bluuebunny/crossref_metadata_2025 huggingface dataset:
A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies
Authors: Hsieh Yuan-Chin , Liao Jun-min , Chuang Kuo-Hsiang , Ho Kai-Wen , Hong Shih-Ting , Liu Hui-Ju , Huang Bo-Cheng , Chen I-Ju , Liu Yen-Ling , Wang Jaw-Yuan , Tsai Hsiang-Lin , Su Yu-Cheng , Wang Yen-Tseng , Cheng Tian-Lu
Published: January 2022

Background

Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed.

Methods

We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1–C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4β1 integrin HP1/2L mAbs.

Results

The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10−10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively).

Conclusions

Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use.

Graphical Abstract
Chondroitin sulfate-AuNRs electroactive scaffolds for on-demand release of biofactors
Authors: Malki Maayan , Shapira Assaf , Dvir Tal
Published: January 2022

Controlled release systems are often integrated into polymeric scaffolds to supply essential biofactors to trigger physiological processes in engineered tissues. Here, we report the modification of chondroitin sulfate (CS) electroactive polymer with gold nanorods (AuNRs) to create hybrid macroporous scaffolds for enhanced on-demand release of growth factors and cytokines. The mechanical properties, porosity and degradation of the hybrid scaffolds were evaluated, and the viability and functionality of seeded cardiac cells were assessed. Following, the ability to control the release of the enzyme lysozyme, and the cytokine, stromal cell-derived factor 1 (SDF-1) by applying electrical stimulation, was demonstrated. The AuNRs were able to increase the current through the scaffolds, providing an efficient on–off release profile of SDF-1, which resulted in higher migration of cells expressing CXCR4 receptor. Finally, the engineered scaffolds were transplanted in rats and SDF-1 was released daily by electrical stimulation, promoting blood vessel-forming cell infiltration and vascularization. We envision that gold nanoparticles and other conducting nanomaterials can be incorporated into different electroactive materials to improve their capabilities not only for tissue engineering applications, but for a variety of biomedical applications, where enhanced electrical stimulation is needed.

Graphical Abstract
Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects
Authors: Arlt Annabelle , Kohlschmidt Nicolai , Hentschel Andreas , Bartels Enrika , Groß Claudia , Töpf Ana , Edem Pınar , Szabo Nora , Sickmann Albert , Meyer Nancy , Schara-Schmidt Ulrike , Lau Jarred , Lochmüller Hanns , Horvath Rita , Oktay Yavuz , Roos Andreas , Hiz Semra
Published: January 2022

Background

Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants.

Results

We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes.

Conclusions

Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.
Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study
Authors: Hennis Philip J. , Murphy Elaine , Meijer Rick I. , Lachmann Robin H. , Ramachandran Radha , Bordoli Claire , Rayat Gurinder , Tomlinson David J.
Published: January 2022

Background

Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment.

Results

Peak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life.

Conclusions

V̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity.
Barriers and facilitators to implementing the HEADSS psychosocial screening tool for adolescents living with HIV/AIDS in teen club program in Malawi: health care providers perspectives
Authors: Kip Esther C. , Udedi Michael , Kulisewa Kazione , Go Vivian F. , Gaynes Bradley N.
Published: January 2022

Background

Adolescents living with HIV (ALHIV) are at high risk of experiencing mental health problems. Depression is a major contributor to the burden of HIV-related disease amongst ALHIV and is significantly linked to non-adherence to anti-retroviral therapy (ART), yet it is under-recognized. In 2015, the Baylor College of Medicine International Pediatric AIDS Initiative (BIPAI) recommended that the psychosocial screening tool Home, Education, Activities, Drugs, Sexuality, Suicide/Depression (HEADSS) be used to screen ALHIV in Malawi who were part of an adolescent antiretroviral therapy program termed “Teen Club”. However, the HEADSS tool has been substantially under-utilized. This study assessed barriers and facilitators to implementing HEADSS for ALHIV attending Teen Club Program in four selected health facilities in Malawi.

