bluuebunny/crossref_metadata_2025 huggingface dataset:
Process optimization and ethanol use for obtaining white and red dragon fruit powder by foam mat drying
Authors: Macedo Leandro Levate , Corrêa Jefferson Luiz Gomes , Araújo Cintia da Silva , Vimercati Wallaf Costa , Pio Leila Aparecida Salles
Published: January 2021

Dragon fruit shows good sensory and nutritional attributes, but it is also highly perishable. Drying is a unitary operation that promotes the reduction of moisture content, extending the useful life of the product. In this study, the elaboration of white and red dragon fruit powder by foam mat drying was studied with optimization of the proportion of foaming agent and stirring time. The use of ethanol and air temperature were evaluated on drying kinetics, effective moisture diffusivity (Deff), and drying rate (DR). The study was divided into two steps. In the first, density, stability, porosity and overrun foam were evaluated and the optimal condition was determined. For the white and red pulp foams, the optimal conditions were, respectively, 26.88 min and 4.12 kg 100 kg–1 and 23.5 min and 3.44 kg 100 kg–1. In the second step, the foam was subjected to ethanol pretreatment and convective drying (50 or 70 °C). The best condition involved pretreatment and the highest tested temperature, with the shortest drying time and the highest Deff and DR.

Practical Application

Foam mat drying is a suitable method for drying perishable fruits, such as dragon fruit. The foam properties need to be optimized to ensure the success of the drying process. The ethanol pretreatment and the drying air temperature influence the drying kinetics. Therefore, determining the optimal process conditions is very important.
Enzyme biotechnology development for treating polymers in hydraulic fracturing operations
Authors: Scheffer Gabrielle , Berdugo‐Clavijo Carolina , Sen Arindom , Gieg Lisa M.
Published: January 2021

Carboxymethyl cellulose (CMC) is a polymer used in many different industrial sectors. In the oil and gas industry, CMC is often used during hydraulic fracturing (fracking) operations as a thickening agent for effective proppant delivery. Accumulations of CMC at fracture faces (known as filter cakes) can impede oil and gas recovery. Although chemical oxidizers are added to disrupt these accumulations, there is industrial interest in developing alternative, enzyme‐based treatments. Little is known about CMC biodegradation under fracking conditions. Here, we enriched a methanogenic CMC‐degrading culture and demonstrated its ability to enzymatically utilize CMC under the conditions that typify oil fields. Using the extracellular enzyme fraction from the culture, significant CMC viscosity reduction was observed between 50 and 80˚C, at salinities up to 20% (w/v) and at pH 5–8 compared to controls. Similar levels of viscosity reduction by extracellular enzymes were observed under oxic and anoxic conditions. This proof‐of‐concept study demonstrates that enzyme biotechnology holds great promise as a viable approach to treating CMC filter cakes under oilfield conditions.
A reference‐free approach to analyse RADseq data using standard next generation sequencing toolkits
Authors: Heller Rasmus , Nursyifa Casia , Garcia‐Erill Genís , Salmona Jordi , Chikhi Lounes , Meisner Jonas , Korneliussen Thorfinn Sand , Albrechtsen Anders
Published: January 2021

Genotyping‐by‐sequencing methods such as RADseq are popular for generating genomic and population‐scale data sets from a diverse range of organisms. These often lack a usable reference genome, restricting users to RADseq specific software for processing. However, these come with limitations compared to generic next generation sequencing (NGS) toolkits. Here, we describe and test a simple pipeline for reference‐free RADseq data processing that blends de novo elements from STACKS with the full suite of state‐of‐the art NGS tools. Specifically, we use the de novo RADseq assembly employed by STACKS to create a catalogue of RAD loci that serves as a reference for read mapping, variant calling and site filters. Using RADseq data from 28 zebra sequenced to ~8x depth‐of‐coverage we evaluate our approach by comparing the site frequency spectra (SFS) to those from alternative pipelines. Most pipelines yielded similar SFS at 8x depth, but only a genotype likelihood based pipeline performed similarly at low sequencing depth (2–4x). We compared the RADseq SFS with medium‐depth (~13x) shotgun sequencing of eight overlapping samples, revealing that the RADseq SFS was persistently slightly skewed towards rare and invariant alleles. Using simulations and human data we confirm that this is expected when there is allelic dropout (AD) in the RADseq data. AD in the RADseq data caused a heterozygosity deficit of ~16%, which dropped to ~5% after filtering AD. Hence, AD was the most important source of bias in our RADseq data.
Clinical utility of the C‐reactive protein:albumin ratio in non‐small cell lung cancer patients treated with nivolumab
Authors: Araki Taisuke , Tateishi Kazunari , Sonehara Kei , Hirota Shuko , Komatsu Masamichi , Yamamoto Manabu , Kanda Shintaro , Kuraishi Hiroshi , Hanaoka Masayuki , Koizumi Tomonobu
Published: January 2021

Background

Nivolumab is a second‐line chemotherapy for non‐small cell lung cancer (NSCLC). This study explored the impact of clinical biomarkers such as neutrophil:lymphocyte ratio (NLR), C‐reactive protein:albumin ratio (CAR), and modified Glasgow prognostic score on the efficacy and outcome of nivolumab monotherapy in previously treated NSCLC patients.

