bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of maraviroc in patients with undetectable viral load: efficacy, tolerance and predictors of viral response in MARAVIROC‐cohort study
Authors: Jesús Pérez Elías María , Arroyo David , Diaz Alberto , Herrero Cristina , Martinez‐Dueñas Loreto , Moreno Ana , Hernández‐Quero Jose , Podzamcer Daniel , Gomez‐Ayerbe Cristina , Luis Casado Jose , Zamora Javier , Rivero Antonio , Moreno Santiago , María Llibre Josep
Published: November 2014

Introduction

No controlled clinical trials had studied the role of maraviroc (MRV) in fully suppressed patients [1].

Materials and Methods

MRV‐cohort is an observational, retrospective, multicentric (27 sites) large cohort study of patients starting MRV in clinical practice under different circumstances, with at least 48 weeks of follow‐up. For the present analysis we selected all those patients starting with an HIV‐RNA<50 copies/mL. Demographics, baseline CD4 cell count, past history of antiretroviral treatment (ART), tropism, reasons for MRV use, MRV based therapy and change/end of MRV use were assessed. Paired analysis of lipid, hepatic and kidney profile changes and univariate and multivariate analyses of HIV‐RNA<50 copies/mL at 48 weeks were explored.

Results

We included 247 out of 667 subjects from the entire cohort. At study entry, their median age was 47 years, 23% were women, 31% MSM, 49% had CDC category C, median CD4+ counts were 468 cells/mm3, 46% were HCV+ and 4.5% AgHBs+. Tropism information was available in 197 (94% R5). Median length of prior ARTV was 10.7 years, with exposure to a median of three drug families. Main reasons for prescribing MRV were: toxicity 38%, inmunodiscordance 23%, simplification 19% and admission in a clinical trial 10.4%. MRV based therapies used were MRV+2NRTIs 9%, MRV+PI 46%, MRV+PI+other 40% and MRV+other 5%. At 48 weeks, 23% of patients had changed or finished MRV therapy due to toxicity 2.4%, virological failure 2%, immunological failure 1.2%, simplification 3,2%, trial requirement 9.7%, medical decision 2.8%, treatment suspension 1.2% and unknown 0.4%. At 48 weeks, no significant changes were observed in lipid, hepatic or kidney profiles, and 85% of patients remained with HIV‐RNA<50 copies/mL. Focusing on viral response univariate and multivariate models did not show any significant baseline variable explaining viral failure.

Conclusions

In clinical practice MRV was used, mostly in R5 positive patients, with adequate efficacy and tolerance, but important number of patients changed due to non‐clinical reasons. In this scenario neither reason for use of MRV nor MRV‐based therapy explained viral failure.
Dual therapy with darunavir/r plus etravirine is safe and effective as switching therapy in antiretroviral experienced HIV‐patients. The BITER Study
Authors: Portilla Joaquín , Arazo Piedad , Crusells Josefa , Pérez‐Martínez Laura , Martínez‐Madrid Onofre , Boix Vicente , Moreno Javier , Navarro Vicente , Rubio Teresa , Reus Sergio , Galera Carlos , Bernal Enrique , Jover Francisco , Amador Concepcion , Baño David , Merino Esperanza , Saiz‐de‐la‐Hoya Pablo
Published: November 2014

Introduction

Switching therapy studies are usually designed as second‐line antiretroviral treatment (ART) in patients without previous virologic failures. Combined ART (cART) with DRV/r and ETR has a good pharmacokinetic profile, high genetic barrier and has been proved as rescue therapy. The aim of our study was to analyze efficacy and safety of therapy with DRV/r plus ETR in treatment experienced HIV‐patients with previous therapeutic failures that need to switch ART. We present results at first 24 weeks.

Methods

Multicentre retrospective observational study. Inclusion criteria: adult HIV‐patients on ART with HIV‐VL <1000 cop/mL who started their ART with DRV/r (600/100 bid or 800/100 qd)+ETR by adverse events, non‐adherence, tolerability or prevention of future complications. Patients with acute AIDS events, HBV, pregnancy, drug addiction or previous selected mutations to DRV or ETR were excluded.

Results

Ninety‐nine patients were included, mean age: 47 years (r: 22–79); 70% men, 40.4% previous AIDS event and 39.3% HCV. Ninety‐one patients had received ≥3 cART regimens and 45≥5, 75 patients had HIV‐VL <50 cop/mL and 24 low‐level viremia (LLV): 297.5±261.4 cop/mL, CD4+ 568±279 cells/µL. ART before switching: NRTI+PI/r (33%), NNRTI (17%), PI/r+NNRTI (23%), PI/r+INI (13%), other (14%). Main reason to switching was: toxicity/intolerance 50 patients (renal 32%, gastrointestinal: 14%, hyperlipidaemia 10%; osteopenia/osteoporosis: 6%); improving adherence 26 patients; prevention of complications 19 patients. Nine subjects withdrew ART during follow‐up because: intolerance or new toxicity three; non‐adherence two; simplification to DRV/r monotherapy two; persistence of previous toxicity one; virologic failure one. At week 24, among patients who continued with DRV/r+ETR (n=90): 81 (89%) had VL<50 cop/mL, in those with with HIV‐VL<50 at baseline (67/90), 94% persisted with <50 cop., and in those with LLV (24/90), 61% (n=14) achieved a VL<50 cop. We didn't observe any significant difference in lab parameters between baseline and week 24. Estimated glomerular filtrate rate increased from 83.4±24.7 to 88.5±56.8 mL/min, p=NS. Regarding reason to switching, it improved in 42 cases, no changes: 20 cases; worsened: 4 cases, and non‐applicable or unknown: 24 cases.