Methods

We conducted a qualitative study using semi-structured interviews at four program sites (one district hospital and one health center each in two districts) between April and May 2019. Twenty key informants were purposively selected to join this study based on their role and experiences. We used the five domains of the Consolidated Framework for Implementation Research (CFIR) to guide the development of the interview guides, analysis and interpretation of results.

Results

Barriers included inadequate planning for integration of the HEADSS approach; concerns that the HEADSS tool was too long, time consuming, lacked appropriate cultural context, and increased workload; and reports by participants that they did not have knowledge and skills to screen ALHIV using this tool. Facilitators to implementing the screening were that health care providers viewed screening as a guide to better systematic counselling, believed that screening could build better client provider relationship, and thought that it could fit into the existing work practice since it is not complex.

Conclusions

A culturally adapted screening tool, especially one that can be used by non-clinicians such as lay health workers, would improve the ability to address mental health needs of ALHIV in many primary care and social service settings where resources for professional mental health staff are limited. These findings are a springboard for efforts to culturally adapt the HEADSS screening tool for detection of mental and risky behaviors among ALHIV attending ART program in Malawi.
TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation
Authors: Chen Yongchang , Liu Lu , Xia Longzheng , Wu Nayiyuan , Wang Ying , Li He , Chen Xue , Zhang Xiaoye , Liu Zhaoyi , Zhu Miaochen , Liao Qianjin , Wang Jing
Published: January 2022

Background

Tumor cell metabolic reprogramming is crucial for the malignant behavior of cancer cells by promoting their proliferation. However, little is known on how transient receptor potential 7 (TRPM7) modulates metabolic reprogramming in ovarian cancer.

Methods

The effects of TRPM7 silencing on transcriptome profile, glucose uptake, lactic acid production, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), intracellular ROS and ATP levels, and NAD+/NADH ratios in ovarian cancer cells were examined. The impacts of TRPM7 silencing on the levels of glycolysis-related HK2, PDK1 and oxidative phosphorylation (OXPHOS)-related IDH3B and UQCRC1, HIF-1α expression and AMPK phosphorylation were determined in ovarian cancer. The effect of AMPK activity on HIF-1α ubiquitination degradation was investigated in ovarian cancer cells.

Results

Compared with the control, TRPM7 silencing suppressed the proliferation of ovarian cancer cells by shifting preferable glycolysis to OXPHOS. In parallel, TRPM7 silencing decreased the glucose uptake of tumor-bearing mice and TRPM7 levels were negatively correlated with IDH3B and UQCRC1, but positively with HK2 and PDK1 expression in ovarian cancer tissues. Mechanistically, TRPM7 silencing significantly increased AMPK phosphorylation and decreased HIF-1α protein levels in ovarian cancer, particularly in HIF-1α silencing cells. The shifting from glycolysis to OXPHOS by TRPM7 silencing was abrogated by HIF-1α over-expression and impaired by inhibiting AMPK activity in ovarian cancer cells. Moreover, enhanced AMPK activation inhibited glycolysis, which was abrogated by HIF-1α over-expression in ovarian cancer cells. Moreover, the enhanced AMPK activation promoted HIF-1α ubiquitination degradation.

Conclusions

TRPM7 silencing enhanced AMPK activation to shift glycolysis to oxidative phosphorylation by promoting HIF-1α ubiquitination degradation in ovarian cancer. Hence, TRPM7 may be a therapeutic target for intervention of ovarian cancer.
DUDE - a universal prevention program for non-suicidal self-injurious behavior in adolescence based on effective emotion regulation: study protocol of a cluster-randomized controlled trial
Authors: Buerger Arne , Emser Theresa , Seidel Alexandra , Scheiner Christin , von Schoenfeld Cornelia , Ruecker Viktoria , Heuschmann Peter U. , Romanos Marcel
Published: January 2022

Background

Non-suicidal self-injury (NSSI) has become a substantial public health problem. NSSI is a high-risk marker for the development and persistence of mental health problems, shows high rates of morbidity and mortality, and causes substantial health care costs. Thus, there is an urgent need for action to develop universal prevention programs for NSSI before adolescents begin to show this dangerous behavior. Currently, however, universal prevention programs are lacking.

