Design:

Cross-sectional questionnaire study.

Setting:

Tertiary medical center.

Patients:

Parents of children who received a CI from October 1996 to June 2013.

Main Outcome Measure(s):

Factors related to access to and barriers in audiology and speech therapy services, factors related to CI use, and performance with CI using the Parents’ Evaluation of Aural/Oral Performance of Children (PEACH).

Results:

Thirty-five parents participated in the study (21 rural residents and 14 urban residents). Distance was a significant barrier to audiology services for rural participants compared with urban participants (p = 0.01). Consistent CI use was complicated by mechanical complications or malfunction in 70% of rural children compared with 33% of urban children (p = 0.05). Only 10% of rural children were able to access speech therapy services at diagnosis compared with 42% of urban children (p = 0.04). Low socioeconomic (SES) status and Medicaid insurance were associated with a lack of local speech therapists and medical/mechanical CI complications. Higher parental educational attainment was associated with higher PEACH scores in quiet conditions compared with families with lower parental education (p = 0.04).

Conclusions:

Rural children are often delayed in receipt of CI rehabilitation services. Multiple barriers including low SES, insurance type, and parental education can affect utilization of these services and may impact the recipient language development. Close follow-up and efforts to expand access to care are needed to maximize CI benefit.
Improved Speech Perception in Cochlear Implant Users With Interleaved High-Rate Pulse Trains
Authors: Runge Christina L. , Du Fang , Hu Yi
Published: April 2018

Objective:

Electrical stimulation with a cochlear implant (CI) elicits abnormally high neural synchrony, which poses significant challenges for speech perception. Previous investigations showed that constant-amplitude high-rate pulse trains (HRPs) desynchronize neural responses and improve stimulus encoding. The study objective was to investigate the effects of HRP on speech perception in adult CI users.

Study Design:

Prospective, within-subject design.

Setting:

Tertiary CI center.

Patients:

Ten adult CI recipients.

Intervention:

Sentence stimuli were created by modifying a basic continuous interleaved sampling (CIS) strategy (1,000 pulses per second; pps) with interleaved biphasic pulse trains (3,000 pps) on even electrodes. Institute of Electrical and Electronics Engineers sentences in quiet and in noise were tested without HRP, and with HRPs of various stimulation levels.

Main Outcome Measure:

Sentence perception in percent correct was calculated for all conditions. The highest speech perception score with HRP stimulation was defined as “max-HRP.”

Results:

Group analyses showed significantly improved sentence perception in background noise with HRPs (p < 0.001). There was no significant difference for sentence perception in quiet for the group. However, seven of 10 subjects experienced some benefit from HRP stimuli in quiet and the degree of HRP benefit showed significant relationships with baseline performance and age at implantation, indicating that HRP stimuli may be most beneficial for older patients or poorer performers.

Conclusions:

Significant improvement in speech perception in noise was observed with HRP stimuli. Some recipients may also benefit from HRP stimulation in quiet. Interleaved HRPs hold promise as a novel stimulation paradigm with clinical sound processing strategies to improve patient performance.
Range of Peak Head Velocity in Video Head Impulse Testing for Pediatric Patients
Authors: Zhou Guangwei , Goutos Cassandra , Lipson Sophie , Brodsky Jacob
Published: April 2018

Objective:

To examine peak head velocity in video head impulse testing of pediatric patients and its effect on vestibulo-ocular reflex (VOR) gain.

Study Design:

Retrospective case review.

Setting:

Tertiary referral center.

Patients:

Pediatric patients ages 3 to 18 years old who underwent video head impulse testing during clinical evaluation of dizziness and/or imbalance.

Intervention(s):

Conducted video head impulse test (vHIT) in horizontal, left anterior–right posterior (LARP), and right anterior–left posterior (RALP) planes.

Main Outcome Measure(s):

Peak head velocity and mean VOR gain for individual semicircular canals in different age groups.