Methods

We retrospectively analyzed advanced or postoperative recurrence of NSCLC in 113 patients in two Japanese facilities from January 2015 to December 2019. Optimal cutoff values of NLR and CAR were assessed by the area under the receiver operating characteristic curves predicting death events to conduct regression analysis. Baseline values and values collected eight weeks after nivolumab treatment were measured to investigate time‐series changes of these markers.

Results

The patients showed median overall survival (OS) and progression‐free survival (PFS) of 14.0 months and 2.3 months, respectively, with both being significantly longer in patients with partial response (PR) than in patients with progressive disease (PD). Optimal cutoff levels for NLR and CAR were 5.8 and 0.83, with significant decrease in CAR (P = 0.002) from baseline levels in PR patients and significant increase in PD patients. Baseline CAR ≥0.83 was significantly associated with one‐year mortality events and overall survival (OS), and multivariate analysis showed significant association of age ≤70 years, an Eastern Cooperative Oncology Group performance status score of 2 or 3, and a baseline CAR ≥0.83 with inferior OS.

Conclusions

For second‐line nivolumab therapy, evaluation of baseline CAR and subsequent changes in CAR may be predictive of therapeutic response to nivolumab and long‐term survival in NSCLC patients.

Key points

Significant findings of the study

The baseline value of C‐reactive protein:albumin ratio was significantly associated with one‐year mortality and overall survival in non‐small cell lung cancer patients treated with nivolumab.

What this study adds

Time‐series change of C‐reactive protein:albumin ratio may be useful for predicting the treatment efficacy in patients treated with nivolumab.
Real‐world efficacy of atezolizumab in non‐small cell lung cancer: A multicenter cohort study focused on performance status and retreatment after failure of anti‐PD‐1 antibody
Authors: Furuya Naoki , Nishino Makoto , Wakuda Kazushige , Ikeda Satoshi , Sato Takashi , Ushio Ryota , Tanzawa Shigeru , Sata Masafumi , Ito Kentaro
Published: January 2021

Background

Atezolizumab is a programmed death‐ligand 1 (PD‐L1) targeted monoclonal antibody that inhibits PD‐L1 interacting with its receptors PD‐1 and B7‐1, thereby enhancing anticancer immunity. Some real‐world efficacy and safety studies of anti‐PD‐1 antibody have been previously reported. However, there have been no reports investigating the efficacy of atezolizumab monotherapy in clinical practice which have focused on performance status and previous anti‐PD‐1 antibody treatment.

Methods

We retrospectively reviewed consecutive advanced NSCLC patients who received atezolizumab monotherapy between April 2018 and February 2019 at eight institutions. A total of 152 patients with NSCLC were enrolled in this study.

Results

A total of 38 patients (25%) had already been treated with anti‐PD‐1 treatment (nivolumab or pembrolizumab) before atezolizumab. The median OS and TTF was 384 days (12.8 months) (95% confidence interval [CI]: 206–424), and 42 days (1.4 months) (95% CI: 27–56) in all patients, respectively.

ECOG PS 0 had significantly longer OS (median OS; not reached, p < 0.0001) and TTF (median TTF; 63 days, p = 0.012) compared with PS 1 or 2–3. Most retreated patients were unable to continue atezolizumab for a longer period, but seven patients (18.4%) were able to continue atezolizumab over four months as an ICI retreatment.

Conclusions

In previously treated advanced NSCLC patients, atezolizumab monotherapy demonstrated good efficacy and safety regardless of heavily treated patients in real‐world clinical practice, and ECOG PS 0 was a favorable predictive factor. The efficacy of retreatment with atezolizumab was limited but was well tolerated in patients treated with prior anti‐PD‐1 antibody.
Beyond Risk Shifting: The Knowledge‐Transferring Role of Audit Liability Insurers*
Authors: Frank Michele , Maksymov Eldar , Peecher Mark , Reffett Andrew
Published: January 2021

Regulators and researchers tend to focus primarily on the risk‐shifting benefits of audit liability insurance. We obtain field data from the US audit insurance industry (16 interviews and 83 survey responses) to examine whether insurers also possess characteristics favorable to transferring their private risk management knowledge to the audit firms they insure. Possessing such characteristics would enable insurers to use their relative knowledge advantage to provide a benefit to audit firms beyond risk shifting. Thus, examining this issue helps broaden our understanding of insurers' role in auditing. We examine our data through the lens of the knowledge transfer theory and find evidence that audit liability insurers have the motivation and capacity to accumulate and transfer risk management knowledge to the audit firms they insure. We find that audit firms, particularly the small resource‐constrained firms (i.e., non–Big 4 and non‐second‐tier), rely on and benefit from their insurers' risk management knowledge. We also find that insurers transfer such knowledge through multiple mechanisms, including free consultative services, policy premium incentives, and continuing professional education classes. Our results highlight the important role of audit insurers as transferors of risk management knowledge to audit firms. Broadly, our results extend knowledge transfer theory and suggest areas for future research in US and international contexts.
Time to ventilation and success rate of airway devices in microgravity: A randomized crossover manikin‐trial using an underwater setting
Authors: Warnecke Tobias , Dauth Lisa , Ahlbäck Anton , DuCanto James , Fleischhammer Elisabeth , Glatz Carlos , Kerkhoff Steffen , Mathes Alexander , Schmitz Jan , Starck Clement , Thierry Seamus , Hinkelbein Jochen
Published: January 2021