Methods

The main objective of the present study is to evaluate a newly developed universal prevention program (“DUDE – Du und deine Emotionen / You and your emotions”), based on a skills-based approach in schools, in 3200 young adolescents (age 11–14 years). The effectiveness of DUDE will be investigated in a cluster-randomized controlled trial (RCT) in schools (N = 16). All groups will receive a minimal intervention called “Stress-free through the school day” as a mental health literacy program to prevent burnout in school. The treatment group (N = 1600; 8 schools) will additionally undergo the universal prevention program DUDE and will be divided into treatment group 1 (DUDE conducted by trained clinical psychologists; N = 800; 4 schools) and treatment group 2 (DUDE conducted by trained teachers; N = 800; 4 schools). The active control group (N = 1600; 8 schools) will only receive the mental health literacy prevention. Besides baseline assessment (T0), measurements will occur at the end of the treatment (T1) and at 6- (T2) and 12-month (T3) follow-up evaluations. The main outcome is the occurrence of NSSI within the last 6 months assessed by a short version of the Deliberate Self-Harm Inventory (DSHI-9) at the 1-year follow-up (primary endpoint; T3). Secondary outcomes are emotion regulation, suicidality, health-related quality of life, self-esteem, and comorbid psychopathology and willingness to change.

Discussion

DUDE is tailored to diminish the incidence of NSSI and to prevent its possible long-term consequences (e.g., suicidality) in adolescents. It is easy to access in the school environment. Furthermore, DUDE is a comprehensive approach to improve mental health via improved emotion regulation.

Trial registration

German Clinical Trials Register (DRKS) DRKS00018945. Registered on 01 April 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00018945
Effects of acupuncture treatment on postoperative gastrointestinal dysfunction in colorectal cancer: study protocol for randomized controlled trials
Authors: Liu Xueyan , Wang Zhijie , Yao Hao , Yang Yanrong , Cao Huijuan , Toh Zhanhao , Zheng Ruwen , Ren Yi
Published: January 2022

Background

Postoperative gastrointestinal dysfunction (PGID) is a common complication arising from colorectal cancer surgery. Attributing factors, such as anesthesia, surgical retraction, and early intake of water, can inhibit gastrointestinal motility, causing constipation, reduction or absence of bowel sounds, nausea, vomiting, and other symptoms. Delayed recovery in gastrointestinal function can lead to intestinal obstructions or paralysis, anastomotic leaks, and other complications, affecting the patient’s recovery and quality of life negatively. Due to its complex pathophysiology, treatment for PGID in colorectal patients has remained a challenge. Acupuncture is an alternative therapy commonly used for postoperative recovery. This study aims to evaluate the therapeutic efficacy and safety of acupuncture on PGID. Through the complementation of acupuncture and enhanced recovery after surgery (ERAS) protocols, the advantages of acupuncture treatments could be demonstrated to promote its application in future clinical practice.

Methods

The study design is a prospective randomized controlled trial (RCT). One hundred sixty postoperative colorectal cancer patients will be recruited from Cancer Hospital Chinese Academy of Medical Sciences (CICAMS). Subjects who fulfill inclusion criteria will be randomly assigned into the acupuncture group (AG) (n = 80) or control group (CG) (n = 80). AG will receive acupuncture treatment and perioperative care guided by ERAS protocols, and CG will only receive perioperative care guided by ERAS protocols. The intervention will begin on the first day post-surgery, continuing for 4 days, with a follow-up assessment in a month. Time of first postoperative flatus would be the primary outcome measure. Secondary outcome measures include the time of first postoperative defecation, time of first fluid intake, time of first ambulation, postoperative hospital stay, gastrointestinal reaction score, acupuncture sensation evaluation scale, laboratory tests, postoperative quality of life, readmission rate, and postoperative complications. All results are evaluated from baseline, post-treatment, and upon follow-up.

Discussion

The results of the study would help elucidate evidence of the therapeutic effects of acupuncture on the recovery of postoperative gastrointestinal function. The objective of the study aims for the eventual inclusion of acupuncture in the ERAS protocol, allowing for wider application in clinical practice.