Results:

For the horizontal plane, vHIT peak head velocity greater than 150 degrees/s was achieved in 43 to 63% of 219 patients. In contrast, vHIT peak head velocity greater than 150 degrees/s was achieved in only 3 to 14% for the LARP and RALP planes. Analyses of differences in mean VOR gains among three ranges of peak head velocity (100–125 degrees/s, 126–150 degrees/s, and >150 degrees/s) by paired-t tests were not significant (p > 0.05) within individual patients. Mean VOR gains of three vertical canals in younger patients were significantly lower with higher peak head velocities compared with older children (p < 0.05).

Conclusions:

Peak head velocities of greater than 150 degrees/s may not be feasible in a large proportion of children and adolescents, especially in LARP and RALP planes. However, such high velocities may not be necessary in the pediatric population since VOR gain values obtained at lower peak head velocities of 100 to 150 degrees/s were found to be comparable to those observed at higher velocities.
Split-dose bowel cleansing with picosulphate is safe and better tolerated than 2-l polyethylene glycol solution
Authors: Mathus-Vliegen Elisabeth M.H. , van der Vliet Karin , Wignand-van der Storm Inge J. , Stadwijk John S.
Published: April 2018

Background

In physically less fit patients and patients requiring repeated exams, adequate bowel preparation for colonoscopy remains problematic, particularly because patients need to drink large volumes of unpleasant-tasting fluids. A further concern is potential unwarranted fluid shifts.

Aims

This study aimed to compare the safety and burden of a small-volume sodium picosulphate/magnesium citrate preparation (SPS-MC) with a 2-l ascorbic-acid-enriched polyethylene glycol solution plus bisacodyl pretreatment (PEG-Asc+B).

Patients and methods

Patients referred for colonoscopy were randomized to SPS-MC or PEG-Asc+B administered as a split-dose regimen. Patients received advice on the recommended 4-l SPS-MC and 2-l PEG-Asc+B fluid intake. Safety was assessed by blood sampling before and after the preparation and during a 30-day follow-up period. A questionnaire assessed tolerability and perceived burden of the preparation.

Results

A total of 341 patients underwent colonoscopy. Blood sampling showed a slight but significant decrease in sodium, chloride and osmolality and increase in magnesium in the SPS-MC group and a decrease in bicarbonate in the PEG-Asc+B group. Hyponatraemia and hypermagnesaemia without clinical signs were observed in 16 (14 SPS-MC) and 13 SPS-MC patients, respectively. Patients reported significantly fewer physical complaints and a significantly higher completion rate with SPS-MC. Patients receiving SPS-MC rated the intake as being easier and better tasting. In the event of a repeat colonoscopy, 59.7% of patients in the PEG-Asc+B and 93.6% of patients in the SPS-MC group would opt for the same preparation again.

Conclusion

Despite electrolyte shifts, both SPS-MC and PEG-Asc+B appeared clinically safe. From a patient’s perspective, a small-volume preparation formula such as SPS-MC is preferred, resulting in fewer physical complaints and greater ease of intake.
Pharmacokinetics of Tenofovir Alafenamide When Coadministered With Other HIV Antiretrovirals
Authors: Begley Rebecca , Das Moupali , Zhong Lijie , Ling John , Kearney Brian P. , Custodio Joseph M.
Published: April 2018

Background:

Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen [elvitegravir/cobicistat/emtricitabine (F)/TAF, rilpivirine/F/TAF, bictegravir/F/TAF], or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by comedications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics of TAF were evaluated in 3 studies.

Methods:

Healthy participants received TAF administered alone or with rilpivirine in study 1, with dolutegravir, ritonavir-boosted atazanavir (ATV + RTV), lopinavir (LPV/RTV), or darunavir (DRV + RTV) in study 2, and with the pharmacokinetic enhancer cobicistat or efavirenz in study 3.