Conclusions

Switching to dual therapy with DRV/r+ETR is an effective strategy in selected heavily experienced ART patients, even in those with LLV (<1000 cop/mL). This cART is safe and well tolerated, can reduce number of pills and improve adherence.
Randomized trial of DRV/r or LPV/r QD monotherapy vs maintaining a PI/r‐based antiretroviral regimen in persons with suppressed HIV replication
Authors: Pinnetti Carmela , Lorenzini Patrizia , Cozzi‐Lepri Alessandro , Sandrine Ottou , Tommasi Chiara , Zaccarelli Mauro , Federico Perno Carlo , Rosaria Capobianchi Maria , Girardi Enrico , Antinori Andrea , Ammassari Adriana
Published: November 2014

Introduction

PI/r monotherapy has been suggested as an attainable maintenance strategy in patients achieving stable HIV suppression in plasma. The objective of trial was to compare the virological outcome of two different PI/r QD monotherapy strategies (LPV/r or DRV/r) with maintaining a triple PI/r‐based ARV regimen.

Material and Methods

Phase III, open‐label, non‐inferiority (−12% margin), randomized trial of HIV adults with HIV‐RNA <50 cp/mL for at least 48 weeks while on PI/r‐based cART, CD4 nadir >100 cell/mm3, without previous PIs virological failure. Eligible patients were randomized to continue PI/r+2NRTIs (Arm A), to switch to LPV/r 800/200 mg QD monotherapy (Arm B), or to switch to DRV/r 800/100 mg QD monotherapy (Arm C). Primary endpoint was proportion of patients with plasma HIV‐1 RNA <50 cp/mL (TLOVR) at 48w by intent to treat (ITT) analysis (missing/re‐induction=failure). FDA snapshot and ITT switch‐included analysis (ITT‐SI) were also used. In ITT‐SI, patients who had <50 copies/mL at 96w were counted as successes even if they had confirmed HIV‐RNA elevations and had subsequently successfully intensified by NRTI.

Results

Due to slow recruitment, only 103 patients were included. No differences were observed between the three arms with respect to gender, age, HIV transmission, CD4 nadir and at screening. At randomization, 61 patients were receiving TDF/FTC (60%), 19 ZDV/3TC (18%), 8 ABV/3TC (8%), 75 LPV/r (73%), 13 ATV/r (13%), 4 DRV/r (4%). Differences in proportion of virological success by groups using Arm A as comparator according to FDA TLOVR were reported in Figure 1. Similar results were obtained by Snapshot analysis. Of 14 patients with virological failure, 8 patients restarted triple therapy with 2NRTI and 7/8 regained a VL <50 cp/mL over time. According to ITT‐SI analysis, 96 week differences [95% CI] were −5.7 [−29.6; +18.2] in Arm B, and +19.6 [−1.6; +40.8] in Arm C. A GRT was performed in 6/14 patients (one not amplifiable; four without mutations; one showed E138A).

Conclusions

Compared to maintaining a PI/r‐based triple ARV regimen, LPV/r QD monotherapy tended to have higher rate of virological failure and of discontinuation due to adverse event. In contrast, the response rate at week 96 during DRV/r QD mono‐therapy was non‐inferior to that of triple PI/r‐based ARV therapy. A re‐induction with 2NRTI was adequate to obtain an undetectable viremia in most of patients with virological failure.
Unboosted atazanavir with lamivudine/emtricitabine for patients with long‐lasting virological suppression
Authors: Carbone Alessia , Galli Laura , Bigoloni Alba , Bossolasco Simona , Guffanti Monica , Maillard Miriam , Carini Elisabetta , Salpietro Stefania , Spagnuolo Vincenzo , Gianotti Nicola , Lazzarin Adriano , Castagna Antonella
Published: November 2014

Introduction

Unboosted atazanavir (ATV) including regimens have been investigated as a ritonavir‐sparing simplification strategy. No data are available on removal of one NRTI in subjects effectively treated with unboosted atazanavir+2NRTIs. We present the 48‐week virological efficacy and safety of unboosted atazanavir plus lamivudine (3TC) or emtricitabine (FTC) (lamivudine/emtricitabine/Reyataz©, LAREY Study).

Materials and Methods

Single arm, prospective, pilot study on HIV‐treated patients, HBsAg negative, with HIV‐RNA<50 cps/mL since at least 2 years, who switched from ATV+2NRTIs to ATV 400 mg QD +3TC or FTC. Virological failure was defined as 2 consecutive values of HIV‐RNA>50 cps/ml; viral blip was defined as a single HIV‐RNA value>50 cps/ml not subsequently confirmed. Results as median (IQR). Changes between baseline (BL) and week 48 assessed by the Wilcoxon signed rank test.

Results

Forty patients enrolled: 75% males, 51 (47–54) years, 14% HCV co‐infected, infected with HIV since 16 (9–21) years, on antiretroviral therapy since 13 (5–16) years, with a nadir CD4+ of 254 (157–307) cells/mm3, virologically suppressed since 4.2 (2.2–5.4) years; 53 patients switched from a tenofovir (TDF)‐based regimens; ATV was associated with 3TC in 83% patients. No virological failures or discontinuations were observed; three patients had a single viral blip in the range 50–250 copies/mL; CD4+ increased from 610 (518–829) cells/mm3 at BL to 697 (579–858) cells/mm3 at week 48 [48‐week change: 39 (−63/+160) cells/mm3 p=0.081]. Three clinical events were observed (one herpes zoster, one pneumonia, one syphilis) in absence of renal lithiasis, AIDS‐defining or drug‐related events or death. Overall, significant 48‐week amelioration of ALP [BL: 83 (71–107) mg/dL; 48‐week change: −15 (−27/−8) mg/dL p<0.0001] and CKD‐EPI [BL: 100 (86–108) ml/min/1.73 m2; 48‐week change: 1.5 (−3/+8) ml/min/1.73 m2, p=0.042] were observed. Patients switching from TDF (Table 1) significantly improved CD4+, lymphocytes, hepatic profile, renal profile and ALP; these patients had also a modest but significant decrease in haemoglobin.