Background

Medical support for space exploration missions must prepare for severe medical events in conditions of microgravity. A key component to managing these events is techniques of airway management. The aim of the present trial is to compare airway management devices in simulated microgravity.

Methods

In this randomized cross‐over trial (RCT), four different devices were compared under simulated microgravity conditions utilizing a neutrally buoyant free‐floating underwater manikin and poolside in normal gravity (control group). The primary endpoint was the successful placement of the airway device. The secondary endpoints were the number of attempts and the duration of each attempt.

Results

A total of 20 participants performed placement of each device in both gravity conditions in an Airway mannequin. The fastest time to initial ventilation in simulated microgravity was possible with the laryngeal tube (18.9 ± 8 seconds) followed by laryngeal mask (20.1 ± 9 seconds). The I‐gel® supraglottic airway device required substantially more time for successful insertion in simulated microgravity (35.4 ± 25 seconds) as did endotracheal tube intubation by direct laryngoscopy (70.4 ± 35 seconds). Simulated microgravity conditions prolonged time to initial ventilation by 3.3 seconds (LM), 3.9 seconds (LT), 19.9 seconds (I‐gel) and 43.1 seconds (endotracheal intubation, ETI) when compared to poolside attempts in normogravity.

Conclusion

In simulated microgravity conditions, use of the laryngeal tube or laryngeal mask provided the quickest time to initial ventilation, without deliberate tethering of the mannequin and rescuer to a fixed surface. Endotracheal intubation required significantly longer procedure times and, thus, was considered insufficient for clinical use in microgravity.
The Effectiveness of Alcohol Impact Areas in Reducing Crime in Washington Neighborhoods
Authors: Jones‐Webb Rhonda , Joshi Spruha , Erickson Darin , McKee Patricia , Nelson Toben , Toomey Traci
Published: January 2021

Background

We evaluated the effectiveness of Alcohol Impact Areas (AIA) in reducing crime around off‐premise alcohol outlets in 3 AIAs in Spokane and Tacoma, Washington, using an interrupted time series design with comparison groups. AIAs only exist in Washington and include designated areas in a city where specific brands of malt liquor are restricted. We hypothesized that mandatory restrictions on malt liquor sales in AIAs would be significantly associated with decreases in crime, especially less‐serious crime.

Methods

In Spokane and Tacoma, targets were 3 AIAs and 3 comparison areas with demographically similar neighborhoods without malt liquor restrictions in the same respective city. Nine different crime outcomes were evaluated: Part I selected crimes, Part II selected crimes (further split into nuisance crimes and other Part II crimes), assaults, vandalism, narcotics, disorderly conduct, and all selected crimes combined. Crime was typically compared 3 years prior to and 3 years following policy adoption using time series and negative‐binomial modeling. Separate models were run for each area and each crime.

Results

Study hypotheses were partially supported. Malt liquor restrictions in AIAs were associated with significant decreases in crime, particularly certain Part II crimes and assaults (simple and aggravated) in 12 of the 23 models. The strength of the observed associations varied by AIA. Average monthly crime counts across all crime categories decreased more in the Tacoma AIA than in Spokane AIAs, and average monthly crime decreased more in Spokane AIA 2 (East Central) than in AIA 1 (Downtown Core). Malt liquor restrictions were significantly associated with increases in disorderly conduct in the Tacoma AIA; the increase, however, was small.

Conclusions

Findings suggest that malt liquor policies such as AIAs may be one of a number of tools local officials can use to reduce alcohol‐related crime in cities, especially less‐serious crime.
Skin defenses of North American salamanders against a deadly salamander fungus
Authors: Pereira K. E. , Woodley S. K.
Published: January 2021