Results:

Across the 3 studies, 98 participants received treatment with TAF and a coadministered agent (n = 10–34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected after co-administration with rilpivirine and dolutegravir. Coadministration with P-gp/BCRP inhibitors such as cobicistat or PI-based regimens (ATV + RTV, LPV/r, or DRV + RTV) resulted in a range of 6%–183% increases in TAF and 105%–316% increases in TFV exposure, whereas coadministration with a P-gp inducer, efavirenz, resulted in a 15%–24% decrease in TAF and TFV exposure.

Conclusions:

Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV pharmacokinetics to inhibitors or inducers of P-gp/BCRP transporters.
Circulating CXCR5-Expressing CD8+ T-Cells Are Major Producers of IL-21 and Associate With Limited HIV Replication
Authors: Perdomo-Celis Federico , Taborda Natalia A. , Rugeles Maria T.
Published: April 2018

Background:

Despite advances made with the highly active antiretroviral therapy (HAART) in the control of the HIV 1 infection, a cure has not been achieved because of the persistence of viral reservoirs. The major HIV reservoirs remain in the lymphoid follicles because of, among other factors, the partial absence of CD8+ T-cells in these structures. Recently, lymphoid follicle–confined and circulating CD8+ T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) were described, possessing antiviral mechanisms that could help to control HIV replication.

Setting and Methods:

By flow cytometry, we characterized the phenotype and function of circulating CXCR5-expressing CD8+ T-cells in HIV-infected patients with natural or HAART-induced control of HIV replication.

Results:

Circulating CXCR5-expressing CD8+ T-cells exhibited low or null expression of the C–C chemokine receptor type 7 (CCR7) and had a transitional memory phenotype. Particular redistributions of CXCR5-expressing CD8+ T-cells were found in HIV-infected patients, and they were partially restored by HAART. The frequency of CXCR5hiCCR7−/lo CD8+ T-cells was higher in spontaneous HIV controllers and negatively correlated with plasma HIV RNA levels. Total and HIV-specific CXCR5+ CD8+ T-cells were major producers of interleukin-21, and this function was positively associated with their interferon-γ production.

Conclusions:

Circulating CXCR5-expressing CD8+ T-cells are associated with low-level HIV replication; these cells could be novel correlates of protection, and potentially useful in the eradication of HIV reservoirs.
Point of Diagnosis and Patient Retention in HIV Care in Western Kenya
Authors: Genberg Becky L. , Lee Hana , Hogan Joseph W. , Some Fatma , Wachira Juddy , Wu Xiaotian K. , Braitstein Paula
Published: April 2018

Background:

Home-based counseling and testing (HBCT) achieves earlier HIV diagnosis than other testing modalities; however, retention in care for these healthier patients is unknown. The objective of this study was to determine the association between point of HIV testing and retention in care and mortality.

Setting:

Academic Model Providing Access to Healthcare (AMPATH) has provided HIV care in western Kenya since 2001.

Methods:

AMPATH initiated HBCT in 2007. This retrospective analysis included individuals 13 years and older, enrolled in care between January 2008 and September 2016, with data on point of testing. Discrete-time multistate models were used to estimate the probability of transition between the following states: engaged, disengaged, transfer, and death, and the association between point of diagnosis and transition probabilities.

Results:

Among 77,358 patients, 67% women, median age: 35 years and median baseline CD4: 248 cells/mm3. Adjusted results demonstrated that patients from HBCT were less likely to disengage [relative risk ratio (RRR) = 0.87, 95% CI: 0.83 to 0.91] and die (RRR = 0.65, 95% CI: 0.55 to 0.75), whereas those diagnosed through provider-initiated counseling and testing were more likely to disengage (RRR = 1.09, 95% CI: 1.07 to 1.12) and die (RRR = 1.13, 95% CI: 1.06 to 1.20), compared with patients from voluntary counseling and testing. Once disengaged, patients from HBCT were less likely to remain disengaged, compared with patients from voluntary counseling and testing.