Conclusions

Switch from an unboosted atazanavir‐based regimen to ATV+3TC or FTC regimen was effective and safe in this small sample, supporting the hypothesis of a potential two‐steps de‐intensification (removal of ritonavir and removal of one NRTI) in patients on long‐lasting virological suppression.
Simplification to co‐formulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: Data from a multicenter cohort
Authors: Pinnetti Carmela , Di Giambenedetto Simona , Maggiolo Franco , Lorenzini Patrizia , Fabbiani Massimiliano , Tommasi Chiara , Latini Alessandra , Ammassari Adriana , Loiacono Laura , Sterrantino Gaetana , Bellagamba Rita , Boumis Evangelo , Antinori Andrea , Zaccarelli Mauro
Published: November 2014

Background

To assess efficacy and safety of treatment simplification to co‐formulated Rilpivirine/Emtricitabine/Tenofovir (RPV/FTC/TDF) in virologically suppressed patients.

Materials and Methods

Endpoints of the analysis were: (a) treatment discontinuation of RPV/FTC/TDF for any reasons and (b) occurrence of virological failure (VF) defined as confirmed HIV‐RNA >50 cp/mL).

Results

Overall, 508 patients from five Italian reference centres were included: male gender 71.9%; median age 47 years (IQR 40–52); IVDU as HIV risk 17.7%; HCV‐AB positive 23.4%; CDC‐C stage 17.5%; median CD4 cells/µL at switch 655 (IQR: 487–843); median number of previous regimens three (IQR 2–7). In a median follow‐up of 196 days (IQR: 84–287), 31 patients discontinued RPV/FTC/TDF (virological failure n=5, hypersensitivity reaction n=2, GI‐toxicity n=6, liver toxicity n=1, CNS‐toxicity n=4, kidney toxicity n=5, patient's decision/lost in follow‐up n=10). Moreover, VF occurred in eight patients (five discontinued regimen, while three remained on RPV/FTC/TDF). At survival analysis, the probabilities of treatment discontinuation or VF were 5.5% and 1.2% at 6 months, 13.2% and 2.8% at 12 months, respectively (Figure 1). At adjusted Cox model, factors associated with discontinuation were: <200 CD4 cells/µL at switch (HR 5.3, 95% CI 1.1–25.9, p=0.038), number of pre‐switch regimens (for each extra regimen: HR 1.05, 95% CI 1.01–1.10, p=0.024), male gender (HR 0.4, 95% CI 0.2–0.9, p=0.032). Only the number of pre‐switch regimens was associated with VF (HR 1.13, 95% CI 1.06–1.21, p=0.001). Type of pre‐switch regimen was not associated with discontinuation or failure, but no VF was observed if switching from co‐formulated Efavirenz/FTC/TDF or from Raltegravir containing regimens. Switching to RPV/FTC/TDF led to significant improvement in fasting lipids levels: the decrease in cholesterol, LDL and triglycerides was observed switching from any regimen, but was more marked from boosted PI. In contrast, a moderate increase in transaminase (switching from all regimens except NNRTI‐containing) and creatinine (except from TDF‐containing regimens) were observed.

Conclusions

Our data suggest that switching to RPV/FTC/TDF in virologically suppressed patients could be a good strategy with low risk of virological failure or treatment discontinuation; the switch is also associated with significant improvement in lipid profile.
Efficacy of a reduced dose of DARUNAVIR/RTV in a cohort of antiretroviral‐naïve and experienced HIV‐infected patients: a medium‐term follow‐up
Authors: Lanzafame Massimiliano , Lattuada Emanuela , Rigo Fabio , Hill Andrew , Vento Sandro
Published: November 2014

Background

The currently approved dose of darunavir/ritonavir is 800/100 mg once daily for PI‐naïve patients, and 600/100 mg twice daily for PI‐pretreated patients. However, in DRV‐sensitive patients at baseline in the POWER 1/2 trials, similar rates of HIV RNA suppression (1 log reduction) were achieved with doses ranging from 400/100 mg once daily to 600/100 mg twice daily. In previously virologically suppressed patients, a reduced dose of DRV (600/100 QD) is non‐inferior to the standard dose (800 mg QD)[1] and DRV concentrations in plasma and CSF are similar in patients receiving the above different doses [1, 2].

Methods

Twelve treatment‐naïve patients were started on darunavir/ritonavir 600/100mg once daily, with TDF/FTC (8) or ABC/3TC (4). Seven patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (2), ABC/3TC (2), NVP (1), AZT/3TC (1). One was on monotherapy with DRV. Seven treatment‐experienced patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (5), ABC/3TC (1), RAL (1).

Results

Of the 12 naïve patients (mean baseline HIV RNA 134,024 log10 copies/mL, range 4,256‐397,932), 11 had HIV RNA <20 c/mL after a mean 27.4 months of follow‐up (range 12–33). Mean PK level was 2,920 ng/mL (1,268–4,562). One patient had virological failure after 14 months (HIV RNA 39,300 copies/mL); no mutations were detected and after introduction of DRV/r 600 mg b.i.d., he returned aviremic. All switched patients maintained HIV RNA suppression (<20 c/mL) for a mean of 32.8 months (range 21‐54). PK level was available for one patient only (Ctrough 3,442 ng/mL). Of the treatment‐experienced patients (mean baseline HIV RNA 24,167 log10 copies/mL, range 112–111,426), five maintained HIV RNA suppression for a mean of 46.2 months (range 31–67). One patient interrupted HAART for three months and then restarted it, the latest HIV RNA level being 628 copies/mL after five weeks of therapy. One patient failed after 42 months (HIV RNA 3,930 copies/mL); after intensification (DRV/r 600 twice daily), he returned aviremic. PK levels were available for three patients (mean 2,502 ng/mL; range 844–4,518).