The recently emerged fungal pathogen,Batrachochytrium salamandrivorans(Bsal) causes the lethal skin disease chytridiomycosis in susceptible salamander species and is predicted to emerge within the Americas with devastating consequences. Host responses toBsalare variable but the factors underlying these differences are unknown. To investigate the role of skin‐associated immune defenses againstBsaland the closely related,B. dendrobatidis(Bd), we sampled skin peptides from wild and captive North American salamanders (spotted salamanders [Ambystoma maculatum], n = 10; hellbenders [Cryptobranchus alleganiensis], n = 2; red‐legged salamanders [Plethodon shermani], n = 18;and Ocoee salamanders [Desmognathus ocoee], n = 15) and conductedin vitroexperimental assays to test whether salamander skin peptides inhibit chytrid growth. Interspecies differences in skin defenses againstBsalandBd, and peptide mixtures were also assessed using a standardized measure and RP‐HPLC, respectively. ForA. maculatum, skin peptides inhibitedBsalandBdgrowth, consistent with knownBsalresistance.Cryptobranchus alleganiensisskin peptides inhibited the growth ofBsalbut notBd. Plethodon shermaniandD. ocoeeskin peptides facilitatedBsalgrowth and had either no effect or inconsistent effects onBdgrowth. With the exception ofA. maculatum, most species had relatively weak skin defenses against both chytrid pathogens. Collectively, we demonstrate that salamander skin peptide defenses against chytrid pathogens are highly variable and not always equally effective againstBsalandBd. By advancing knowledge about the factors underlying chytrid susceptibility, particularlyBsal, our findings will help inform conservation initiatives aimed at reducing disease impacts and biodiversity loss.
Propaganda and Skepticism
Authors: Horz Carlo M.
Published: January 2021

Existing work on propaganda finds that its extremeness and effectiveness vary in sometimes puzzling ways in response to major environmental factors such as repression, diversion, and crisis. Formal models of propaganda generally examine these factors in isolation, rendering a comprehensive understanding difficult; moreover, they often impose rationality assumptions at odds with experimental findings. I propose a behavioral game‐theoretic model of propaganda in which, consistent with psychology research, citizens are cognitively constrained and their skepticism toward propaganda is endogenous. These cognitive constraints generate a trade‐off for the propagandist between motivating extreme action through extreme statements and triggering citizen skepticism. I then incorporate repression, diversion, and crisis into the model. I synthesize, and explain, empirical findings on the relationships between these factors by showing how each affects both the citizen's level of skepticism and the propagandist's calculus.
The role of regional anaesthesia in the emerging subspecialty of onco‐anaesthesia: a state‐of‐the‐art review
Authors: Dockrell L. , Buggy D. J.
Published: January 2021

Cancer accounts for millions of deaths globally each year, predominantly due to recurrence and metastatic disease. The majority of patients with primary solid organ cancers require surgery, however, some degree of tumour dissemination related to surgery is inevitable. The surgical stress response and associated immunosuppression, pain, inflammation, tissue hypoxia and angiogenesis have all been implicated in promoting tumour survival, proliferation and recurrence. Regional anaesthesia was hypothesised to reduce the surgical stress response and immunosuppression, minimise the need for volatile anaesthesia and reduce pain and opioid requirements, thus mitigating pro‐tumour pathways associated with the peri‐operative period and improving long‐term oncological outcomes. While some retrospective studies suggested an association between regional anaesthesia and reduced cancer recurrence, the first large randomised controlled trial on the effect of anaesthetic technique on cancer outcome found no significant difference between paravertebral regional anaesthesia and volatile anaesthesia with opioid analgesia in patients undergoing breast cancer surgery. Randomised controlled trials on the long‐term oncological outcomes of regional anaesthesia in other tumour types are ongoing. The focus on how peri‐operative interventions, especially regional anaesthesia, during cancer resection surgery, may enhance short‐term recovery and perhaps influence long‐term outcome has spawned the global emergence of the subspecialty of onco‐anaesthesia. This review aims to discuss the most recent evidence on the use of regional anaesthesia in cancer surgery and the significance of its role in onco‐anaesthesia.
The role of regional anaesthesia and multimodal analgesia in the prevention of chronic postoperative pain: a narrative review
Authors: Chen Y.‐Y. K. , Boden K. A. , Schreiber K. L.
Published: January 2021

Effective prevention of chronic postoperative pain is an important clinical goal, informed by a growing body of studies. Peri‐operative regional anaesthesia remains one of the most important tools in the multimodal analgesic toolbox, blocking injury‐induced activation and sensitisation of both the peripheral and central nervous system. We review the definition and taxonomy of chronic postoperative pain, its mechanistic basis and the most recent evidence for the preventative potential of multimodal analgesia, with a special focus on regional anaesthesia. While regional anaesthesia targets several important aspects of the mechanistic pathway leading to chronic postoperative pain, evidence for its efficacy is still mixed, possibly owing to the heterogeneity of risk profiles within the surgical patient, but also to variation in techniques and medications reported in the literature.
Pros and cons of hemi‐thyroidectomy for low‐risk differentiated thyroid cancer
Authors: Papachristos Alexander J. , Glover Anthony , Sywak Mark S. , Sidhu Stan B.
Published: January 2021

The debate regarding the surgical management of low‐risk differentiated thyroid cancer (DTC) is ongoing. The recommended extent of surgery in DTC is based on an assessment of the predicted risk of recurrence and recent guidelines reflect an evolving philosophy of de‐escalation of surgical management, informed by a growing understanding of the determinants of tumour biology and important prognostic factors. However, our current clinical and pathological risk stratification processes are imperfect and hence there is significant variation in clinical practice. Surgeons face the challenge of finding the balance between avoiding overtreatment, minimizing complications and providing adequate oncological management. This article discusses the nuances of the current management guidelines as well as the important considerations in preoperative decision making.
One‐year follow up on post‐placental IUD insertion: A randomized clinical trial
Authors: Marangoni Marcos , Laporte Montas , Surita Fernanda , Kraft Maria B. , Bahamondes Luis , Juliato Cássia R. T.
Published: January 2021

Introduction

Our objectives were to compare the 1‐year follow‐up clinical performance of the TCu380A intrauterine device (TCu380A‐IUD) and levonorgestrel (LNG) 52‐mg intrauterine system (IUS) inserted at post‐placental period.