Conclusions:

Patients entering care from different HIV-testing programs demonstrate differences in retention in HIV care over time beyond disease severity. Additional research is needed to understand the patient and system level factors that may explain the associations between testing program, retention, and mortality.
[68Ga]Ga-Pentixafor PET/MRI for CXCR4 Imaging of Chronic Lymphocytic Leukemia
Authors: Mayerhoefer Marius E. , Jaeger Ulrich , Staber Philipp , Raderer Markus , Wadsak Wolfgang , Pfaff Sarah , Kornauth Christoph , Senn Daniela , Weber Michael , Wester Hans-Juergen , Skrabs Cathrin , Haug Alexander
Published: April 2018

Objectives

This prospective proof-of-principle study aimed to determine whether [68Ga]Ga-Pentixafor uptake, which reflects CXCR4 expression, is higher in the bone marrow of chronic lymphocytic leukemia (CLL) than in other oncological diseases without bone marrow infiltration and can therefore be used for CLL imaging.

Materials and Methods

Thirteen CLL patients and 20 controls (10 with pancreatic adenocarcinoma and 10 with mucosa-associated lymphoid tissue lymphoma) with histologically proven cancer underwent [68Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging. Standardized [68Ga]Ga-Pentixafor uptake values (SUVmax, SUVmean) were measured in the bone marrow of the pelvis, the lumbar vertebra L4, and the bony structure with the visually highest tracer uptake (“hottest lesion”). Mean apparent diffusion coefficient values were also measured in the pelvis. Serum leukocyte count (gram per liter), lymphocyte percentage (percent), lactate dehydrogenase (unit per liter), β2-microglobulin (milligram per deciliter), and C-reactive protein (milligram per deciliter) were measured. Statistical analyses comprised analysis of variance with Games-Howell post hoc tests and Spearman correlation coefficients.

Results

SUVmax and SUVmean differed significantly between CLL and pancreatic adenocarcinoma in the pelvis (P = 0.032 and P = 0.008) and lumbar vertebra L4 (both P < 0.001). SUVmean also differed in the pelvis (P = 0.020) and L4 (P = 0.041), and SUVmax in L4 (P = 0.019), between CLL and mucosa-associated lymphoid tissue lymphoma. Receiver operating characteristic–based areas under the curve for separation of CLL from the control groups were greatest for the SUVmax of the bony structure with the strongest [68Ga]Ga-Pentixafor uptake (0.94) and the SUVmax of L4 (0.92). There was no significant correlation between [68Ga]Ga-Pentixafor uptake and pelvic apparent diffusion coefficients or serum parameters.

Conclusions

[68Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging may possibly be useful for CXCR4-based CLL imaging.
In vivo
characterization of bivalve larval shells: a confocal Raman microscopy study
Authors: Ramesh Kirti , Melzner Frank , Griffith Andrew W. , Gobler Christopher J. , Rouger Caroline , Tasdemir Deniz , Nehrke Gernot
Published: April 2018

In vivo
confocal Raman microscopy (CRM), polarized light microscopy and Fourier transform infrared spectroscopy (FTIR) were used to determine if a significant amount of amorphous calcium carbonate (ACC) exists within larval shells of Baltic mytilid mussels (
Mytilus edulis
-like) and whether the amount of ACC varies during larval development. No evidence for ACC was found from the onset of shell deposition at 21 h post-fertilization (hpf) until 48 hpf. Larval
Mytilus
shells were crystalline from 21 hpf onwards and exhibited CRM and FTIR peaks characteristic of aragonite. Prior to shell deposition at 21 hpf, no evidence for carbonates was observed through
in vivo
CRM. We further analysed the composition of larval shells in three other bivalve species,
Mercenaria mercenaria
,
Crassostrea gigas
and
Crassostrea virginica
and observed no evidence for ACC, which is in contrast to previous work on the same species. Our findings indicate that larval bivalve shells are composed of crystalline aragonite and we demonstrate that conflicting results are related to sub-optimal measurements and misinterpretation of CRM spectra. Our results demonstrate that the common perception that ACC generally occurs as a stable and abundant precursor during larval bivalve calcification needs to be critically reviewed.
Voltage and pH sensing by the voltage-gated proton channel, HV1
Authors: DeCoursey Thomas E.
Published: April 2018