Conclusions

In this pilot study of 26 patients, use of DRV/r at 600/100 mg OD dose led to sustained HIV RNA suppression in 23 patients with acceptable PK exposures to DRV. Large non‐inferiority trials are warranted to establish its efficacy.
The impact of nevirapine‐ versus protease inhibitor‐based regimens on virological markers of HIV‐1 persistence during seemingly suppressive ART
Authors: Kiselinova Maja , Anna Maria , Malatinkova Eva , Vervish Karen , Beloukas Apostolos , Messiaen Peter , Bonczkowski Pawel , Trypsteen Wim , Callens Steven , Verhofstede Chris , De Spiegelaere Ward , Vandekerckhove Linos
Published: November 2014

Introduction

The source and significance of residual plasma HIV‐1 RNA detection during suppressive ART remain controversial. It has been proposed that nevirapine (NVP)‐based regimens achieve a greater HIV‐1 RNA suppression than regimens containing a protease inhibitor (PI). The aim of this study was to compare the effect of receiving NVP‐ vs PI‐based ART on the virological markers of HIV persistence in peripheral blood.

Material and Methods

The study population comprised 161 HIV‐1 infected patients receiving either NVP‐based (n=81) or PI‐based (n=80) ART and showing a HIV‐1 RNA load stably suppressed <40 copies/mL for median of 5.2 years (IQR 2.2–8.0). Residual viraemia was detected by real‐time PCR with 50% and 95% detection thresholds of 1 and 3 HIV‐1 RNA copies/mL, respectively. Cell‐associated (CA) unspliced HIV‐1 RNA, total HIV‐1 DNA and 2 LTR circles were quantified in peripheral blood mononuclear cells (PBMCs) using droplet digital PCR. Groups were compared by standard non‐parametric tests; factors associated with HIV‐1 detection were analyzed by univariate regression analysis and generalized linear models (SPSS® V22 and Rstudio).

Results

Plasma HIV‐1 RNA was detected in 37/81 (45.7%) and 47/80 (58.8%) subjects on NVP‐ and PI‐based ART, with median (IQR) levels of 5 (3–6) and 5 (3–8) copies/mL, respectively. HIV‐1 RNA detection was associated with shorter duration of suppressive ART regardless of treatment arm (p=0.007), and lower CD4 nadir (p=0.015). HIV‐1 DNA levels were median 282 (120–484) and 213 (87–494) copies/106 PBMCs in the two groups respectively, and were lowest (<100 copies/106 PBMCs) in subjects with lower plasma HIV‐1 RNA (p=0.049), CA unspliced HIV‐1 RNA (p=0.0001), 2 LTR circles (p=0.005) and pre‐ART HIV‐1 RNA load (p=0.0001).

Conclusions

In this comprehensive characterization of patients on long‐term suppressive ART, we did not observe evidence for a greater suppressive activity of NVP‐based over PI‐based therapy on plasma and intracellular markers of virus persistence. Overall excellent correlation was observed between the markers, allowing the identification of a subset of treated patients with low HIV‐1 expression as an important cohort for future HIV cure studies.
Treatment discontinuation in HIV‐1‐infected individuals starting their first‐line HAART after 2008: data from the ICONA Foundation Study Cohort
Authors: Di Biagio Antonio , Cozzi‐Lepri Alessandro , Prinapori Roberta , Angarano Gioacchino , Gori Andrea , Quirino Tiziana , De Luca Andrea , Costantini Andrea , Mussini Cristina , Rizzardini Giuliano , Antinori Andrea , D'Arminio Monforte Antonella ,   on behalf of the ICONA, Foundation Study
Published: November 2014

Introduction

The aim of this study was to analyze the likelihood and the predictors of discontinuation of first‐line regimen in the late HAART era.

Methodology

An observational multi‐center analysis of HIV‐positive patients enrolled in ICONA. Patients eligible were those starting a first‐line HAART after 1 January 2008. Discontinuation was defined as stop and/or switch of at least one drug of the regimen. All causes of discontinuation, as reported by the treating physician, were evaluated and cumulative risk of stopping was investigated according to age, gender, co‐morbidity, years since starting HAART, immuno‐virological status, third drug and backbone of the first regimen. Kaplan Meier (KM) analysis and Cox proportional hazards model were used for the outcome discontinuation of ≥1 drug regardless of the reason. For the KM estimates a competing risk approach was used to estimate the contribution of each of the reasons over time to the cumulative risk of stopping over time.

Results

Data of 1759 patients who started first HAART and had at least one month of clinical follow‐up were analyzed. The overall discontinuation risk was 33% over a median follow‐up of 12 months. The likelihood of discontinuation by KM was 27% by one year (95% CI 25–29) and 41% by two years (95% CI 38–44). Main reason for stopping at least one drug in regimen was simplification (10%), followed by intolerance (7%), toxicity (5%), failure (2%) and other causes (8%). Estimates of the cumulative risk of discontinuation of ≥1 drug over time and according to reason are shown in Figure 1. In a multivariable Cox model independent predictors of discontinuation regardless of the reason were: longer time from HIV diagnosis to date of starting HAART (hazard ratio [HR] 0.96; 95% CI 0.93–1.00; p=0.039), regimens containing ZDV/3TC (HR 2.86; 95% CI 1.42–5.76; p=0.003 vs TDF/FTC) and an NNRTI‐based regimen (HR 2.47; 95% CI 0.91–6.72; p=0.07 vs regimens not NNRTI‐based).