Material and methods

We conducted an open‐label, parallel‐group, randomized clinical trial, 1:1 with pregnant women admitted for childbirth independently of the mode of birth. Our primary outcome was expulsion up to 1 year after device placement by type of IUD and mode of delivery. During the follow up (42, 90 and 365 days (±7 days) after device placement), an ultrasound was performed to evaluate the device position. Kaplan–Meier with log‐rank test was used to compare the survival curves of the TCu380A IUD and the LNG IUS. Couple‐Years of Protection after insertion of both devices was calculated.

Results

One hundred and forty women were randomized to the TCu380A IUD (n = 70) or the LNG IUS (n = 70). By the end of the first year after device placement, 38 women experienced device expulsion (27.1%), most of them (33/38; 86.8%) within the first 42 days after delivery. The expulsions were significantly higher among users of TCu380A IUD (39.4%) than among users of the LNG IUS (22.2%; P = .039), and among those with vaginal delivery (43.8%) than among women with cesarean delivery (15%; P = .003). The 1‐year cumulative continuation rate was 64.2%, significantly higher for LNG IUS (73.1%) than for TCu380A IUD (54.4%; P = .03), and among women with cesarean delivery (77.6%) than for vaginal delivery (52%; P = .00). The post‐placental IUD insertion provided 356.4 Couple‐Years of Protection.

Conclusions

Two‐thirds of women who accepted a post‐placental IUD placement still used the device 1 year after childbirth. However, expulsion was the most prevalent reason for discontinuation, mainly within 42 days after device placement. The expulsion rate was significantly higher among TCu380A IUD users and among women with vaginal delivery.
Induction of labor in breech presentations ‐ a retrospective cohort study
Authors: Welle‐Strand Johanne Augusta Horn , Tappert Christian , Eggebø Torbjørn Moe
Published: January 2021

Introduction

There is limited evidence on the safety and outcome of induction of breech labor. In this study, we aimed to compare the outcomes of spontaneous and induced breech deliveries and to describe variations in induction rates.

Material and methods

This was a retrospective cohort study comprising 1054 singleton live fetuses in breech presentation at Trondheim University Hospital from 2012 to 2019. The main outcome was intrapartum cesarean section, and secondary outcomes were postpartum hemorrhage, anal sphincter ruptures, Apgar scores, pH in the umbilical artery, and metabolic acidosis. All data were obtained from the hospital birth journal.

Results

Induction of labor was performed in 127/606 (21.0%) women with planned vaginal birth. The frequency of intrapartum cesarean section was 48.0% for induced labor vs 45.7% for spontaneous labor (P = .64). We found no differences in the frequency of postpartum hemorrhage or anal sphincter ruptures between induced and spontaneous births. The median pH in the umbilical artery was significantly lower in neonates with induced labor compared with neonates with spontaneous labor (7.22 vs 7.25; P = .02). The frequency of pH <7.05 was 7.0% for induced labor vs 2.9% (P = .05) for spontaneous labor, but the frequency of pH <7.0 was not significantly different: 2.6% vs 0.8% (P = .14), respectively. Three neonates with planned vaginal birth had metabolic acidosis: two with spontaneous labors and one with induced labor. Three fetuses with planned vaginal birth died during labor: two with spontaneous onset of labor and one with induced labor. All three were extremely preterm: two were delivered in week 23 and one in week 25. We did not observe any significant trend in induction rates in either parous or nulliparous women.

Conclusions

The induction rates were stable during the study period. We did not observe any significant difference in intrapartum cesarean section rates, in the frequency of pH <7.0 in the umbilical artery, or in the frequency of metabolic acidosis when comparing induced and spontaneous breech deliveries.
Efficacy and safety of different agents, dosages and strategies of anti‐vascular endothelial growth factor treatment for neovascular age‐related macular degeneration: a network meta‐analysis of randomized controlled trials
Authors: Zhao Xin‐Yu , Meng Li‐Hui , Liu Sheng‐zhi , Chen You‐Xin
Published: January 2021

Purpose

To evaluate the efficacy and safety of different agents, dosages and strategies of anti‐vascular endothelial growth factor (VEGF) treatment for neovascular age‐related macular degeneration (nAMD) by network meta‐analysis.

Methods

Electronic database searches were conducted on PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 December 2019 to `identify relevant randomized controlled trials (RCTs). The standardized mean difference (SMD), odds ratios (OR), 95% confidence intervals (CI), the surface under the cumulative ranking curves and the mean ranks of each outcome were estimated by Stata 14.0.