Voltage-gated proton channels are unique ion channels, membrane proteins that allow protons but no other ions to cross cell membranes. They are found in diverse species, from unicellular marine life to humans. In all cells, their function requires that they open and conduct current only under certain conditions, typically when the electrochemical gradient for protons is outwards. Consequently, these proteins behave like rectifiers, conducting protons out of cells. Their activity has electrical consequences and also changes the pH on both sides of the membrane. Here we summarize what is known about the way these proteins sense the membrane potential and the pH inside and outside the cell. Currently, it is hypothesized that membrane potential is sensed by permanently charged arginines (with very high pKa) within the protein, which results in parts of the protein moving to produce a conduction pathway. The mechanism of pH sensing appears to involve titratable side chains of particular amino acids. For this purpose their pKaneeds to be within the operational pH range. We propose a ‘counter-charge’ model for pH sensing in which electrostatic interactions within the protein are selectively disrupted by protonation of internally or externally accessible groups.
Robert Sibbald's
Scotia Illustrata
(1684): A faunal baseline for Britain
Authors: Raye Lee
Published: April 2018

This paper examines a pre-industrial Scottish natural history text by Robert Sibbald called
Scotia Illustrata
(Edinburgh, 1684), which is significant for two reasons: (i) it is based on data submitted by correspondents from across Scotland, and (ii) it only includes biological species attested to be present by witnesses or found in previous historical accounts of the country. These facts allow us to adopt a unique methodology: After its introduction, this paper approaches the text as a potential source of biodiversity information, and extracts data on the presence/absence of fauna in the seventeenth century. The extracted species are identified (as far as possible) to species level, and then the gathered information is used as a baseline to discuss later losses from the biodiversity of Scotland during the industrial period.
Deep cultural ancestry and human development indicators across nation states
Authors: Sookias Roland B. , Passmore Samuel , Atkinson Quentin D.
Published: April 2018

How historical connections, events and cultural proximity can influence human development is being increasingly recognized. One aspect of history that has only recently begun to be examined is deep cultural ancestry, i.e. the vertical relationships of descent between cultures, which can be represented by a phylogenetic tree of descent. Here, we test whether deep cultural ancestry predicts the United Nations Human Development Index (HDI) for 44 Eurasian countries, using language ancestry as a proxy for cultural relatedness and controlling for three additional factors—geographical proximity, religion and former communism. While cultural ancestry alone predicts HDI and its subcomponents (income, health and education indices), when geographical proximity is included only income and health indices remain significant and the effect is small. When communism and religion variables are included, cultural ancestry is no longer a significant predictor; communism significantly negatively predicts HDI, income and health indices, and Muslim percentage of the population significantly negatively predicts education index, although the latter result may not be robust. These findings indicate that geographical proximity and recent cultural history—especially communism—are more important than deep cultural factors in current human development and suggest the efficacy of modern policy initiatives is not tightly constrained by cultural ancestry.
Determination of carcinogenic herbicides in milk samples using green non-ionic silicone surfactant of cloud point extraction and spectrophotometry
Authors: Mohd N. I. , Zain N. N. M. , Raoov M. , Mohamad S.
Published: April 2018

A new cloud point methodology was successfully used for the extraction of carcinogenic pesticides in milk samples as a prior step to their determination by spectrophotometry. In this work, non-ionic silicone surfactant, also known as 3-(3-hydroxypropyl-heptatrimethylxyloxane), was chosen as a green extraction solvent because of its structure and properties. The effect of different parameters, such as the type of surfactant, concentration and volume of surfactant, pH, salt, temperature, incubation time and water content on the cloud point extraction of carcinogenic pesticides such as atrazine and propazine, was studied in detail and a set of optimum conditions was established. A good correlation coefficient (