Conclusions

In a previously reported analysis of the ICONA data [1], the overall risk of discontinuation of first‐line HAART was 36% with 21% due to intolerance/toxicity. In this updated analysis, the main reason for stopping is simplification (accounting for 32% of stops), reflecting the recent changes in recommendations aimed to minimize drug toxicity, enhancing adherence and quality of life.
Preparation of Soluble Proteins fromEscherichia coli
Authors: Wingfield Paul T.
Published: November 2014

Purification of human IL‐1β is used in this unit as an example of the preparation of a soluble protein fromE. coli. Bacteria containing IL‐1β are lysed, and IL‐1 β in the resulting supernatant is purified by anion‐exchange chromatography, salt precipitation, and cation‐exchange chromatography, and then concentrated. Finally, the IL‐1 β protein is applied to a gel‐filtration column to separate it from remaining higher‐ and lower‐molecular‐weight contaminants, the purified protein is stored frozen or is lyophilized. The purification protocol described is typical for a protein that is expressed in fairly high abundance (i.e., >5% total protein) and accumulates in a soluble state. In addition, the purification procedure serves as an example of how to use classical protein purifications methods, which may also be used in conjunction with the affinity‐based methods now more commonly used. © 2014 by John Wiley & Sons, Inc.
Cryopreservation of Human Pluripotent Stem Cells in Defined Medium
Authors: Liu Weiwei , Chen Guokai
Published: November 2014

This unit describes a cryopreservation procedure using an enzyme‐free dissociation method to harvest cells and preserve cells in albumin‐free chemically defined E8 medium for human pluripotent stem cells (hPSCs). The dissociation by EDTA/PBS produces small cell aggregates that allow high survival efficiency in passaging and cryopreservation. Cryopreservation in E8 medium eliminates serum and other animal products, and is suitable for dealing with the increasing demand for high‐quality hPSCs in translational research. In combination with the special feature of EDTA/PBS dissociation, the protocols in this unit allow for efficient cryopreservation in a more time‐saving manner. © 2014 by John Wiley & Sons, Inc.
Isolation and Long‐Term Expansion of Functional, Myelinating Oligodendrocyte Progenitor Cells from Neonatal Rat Brain
Authors: Zhu Bangfu , Zhao Chao , Young Fraser I. , Franklin Robin J.M. , Song Bing
Published: November 2014

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). The isolation of purified oligodendrocyte progenitor cells (OPCs) in large numbers has been sought after as a source of cells for repair following CNS‐demyelinating diseases and injuries, such as multiple sclerosis (MS) and spinal cord injury (SCI). Methods for isolation of OPCs from rodent neonatal brains are well established and have formed the basis for research in myelin repair within the CNS for many years. However, long‐term maintenance of OPCs has been a challenge owing to small cellular yields per animal and spontaneous differentiation within a short period of time. Much effort has been devoted to achieving long‐term culture and maintenance of OPCs, but little progress has been made. Here, protocols are presented for preparation of highly enriched rat OPC populations and for their long‐term maintenance as oligospheres using mixed‐glial‐conditioned medium. Functional myelinating oligodendrocytes can be achieved from such protocols, when co‐cultured with primary neurons. This approach is an extension of our normal shaking method for isolating OPCs, and incorporates some adaptations from previous OPC culture methods. © 2014 by John Wiley & Sons, Inc.
Vibrio cholerae: Measuring Natural Transformation Frequency
Authors: Watve Samit S. , Bernardy Eryn E. , Hammer Brian K.
Published: November 2014

Many bacteria can become naturally competent to take up extracellular DNA across their outer and inner membranes by a dedicated competence apparatus. Whereas some studies show that the DNA delivered to the cytoplasm may be used for genome repair or for nutrition, it can also be recombined onto the chromosome by homologous recombination: a process called natural transformation. Along with conjugation and transduction, natural transformation represents a mechanism for horizontal transfer of genetic material, e.g., antibiotic resistance genes, which can confer new beneficial characteristics onto the recipient bacteria. Described here are protocols for quantifying the frequency of transformation for the human pathogen Vibrio cholerae, one of several Vibrio species recently shown to be capable of natural transformation. © 2014 by John Wiley & Sons, Inc.
Observer error, dental wear, and the inference of new world sundadonty
Authors: Stojanowski Christopher M. , Johnson Kent M.
Published: November 2014

Dental morphology provides important information on human evolution and interpopulation relationships. Dental wear is one of the major limitations of morphological data analysis. Wear figures heavily in existing debates about patterns of New World dental variation with some scholars finding evidence for a more generalized dentition in early New World populations (Powell: Doctoral Dissertation, Texas A&M University, TX (1995)) and others questioning these findings based on the probable effects of dental wear on trait scores (Turner, The First Americans: the Pleistocene Colonization of the New World. San Francisco: California Academy of Sciences (2002) 123–158; Turner: Am J Phys Anthropol 130 (2006) 455–461; Turner and Scott, Handbook of paleoanthropology, Vol. III: Phylogeny of Hominids. New York: Springer (2007) 1901–1941). Here we evaluate these competing claims using data from the Early Archaic Windover sample. Results confirm the dental distinctiveness of Windover with respect to other Old World Asian (i.e., sinodont/sundadont) populations. However, comparison of our results to those of Powell (1995) also highlights significant interobserver error. Statistical analysis of matched wear and morphology scores suggests trait downgrading for some traits. Patterns of missing data present a more challenging (and potentially serious) problem. Use of Little's MCAR test for missing data mechanisms indicates a complex process of data collection in which incidental and opportunistic recording of both highly worn and unerupted teeth introduce a “missing not at random” mechanism into our dataset that biases dental trait frequencies. We conclude that patterns of missingness and formal research designs for “planned missingness” are needed to help mitigate this bias. Am J Phys Anthropol 156:349–362, 2015. © 2014 Wiley Periodicals, Inc.
Geographic and temporal trends in frontal sinus surgery
Authors: Svider Peter F. , Sekhsaria Vibhav , Cohen David S. , Eloy Jean Anderson , Setzen Michael , Folbe Adam J.
Published: November 2014

Background

The purpose of this study was to evaluate geographic and temporal trends in frontal sinus surgery procedures.