Results

Forty‐seven RCTs encompassing 17 872 nAMD patients randomly assigned to 36 regimens of anti‐VEGF agents or sham treatment were included. T&E strategy shows top‐level effect both in BCVA changes and the percentage of patients with a gain of 3 lines or more of BCVA. When taking the same strategy, there is no significant difference of efficacy among ranibizumab, bevacizumab and aflibercept (p > 0.05); The combination of radiation, topical NSAIDs and photodynamic therapy (PDT) might provide additional benefit in central retinal thickness (CRT) reduction; all these therapeutic regimens of different anti‐VEGF agents do not significantly increase the risk of severe ocular or cardiocerebral vascular adverse events (ADEs) compared with sham treatment (p > 0.05).

Conclusions

T&E strategy showed a satisfactory effect in visual improvement and there is no significant difference in efficacy or safety among ranibizumab, bevacizumab and aflibercept. All the included regimens have an acceptable risk of ADEs.
MicroRNA‐122 and cytokeratin‐18 have potential as a biomarkers of drug‐induced liver injury in European and African patients on treatment for mycobacterial infection
Authors: Rupprechter Sarah A.E. , Sloan Derek J. , Oosthuyzen Wilna , Bachmann Till T. , Hill Adam T. , Dhaliwal Kevin , Templeton Kate , Matovu Joshua , Sekaggya‐Wiltshire Christine , Dear James W.
Published: January 2021

Aims

Patients on antituberculosis (anti‐TB) therapy are at risk of drug‐induced liver injury (DILI). MicroRNA‐122 (miR‐122) and cytokeratin‐18 (K18) are DILI biomarkers. To explore their utility in this global context, circulating miR‐122 and K18 were measured in UK and Ugandan populations on anti‐TB therapy for mycobacterial infection.

Methods

Healthy subjects and patients receiving anti‐TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER—ClinicalTrials.gov Identifier: NCT03211208). African patients with human immunodeficiency virus–TB coinfection were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF—NCT03982277). Serial blood samples, demographic and clinical data were collected. In ALISTER samples, MiR‐122 was quantified using polymerase chain reaction. In ALISTER and SAEFRIF samples, K18 was quantified by enzyme‐linked immunosorbent assay.

Results

The study had 235 participants (healthy volunteers [n = 28]; ALISTER: active TB [n = 30], latent TB [n = 88], nontuberculous mycobacterial infection [n = 25]; SAEFRIF: human immunodeficiency virus‐TB coinfection [n = 64]). In the absence of DILI, there was no difference in miR‐122 and K18 across the groups. Both miR‐122 and K18 correlated with alanine transaminase (ALT) activity (miR‐122: R = .52, 95%CI = 0.42–0.61, P < .0001. K18: R =0.42, 95%CI = 0.34–0.49, P < .0001). miR‐122 distinguished those patients with ALT>50 U/L with higher sensitivity/specificity than K18. There were 2 DILI cases: baseline ALT, 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18, 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR‐122 4 and 17 fM, peak miR‐122 60 and 336 fM, respectively.

Conclusion

In patients treated with anti‐TB therapy, miR‐122 and K18 correlated with ALT and increased with DILI. Further work should determine their diagnostic and prognostic utility in this global context‐of‐use.
Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in paediatric patients
Authors: Nijstad A. Laura , Nierkens Stefan , Lindemans Caroline A. , Boelens Jaap Jan , Bierings Marc , Versluys A. Birgitta , van der Elst Kim C.M. , Huitema Alwin D.R.
Published: January 2021

Aims

Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in paediatric patients and one adult.

Methods

From 80 paediatric (0.5–18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using nonlinear mixed effects modelling.

Results

A two‐compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into nonrenal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval [CI] 13.7–34.4) and 29.8 L/h (95% CI 23.9–36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6–22.4). A high variability in exposure was observed (range area under the curveT0‐inf 1.8–6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practised BSA‐based dosing is not adequate for clofarabine.

Conclusion

A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA‐based dosing. However, the exact target exposure needs to be further investigated.
Finding the voice of students engaging in online alternative provision via digital data collection methods
Authors: Smith Sharon
Published: January 2021

The number of students accessing Alternative Provision (AP) in the UK is growing and the ways in which such provision is facilitated is evolving with the use of EdTech. However, there is very little evidence of such provisions being evaluated in terms of their educational impact nor regarding the way in which students engage with them. This results in the voices of students participating in AP being further marginalised by being out of mainstream education, as they fail to be heard by their educators, schools or local authorities. Within this exploratory paper digital data collection methods are shown to offer a solution to this problem and reveal student voice insights into how they engage with and experience one specific form of synchronistic online AP. This study provides evidence of how student voice can effectively be collated in order to provide an opportunity for marginalised student voices to be heard.

Practitioner Notes

What is already known about this topic

Student voice is a critical tool in both engaging students and student engagement.

There is a preference in students to give anonymous feedback and this facilitates more honest, open responses.