R
2

) in the range of 0.991–0.997 for all calibration curves was obtained. The limit of detection was 1.06 µg l
−1
(atrazine) and 1.22 µg l
−1
(propazine), and the limit of quantitation was 3.54 µg l
−1
(atrazine) and 4.07 µg l
−1
(propazine). Satisfactory recoveries in the range of 81–108% were determined in milk samples at 5 and 1000 µg l
−1
, respectively, with low relative standard deviation,
n
 = 3 of 0.301–7.45% in milk matrices. The proposed method is very convenient, rapid, cost-effective and environmentally friendly for food analysis.
Towards the fluorogenic detection of peroxide explosives through host–guest chemistry
Authors: Almenar Estefanía , Costero Ana M. , Gaviña Pablo , Gil Salvador , Parra Margarita
Published: April 2018

Two dansyl-modified β-cyclodextrin derivatives (
1
and
2
) have been synthesized as host–guest sensory systems for the direct fluorescent detection of the peroxide explosives diacetone diperoxide (DADP) and triacetone triperoxide (TATP) in aqueous media. The sensing is based on the displacement of the dansyl moiety from the cavity of the cyclodextrin by the peroxide guest resulting in a decrease of the intensity of the fluorescence of the dye. Both systems showed similar fluorescent responses and were more sensitive towards TATP than DADP.
Synchronous diversification of Sulawesi's iconic artiodactyls driven by recent geological events
Authors: Frantz Laurent A. F. , Rudzinski Anna , Nugraha Abang Mansyursyah Surya , Evin Allowen , Burton James , Hulme-Beaman Ardern , Linderholm Anna , Barnett Ross , Vega Rodrigo , Irving-Pease Evan K. , Haile James , Allen Richard , Leus Kristin , Shephard Jill , Hillyer Mia , Gillemot Sarah , van den Hurk Jeroen , Ogle Sharron , Atofanei Cristina , Thomas Mark G. , Johansson Friederike , Mustari Abdul Haris , Williams John , Mohamad Kusdiantoro , Damayanti Chandramaya Siska , Wiryadi Ita Djuwita , Obbles Dagmar , Mona Stephano , Day Hally , Yasin Muhammad , Meker Stefan , McGuire Jimmy A. , Evans Ben J. , von Rintelen Thomas , Ho Simon Y. W. , Searle Jeremy B. , Kitchener Andrew C. , Macdonald Alastair A. , Shaw Darren J. , Hall Robert , Galbusera Peter , Larson Greger
Published: April 2018

The high degree of endemism on Sulawesi has previously been suggested to have vicariant origins, dating back to 40 Ma. Recent studies, however, suggest that much of Sulawesi's fauna assembled over the last 15 Myr. Here, we test the hypothesis that more recent uplift of previously submerged portions of land on Sulawesi promoted diversification and that much of its faunal assemblage is much younger than the island itself. To do so, we combined palaeogeographical reconstructions with genetic and morphometric datasets derived from Sulawesi's three largest mammals: the babirusa, anoa and Sulawesi warty pig. Our results indicate that although these species most likely colonized the area that is now Sulawesi at different times (14 Ma to 2–3 Ma), they experienced an almost synchronous expansion from the central part of the island. Geological reconstructions indicate that this area was above sea level for most of the last 4 Myr, unlike most parts of the island. We conclude that emergence of land on Sulawesi (approx. 1–2 Myr) may have allowed species to expand synchronously. Altogether, our results indicate that the establishment of the highly endemic faunal assemblage on Sulawesi was driven by geological events over the last few million years.
Feedback between environment and traits under selection in a seasonal environment: consequences for experimental evolution
Authors: Collot Dorian , Nidelet Thibault , Ramsayer Johan , Martin Olivier C. , Méléard Sylvie , Dillmann Christine , Sicard Delphine , Legrand Judith
Published: April 2018