Methods

Medicare Part B data files from 2000 to 2011 were examined for temporal trends in various frontal sinus procedures, and the most recent year containing geographic information (2010) was evaluated for Current Procedural Terminology (CPT) code use. Additionally, nationwide charges per procedure were recorded. Regional populations of individuals ≥65 years old were obtained from the 2010 U.S. Census, and surgical society websites were used to determine the number of practicing rhinologists and otolaryngologists in each region.

Results

The use of open approaches declined by one third, while endoscopic procedures went from 6463 to 19262 annually, with the most marked increases occurring from 2006 through 2011. Geographic variation was noted, with practitioners in the South Atlantic states performing the greatest number of endoscopic procedures in 2010, whereas the East South Central states had the greatest number when controlling for population. There was an inverse relationship between endoscopic procedures performed and number of fellowship‐trained rhinologists (controlling for regional populations) (R2 = 0.66). The first year frontal sinus ballooning had a unique CPT code illustrated decreased reimbursements for non‐balloon endoscopic surgery ($609) relative to balloon approaches ($2635).

Conclusion

Declines in open frontal sinus surgery and marked increases in endoscopic approaches have potential implications for residency training. Potential reasons for marked increases in endoscopic approaches include the rising popularity of balloon technologies, although this is speculative. Geographic variation exists in frontal sinus surgery patterns, including an inverse relationship between endoscopic approaches and the number of fellowship‐trained rhinologists.
Topical intranasal corticosteroids and growth velocity in children: a meta‐analysis
Authors: Mener David J. , Shargorodsky Josef , Varadhan Ravi , Lin Sandra Y.
Published: November 2014

Background

There is no consensus regarding the effects on growth velocity of intranasal topical corticosteroid (ITC) use in children. The objective of this study was to determine whether ITC use reduces growth velocity in children with allergic rhinitis (AR).

Methods

A literature search of the National Center for Biotechnology Information PubMed, EMBASE, SCOPUS, and Cochrane databases from January 1, 1988 to October 7, 2013. The study selection was composed of randomized clinical trials investigating ITC for treatment of AR in children (age <18 years of age) with appropriate controls. Studies must have included interval change in growth as an outcome. Two authors independently extracted data and assessed study quality. Eligible studies were pooled using a random‐effects approach.

Results

Eight studies with 755 participants from 3 countries provided data for the meta‐analysis (knemometry, n =342 participants; stadiometry, n =413 participants). Study duration ranged from 2 to 4 weeks for trials evaluating knemometry outcomes, and 12 months for trials evaluating stadiometry outcomes. Age of participants ranged from 3 to 12 years. The pooled standardized mean difference showed that among studies using knemometry, mean growth was statistically significantly lower among children using ITC vs placebo (−.223 mm/week; 95% confidence interval [CI], −0.429 to −0.017; p < 0.034).The pooled standardized mean difference showed that among studies using stadiometry, there was no significant growth difference among children using ITC vs placebo (−0.053 cm/year; 95% CI, −0.491 to 0.385; p = 0.813). The limitations of this study were the difficulty in predicting longer‐term or catch‐up growth in children.

Conclusion

Meta‐analytic pooling of trials suggest that short‐term ITC for the treatment of AR in children may decrease short‐term growth velocity using knemometry; however, the effect on longer‐term growth velocity as measured by stadiometry is unclear.
Quinone Diazides for Olefin Functionalization
Authors: Dao Hai T. , Baran Phil S.
Published: November 2014

The utility of quinone diazides in materials science is vast and well‐documented, yet this potentially useful motif has languished in the annals of organic synthesis. Herein we show that modern tools of catalysis can be employed with free or suitably masked quinone diazides to unleash the power of these classic diazo compounds in the context of both inter‐ and intramolecular olefin cyclopropanation.
Colloidal Nanocrystals of Lithiated Group 14 Elements
Authors: Cloud Jacqueline E. , Wang Yonglong , Yoder Tara S. , Taylor Lauren W. , Yang Yongan
Published: November 2014

The synthesis of colloidal nanocrystals (NCs) of lithiated group 14 elements (Z=Si, Ge, and Sn) is reported, which are Li4.4Si, Li3.75Si, Li4.4Ge, and Li4.4Sn. LixZ compounds are highly reactive and cannot be synthesized by existing methods. The success relied on separating the surface protection from the crystal formation and using a unique passivating ligand. Bare LixZ crystals were first produced by milling elemental Li and Z in an argon‐filled jar. Then, under the assistance of additional milling, hexyllithium was added to passivate the freshly generated LixZ NCs. This ball‐milling‐assisted surface protection method may be generalized to similar systems, such as NaxZ and KxZ. Moreover, Li4.4Si and Li4.4Ge NCs were conformally encapsulated in carbon fibers, providing great opportunities for studying the potential of using LixZ to mitigate the volume‐fluctuation‐induced poor cyclability problem confronted by Z anodes in lithium‐ion batteries.
Prüfen der Pumpbarkeit von Beton – Vom Labor in die Praxis
Authors: Secrieru Egor , Butler Marko , Mechtcherine Viktor
Published: November 2014