AP uptake is increasing.

There has been little evidence of any effort to obtain student voice from students in AP.

What this paper adds

Gathering student voice from students in AP is critical to assess how students view and respond to their provision.

Digital data collection facilitates AP student voice; students both younger and potentially more vulnerable to disengagement can have their voices heard more easily.

A substantial majority of students in AP who have left mainstream education perceive online learning delivery methods to have positive impacts.

Implications for practice/pedagogy

Practitioners should strive to ensure AP students have avenues through which they may have their student voices heard to gain insights into the effectiveness of the provision from a student perspective.

Anonymous feedback, which enables students to be confident in expressing their views, even when verbally expressed, can be facilitated through digital data collection methods.

Use of live, online interactive lessons are a valuable form of AP worthy of further exploration.
Non‐renewable resources and the possibility of sustainable economic development in an economy with positive or negative population growth
Authors: Sasaki Hiroaki
Published: January 2021

The purpose of this study is to investigate how the long‐run growth rate of per capita output is determined when an economy is subject to non‐renewable resource constraints and the population growth is negative by using a theoretical model. From this, we can examine the effect of population decline and the effect of depletion of natural resources on economic growth. Our results show that irrespective of whether the population growth rate is positive or negative, the long‐run growth rate of per capita output can be positive depending on conditions. This result suggests that even an economy with non‐renewable resources and declining population can obtain sustainable economic growth.
Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins
Authors: Neul Claudia , Hofmann Ute , Schaeffeler Elke , Winter Stefan , Klein Kathrin , Giacomini Kathleen M. , Eichelbaum Michel , Schwab Matthias , Nies Anne T.
Published: January 2021

Background and Purpose

The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine.

Experimental Approach

OCT1/SLC22A1‐, OCT2/SLC22A2‐, OCT3/SLC22A3‐, MATE1/SLC47A1‐, and MATE2K/SLC47A2‐overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1‐R61C), rs34130495 (OCT1‐G401S), rs202220802 (OCT1‐Met420del), rs34059508 (OCT1‐G465R), OCT2 variant rs316019 (OCT2‐A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype.

Key Results

OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT‐ and MATE1‐dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype.

Conclusions and Implications

Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose‐dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.
Invasion of temperate deciduous broadleaf forests by N‐fixing tree species – consequences for stream ecosystems
Authors: Ferreira Verónica , Figueiredo Albano , Graça Manuel A. S. , Marchante Elizabete , Pereira Ana
Published: January 2021

Biological invasions are a major threat to biodiversity and ecosystem functioning. Forest invasion by alien woody species can have cross‐ecosystem effects. This is especially relevant in the case of stream–riparian forest meta‐ecosystems as forest streams depend strongly on riparian vegetation for carbon, nutrients and energy. Forest invasion by woody species with dissimilar characteristics from native species may be particularly troublesome. The invasion of temperate deciduous broadleaf forests with low representation of nitrogen (N)‐fixing species by N‐fixers has the potential to induce ecosystem changes at the stream level. Although effects of tree invasion on stream ecosystems have been under assessed, knowledge of native and invasive tree characteristics allows prediction of invasion effects on streams. Here we present a conceptual model to predict the effects of forest invasion by alien N‐fixing species on streams, using as a background the invasion of temperate deciduous broadleaf forests by leguminousAcaciaspecies, which are among the most aggressive invaders worldwide. Effects are discussed using a trait‐based approach to allow the model to be applied to other pairs of invaded ecosystem–invasive species, taking into account differences in species traits and environmental conditions. Anticipated effects of N‐fixing species invasions include changes in water quality (increase in N concentration) and quantity (decrease in flow) and changes in litter input characteristics (altered diversity, seasonality, typology, quantity and quality). The magnitude of these changes will depend on the magnitude of differences in species traits, the extent and duration of the invasion and stream characteristics (e.g. basal nutrient concentration). The extensive literature on effects of nutrient enrichment of stream water, water scarcity and changes in litter input characteristics on aquatic communities and processes allows prediction of invasion effects on stream structure and function. The magnitude of invasion effects on aquatic communities and processes may, however, depend on interactions among different pathways (e.g. effects mediated by increases in stream nutrient concentration may contrast with those mediated by decreases in water availability or by decreases in litter nutritional quality). A review of the literature addressing effects of increasing cover of N‐fixing species on streams suggests a wide application of the model, while it highlights the need to consider differences in the type of system and species when making generalizations. Changes induced by N‐fixing species invasion on streams can jeopardize multiple ecosystem services (e.g. good quality water, hydroelectricity, leisure activities), with relevant social and economic consequences.
Visualizing and forecasting the association of air quality and health outcomes in Ontario, Canada
Authors: Liang Siwei , Zhu Jingqin , McGihon Rachel , Terebessy Emilie , Ge Erjia , Su Yushan , Fong Ivy , To Teresa
Published: January 2021