Batch cultures are frequently used in experimental evolution to study the dynamics of adaptation. Although they are generally considered to simply drive a growth rate increase, other fitness components can also be selected for. Indeed, recurrent batches form a seasonal environment where different phases repeat periodically and different traits can be under selection in the different seasons. Moreover, the system being closed, organisms may have a strong impact on the environment. Thus, the study of adaptation should take into account the environment and eco-evolutionary feedbacks. Using data from an experimental evolution on yeast
Saccharomyces cerevisiae
, we developed a mathematical model to understand which traits are under selection, and what is the impact of the environment for selection in a batch culture. We showed that two kinds of traits are under selection in seasonal environments: life-history traits, related to growth and mortality, but also transition traits, related to the ability to react to environmental changes. The impact of environmental conditions can be summarized by the length of the different seasons which weight selection on each trait: the longer a season is, the higher the selection on associated traits. Since phenotypes drive season length, eco-evolutionary feedbacks emerge. Our results show how evolution in successive batches can affect season lengths and strength of selection on different traits.
JACKS: joint analysis of CRISPR/Cas9 knock-out screens
Authors: Allen Felicity , Behan Fiona , Iorio Francesco , Yusa Kosuke , Garnett Mathew , Parts Leopold
Published: April 2018

Genome-wide CRISPR/Cas9 knockout screens are revolutionizing mammalian functional genomics. Their range of applications remains limited by signal variability from different guide RNAs targeting the same gene, which confounds analysis, and dictates large experiment sizes. To address this problem, we report JACKS, a Bayesian method that jointly analyses screens performed with the same guide RNA library. Modeling the variable guide efficacies greatly improves hit identification, and allows a 2.5-fold reduction in required cell numbers without sacrificing performance compared to current analysis standards.
Developmentally arrested precursors of pontine neurons establish an embryonic blueprint of theDrosophilacentral complex
Authors: Andrade Ingrid V. , Riebli Nadia , Nguyen Bao-Chau M. , Omoto Jaison J. , Fetter Richard D. , Cardona Albert , Hartenstein Volker
Published: April 2018

Serial electron microscopic analysis shows that theDrosophilabrain at hatching possesses a large fraction of developmentally arrested neurons with a small soma, heterochromatin-rich nucleus, and unbranched axon lacking synapses. We digitally reconstructed all 812 “ small undifferentiated” (SU) neurons on both hemispheres and assigned them to the known brain lineages. 54 SU neurons belonging to the DM1-4 lineages, which generate all columnar neurons of the central complex, form an embryonic nucleus of the fan-shaped body (FB). These “ FB pioneers” develop into a speci1c class of bi-columnar elements, the pontine neurons. Even though later born, unicolumnar DM1-4 neurons fasciculate with the FB pioneers, selective ablation of these cells did not result in gross abnormalities of the trajectories of unicolumnar neurons, indicating that axonal path1nding of the two systems is controlled independently. Our comprehensive spatial and developmental analysis of the SU neuron adds to our understanding of the establishment of neuronal circuitry.
A Con Artist: Phenylphenoxybenzamide is not a Glycosyltransferase Inhibitor
Authors: Wybenga Gjalt G. , Wu Wei-Shen
Published: April 2018

To combat bacterial resistance against antibiotics, glycosyltransferase inhibiting molecules, which block the synthesis of the pre-cursor of the bacterial cell wall, need to be discovered and developed. In this study, we demonstrate that phenylphenoxybenzamide, a salicylanilide, is not a glycosyltransferase inhibiting molecule, despite claims in literature to the contrary, and through our work show that glycosyltransferase construct choice and detergent choice are crucial parameters to consider when designing glycosyltransferase assays that aim to discover and develop molecules that inhibit these types of enzymes.