Für die Beurteilung der Pumpbarkeit von Frischbeton existieren bislang keine normativen Regelungen, in denen die Anforderungen an seine rheologischen Eigenschaften festgeschrieben sind. Zur Prüfung der Pumpbarkeit von Frischbeton – vor allem auf der Baustelle – ist die Etablierung einfacher, robuster und dennoch aussagekräftiger rheologischer Messtechniken von elementarer Bedeutung. Im vorliegenden Beitrag werden die neuen prüftechnischen Ansätze für eine zielsichere Optimierung des Pumpens von Frischbeton vorgestellt. Insbesondere wird die Funktionsweise des sog. Gleitrohr‐Rheometers (Sliding Pipe Rheometer, SLIPER) erläutert, mit dem Fördermengen, Druckverhältnisse und resultierende Bewegungszustände des Frischbetons in einer Betonförderleitung in guter Näherung quantitativ abgeschätzt werden können. Im Rahmen einer Parameterstudie werden die unter Verwendung von SLIPER erzielten Ergebnisse analysiert und mit denen eines stationären Betonviskosimeters verglichen. Es werden die ermittelten Zusammenhänge zwischen Rheologie und Pumpbarkeit sowohl von Normalbetonen als auch von Sonderbetonen (selbstverdichtender Beton (SVB) und hochduktiler Beton (SHCC)) dargestellt. Schließlich wird die Vorhersagefähigkeit des Pumpverhaltens von Beton auf der Basis der SLIPER‐Untersuchungen durch Messung des Pumpdruckes unter Baustellenbedingungen validiert.

Testing pumpability of concrete – From laboratory into practice

In assessing concrete pumpability, there are still no norms or regulations providing guidelines with regard of fresh concrete's rheological properties. For testing concrete pumpability, especially on the construction site, the establishment of simple, robust but reliable testing techniques is of great importance. The paper at hand gives an overview of the new approaches in estimating pumpability of fresh concrete. In particular, the idea and working principle of the so‐called Sliding Pipe Rheometer (SLIPER) are explained. Using SLIPER, pumping pressure vs. discharge rate relationships can be reliably estimated for various pipe lengths and diameters. A parameter study on the effect of concrete composition on its pumpability is also presented. The results obtained from the SLIPER tests are analysed and compared with those obtained during tests with a stationary concrete viscometer and testing using conventional, empirical tests. The correlations between the rheological properties according to the BINGHAM model and the pumpability of four various ordinary concretes and two high performance concretes (self‐compacting concrete (SCC) and strain‐hardening cement‐based composite (SHCC)) are investigated. Finally, based on the investigations the predictive capacity of the SLIPER in respect of concrete pumpability is validated by measuring the discharge pressure under field conditions.
Experimentelle Untersuchungen und numerische Verifizierung zum Frischbetondruck bei geneigten Schalungssystemen
Authors: Freund Björn , Proske Tilo , Graubner Carl‐Alexander
Published: November 2014

Moderne Massivbauwerke weisen als Gestaltungselement immer häufiger geneigte Betonbauteile auf. Bei der Herstellung von Ingenieurbauwerken, wie Kühltürmen oder Faulbehältern, kommen ebenfalls geneigte Schalungen zum Einsatz. Hinsichtlich der Dimensionierung von Schalungssystemen stellt der Frischbetondruck die maßgebliche Einwirkung dar. Die existierende Norm zum Frischbetondruck DIN 18218 enthält bisher keine Angaben für geneigte Schalungen. Daher wird in der Baupraxis bei geneigten Schalungen oftmals der hydrostatische Frischbetondruck angesetzt, was u. U. zu einer Überdimensionierung des Schalungssystems bzw. zu einer unnötigen Verlangsamung der zulässigen Betoniergeschwindigkeit und somit zu einer längeren Herstellzeit führt. Die durchgeführten Untersuchungen zeigen, dass der Frischbetondruck bei geneigten Schalungen mit konstanter Bauteildicke kleiner ausfällt als bei lotrechten Schalungen. Bestätigt wird dies durch numerische Analysen.

Experimental investigation and numerical verification of the pressure of fresh concrete on inclined formwork systems

Modern concrete structures have often inclined concrete components as their design elements. Inclined formwork is also used for the construction of other engineering structures such as cooling towers and digesters. The pressure of fresh concrete determines the dimensioning of formwork systems and the possible rate of casting. DIN 18218 as the available code for calculation of fresh concrete pressure does not contain any provisions for inclined formwork. Thus, in construction practice, the hydrostatic pressure is often used as the design value. This can lead to an over‐dimensioning of the formwork system or to an unnecessary reduction of pouring rate. The results of current investigation show that the pressure of fresh concrete on the inclined formwork with a constant thickness is lower than on the vertical one.
Ermüdungsverhalten von Beton unter zyklischer Beanspruchung aus dem Betrieb von Windenergieanlagen
Authors: Roggendorf Thomas , Goralski Claus
Published: November 2014

Da hinsichtlich der Nachweisführung für die charakteristischen Bereiche einer Windenergieanlage (WEA) unter Ermüdungsbeanspruchung aus der Bemessungspraxis verschiedene offene Punkte bekannt sind, wurde im Auftrag des Deutschen Instituts für Bautechnik (DIBt) der Sachstandsbericht “Ermüdungsverhalten von Beton unter zyklischer Beanspruchung aus dem Betrieb von Windkraftanlagen” [1] erstellt. Ziel der durchgeführten Untersuchungen war die Schaffung einer objektiven Bewertungsgrundlage zur Einstufung der derzeitigen Nachweiskonzepte für zyklische Beanspruchungen aus dem Betrieb von WEA. Dazu wurden theoretische und experimentelle Untersuchungen, die als Grundlage für die in bestehenden Regelwerken verankerten Ansätze dienen, zusammengestellt und bewertet. Darüber hinaus wurden weiterführende Bemessungsansätze aus der Literatur dargestellt und verglichen. Es folgten eigene Vergleichsberechnungen zur Ermüdungsfestigkeit an für WEA spezifischen Beispielen. Basierend auf diesen Untersuchungen wurden abschließend unter Berücksichtigung der speziellen Beanspruchungsszenarien für Bauteile von WEA der weitere Forschungsbedarf aufgezeigt und Empfehlungen für Modellversuche erarbeitet. Im vorliegenden Bericht werden die Untersuchungen und wesentliche Ergebnisse kurz zusammengefasst.