Research has shown that air pollution is associated with risks of development and worsening of chronic diseases. The Air Quality Health Index (AQHI) is a numerical scale that reports air quality and health risk, and includes messages that advise on health risk reduction actions according to AQHI levels. Our study aimed to (1) characterize geographical variations between air pollution (AQHI) and health outcomes (incidence, prevalence, and health services use) of asthma, COPD, diabetes, and hypertension; (2) forecast the trend of associations using observed data; and (3) develop visualization tools that help the public identify risks of air pollution and health outcomes. Observed trends of AQHI and health outcomes from 2003 to 2014 were plotted and forecasted up to 2025, while maps showed their geographical variations. Overall, the highest incidence and prevalence of each disease were observed in regions with higher annual mean AQHI. Chronic diseases' acute health services use was higher in northern Ontario, while physician office visits were higher in southern Ontario. The positive correlations between AQHI and health outcomes in Ontario suggests that increasing public awareness of potential health risks of air pollution is important, especially among people with chronic diseases.
Health professional–educator collaboration in the delivery of school‐based tiered support services: A qualitative case study
Authors: Phoenix Michelle , Dix Leah , DeCola Cindy , Eisen Isabel , Campbell Wenonah
Published: January 2021

Background

Educators and health professionals support the learning and participation of diverse children in school environments. Tiered approaches to service delivery may assist these efforts through consideration of universal supports that are useful to all children, targeted supports for some children and individualized supports for the smallest number of children. This study explored how an interprofessional team worked with educators to develop and implement tiered services in two school communities where many families experience economic and social disadvantages.

Methods

Using a participatory action research approach and qualitative case study methods, the research and stakeholder teams jointly designed and conducted this study in two schools during the 2017–2018 school year. Data collected included weekly logs written by the interprofessional team members and 16 interviews conducted with team members, parents, educators and administrators.

Results

The team provided a variety of services to individual students, groups, whole classes and the school community. Collaboration and communication were needed to define roles and expectations and to plan and share student information. Reported benefits included timely service, capacity building and student goal achievement. The main barriers were related to service fragmentation, time and workload.

Conclusions

Recommendations included clearer direction about expectations and improved coordination within the systems that offer services. Further research should include exploration of comparative cases with varying contexts, the inclusion of child perspectives and direct observation.
Profiles of Childhood Maltreatment: Associations with Sexual Risk Behavior during Adolescence in a Sample of Racial/Ethnic Minority Girls
Authors: Niu Li , Brown Joshua , Till Hoyt Lindsay , Salandy Anthony , Nucci‐Sack Anne , Shankar Viswanathan , Burk Robert D. , Schlecht Nicolas F. , Diaz Angela
Published: January 2021

This study examines associations between childhood maltreatment and developmental trajectories of sexual risk behaviors (SRBs) in a sample of 882 sexually active adolescent girls, predominantly Hispanic or Black, assessed every 6 months between 13 and 23 years. Latent profile analyses revealed four distinct maltreatment profiles: Low Maltreatment (76%), Moderate Emotional Neglect Only (15%), Severe Physical/Emotional Abuse (3%), and Severe Sexual Abuse (6%). Multilevel growth analyses showed the Moderate Emotional Neglect Only and Severe Sexual Abuse profiles exhibited more SRBs starting in late adolescence, and the Severe Sexual Abuse profile also exhibited a faster increase than the Low Maltreatment profile. Understanding heterogeneity within maltreated populations may have important implications for healthy sexual development.
Individual Differences in the Stability and Change of Childhood Depression: A Growth Mixture Model With Structured Residuals
Authors: Hawrilenko Matt , Masyn Katherine E. , Cerutti Janine , Dunn Erin C.
Published: January 2021

Studies of developmental trajectories of depression are important for understanding depression etiology. Existing studies have been limited by short time frames and no studies have explored a key factor: differential patterns of responding to life events. This article introduces a novel analytic technique, growth mixture modeling with structured residuals, to examine the course of youth depression in a large, prospective cohort (N = 11,641, ages 4–16.5, 96% White). Age‐specific critical points were identified at ages 8 and 13 where depression symptoms spiked for a minority of children. Most depression risk was due to dynamic responses to environmental events, drawn not from a small pool of persistently depressed children, but a larger pool of children who varied across higher and lower symptom levels.
Thinking Counterfactually Supports Children’s Evidence Evaluation in Causal Learning
Authors: Engle Jae , Walker Caren M.
Published: January 2021

Often, the evidence we observe is consistent with more than one explanation. How do learners discriminate among candidate causes? The current studies examine whether counterfactuals help 5‐year olds (N = 120) select between competing hypotheses and compares the effectiveness of these prompts to a related scaffold. In Experiment 1, counterfactuals support evidence evaluation, leading children to privilege and extend the cause that accounted for more data. In Experiment 2, the hypothesis that accounted for the most evidence was pitted against children’s prior beliefs. Children who considered alternative outcomes privileged the hypothesis that accounted for more observations, whereas those who explained relied on prior beliefs. Findings demonstrate that counterfactuals recruit attention to disambiguating evidence and outperform explanation when data contrast with existing beliefs.