Concrete fatigue behaviour under cyclic loading from the operation of wind turbine generators

When it comes to the verification of characteristic sections in the structures for wind turbine generators under cyclic loading, various questions are known in the current design practice. Thus, the German building authorities “Deutsches Institut für Bautechnik (DIBt)” commissioned the status report “Concrete fatigue behaviour under cyclic loading from the operation of wind turbine generators” [1]. The intention of the investigations was to establish an objective criterion for the assessment of current design principles for cyclic loading from the operation of wind turbine generators. For this purpose, theoretical and experimental examinations providing a basis for the present approaches in existing codes and regulations were assembled and evaluated. In addition, advanced design approaches from literature were summarised and compared. Following this, comparative calculations concerning the resistance against concrete fatigue for typical impacts from wind turbine generators were performed. Based on these examinations and in consideration of the particular loading scenarios of structures for wind turbine generators, the need for further research was identified and recommendations for theoretical and experimental investigations were developed. The investigations and significant results are summarised in the present report.
Hierarchically Organized Silica–Titania Monoliths Prepared under Purely Aqueous Conditions
Authors: Flaig Sylvia , Akbarzadeh Johanna , Dolcet Paolo , Gross Silvia , Peterlik Herwig , Hüsing Nicola
Published: November 2014

Hierarchically organized silica–titania monoliths were synthesized under purely aqueous conditions by applying a new ethylene glycol‐modified single‐source precursor, such as 3‐[3‐{tris(2‐hydroxyethoxy)silyl}propyl]acetylacetone coordinated to a titanium center. The influence of the silicon‐ and titanium‐containing single‐source precursor, the novel glycolated organofunctional silane, and the addition of tetrakis(2‐hydroxyethyl)orthosilicate on the formation of the final porous network was investigated by SEM, TEM, nitrogen sorption, and SAXS/WAXS. In situ SAXS measurements were performed to obtain insight into the development of the mesoporous network during sol–gel transition. IR‐ATR, UV/Vis, XPS, and XAFS measurements showed that up to a Si/Ti ratio of 35:1, well‐dispersed titanium centers in a macro‐/mesoporous SiO2 network with a specific surface area of up to 582 m2 g−1 were obtained. An increase in Ti content resulted in a decrease in specific surface area and a loss of the cellular character of the macroporous network. With a 1:1 Si/Ti ratio, silica–titania powders with circa 100 m2 g−1 and anatase domains within the SiO2 matrix were obtained.
Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine, Fasicularin, and Isomers of Polycitorols by Reagent‐Controlled Diastereoselective Reductive Amination
Authors: In Jinkyung , Lee Seokwoo , Kwon Yongseok , Kim Sanghee
Published: November 2014

We describe a flexible and divergent route to the pyrrolo‐/pyrido[1,2‐j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester–enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (−)‐lepadiformine and (−)‐fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate‐controlled manner. The key step in these total syntheses was the reagent‐dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b. Aziridinium‐mediated carbon homologation of the hindered C‐10 group to the homoallylic group facilitated the synthesis.
Two‐dimensional (2D) Supramolecular Coordination at Liquid/Solid Interfaces Studied by Scanning Tunneling Microscopy
Authors: Xu Jing , Zeng Qingdao
Published: November 2014

In this review, supramolecular coordination processes on two‐dimensional (2D) surfaces or interfaces observed by scanning tunneling microscopy (STM) are discussed. Four parts are mainly involved, which include (1) recognition of Fe3+ through functional molecular networks, (2) K+‐induced switching of valinomycin, (3) supramolecular coordination happened in a nano‐reactor, (4) reversible 2D supramolecular spring driven by coordination. The direct insight of the coordination phenomena provided by STM supplements our knowledge of its mechanism. Since different building blocks can be connected into a whole part through coordination, the understanding of its mechanism will be beneficial to the future design of molecular devices.
A closed‐form equation approach to multi‐port/multi‐zone behavioral modeling of GaN FET Amplifiers
Authors: Crespo‐Cadenas Carlos , Reina‐Tosina Javier , Madero‐Ayora María J. , Allegue‐Martínez Michel
Published: November 2014

In this paper, a systematic method for the simulation of weakly and mildly nonlinear GaN FET amplifiers is reported. The core of the proposal is a third‐order Volterra‐based behavioral model with multi‐spectral and multi‐node capabilities that is formally derived from a circuit‐level representation. Starting with the equivalent circuit of a typical FET device with thermal power feedback and fading memory, described in terms of its large‐signal functions, closed‐form expressions for the kernels at the gate, drain and thermal nodes are developed up to the third order. The use of these kernels allows the calculation of the responses in the dc, first‐, second‐ and third‐harmonic zones, which are shown to be dependent on the frequency response of the amplifier circuit terminating impedances and thermal filter. The simulation approach has been applied to calculate the nonlinear response of a typical power amplifier circuit, showing the ability of the proposed approach to provide an accurate prediction of multi‐spectral, multi‐node, multi‐bias characteristics, including AM/AM‐AM/PM conversion, spectral regrowth, intermodulation, and temperature rise, under diverse input signal waveforms and bandwidths. These results have been successfully compared with commercial CAD tools based on harmonic balance or envelope simulation. Copyright © 2014 John Wiley & Sons, Ltd.