Trial registration

ClinicalTrials.gov ChiCTR2000036351. Registered on August 22, 2020
Molecular and functional characterization of a conserved odorant receptor from Aedes albopictus
Authors: Yan Ru , Xu Zhanyi , Qian Jiali , Zhou Qiaoling , Wu Huiming , Liu Yahui , Guo Yirong , Zhu Guonian , Chen Mengli
Published: January 2022

Background

The Asian tiger mosquitoAedes albopictusis a competent vector of several viral arboviruses including yellow fever, dengue fever, and chikungunya. Several vital mosquito behaviors (e.g., feeding, host-seeking, mating, and oviposition) are primarily dependent on the olfactory system for semiochemicals detection and discrimination. However, the limited number of studies hampers our understanding of the relationships between theAe. albopictusolfactory system and the complex chemical world.

Methods

We performed RT-qPCR assay on antennae ofAe. albopictusmosquitoes of different sexes, ages and physiological states, and found odorant receptor 11 (AalbOr11) enriched in non-blood-fed female mosquitoes. Then, we examined the odorant preference with a panel of physiologically and behaviorally relevant odorants inXenopusoocytes.

Results

The results indicated that AalbOr11 could be activated by ten aromatics, seven terpenes, six heterocyclics, and three alcohols. Furthermore, using post-RNA interference (RNAi) hand-in-cage assay, we found that reducing the transcript level of AalbOr11 affected the repellency activity mediated by (+)-fenchone at a lower concentration (0.01% v/v).

Conclusions

Using in vitro functional characterization, we found that AalbOr11 was a broadly tuned receptor. Moreover, we found that AalbOr11 shared a conserved odorant reception profile with homologousAnopheles gambiaeOr11. In addition, RNAi and bioassay suggested that AablOr11 might be one of the receptors mediating (+)-fenchone repellency activity. Our study attempted to link odor-induced behaviors to odorant reception and may lay the foundation for identifying active semiochemicals for monitoring or controlling mosquito populations.

Graphical Abstract
Lessons learned in allergy and immunology training: a survey analysis
Authors: Cyr Chloe , Cyr Michael , Quirt Jaclyn , Connors Lori
Published: January 2022

Background

There is currently little Canadian data to assess how well traditional time-based residency training programs have prepared residents for careers in Clinical Immunology and Allergy (CIA). This study aims to identify the perceived preparedness of residents in various areas of practice upon the completion of a Canadian CIA residency training program.

Methods

In the summer of 2020, an electronic survey was sent to 2018 and 2019 graduates of Canadian CIA training programs by the Canadian Society of Allergy and Clinical Immunology (CSACI).

Results

Former residents felt well prepared in most Medical Expert areas. Residents felt less prepared for the intrinsic roles of Leader, Communicator, Collaborator, Health Advocate, Scholar, and Professional. The majority of the intrinsic competencies were learned through mentorship and on the job after finishing training.

Conclusions

Upon completion of training, Canadian CIA residents felt well prepared for many competencies, particularly in Medical Expert areas. Training programs may wish to focus on various intrinsic competencies in order to better prepare residents for transition to practice. Academic half-day was not identified as a primary learning centre for intrinsic competencies, suggesting that new teaching strategies may be required.
Structure-based knowledge acquisition from electronic lab notebooks for research data provenance documentation
Authors: Schröder Max , Staehlke Susanne , Groth Paul , Nebe J. Barbara , Spors Sascha , Krüger Frank
Published: January 2022

Background

Electronic Laboratory Notebooks (ELNs) are used to document experiments and investigations in the wet-lab. Protocols in ELNs contain a detailed description of the conducted steps including the necessary information to understand the procedure and the raised research data as well as to reproduce the research investigation. The purpose of this study is to investigate whether such ELN protocols can be used to create semantic documentation of the provenance of research data by the use of ontologies and linked data methodologies.

Methods

Based on an ELN protocol of a biomedical wet-lab experiment, a retrospective provenance model of the raised research data describing the details of the experiment in a machine-interpretable way is manually engineered. Furthermore, an automated approach for knowledge acquisition from ELN protocols is derived from these results. This structure-based approach exploits the structure in the experiment’s description such as headings, tables, and links, to translate the ELN protocol into a semantic knowledge representation. To satisfy the Findable, Accessible, Interoperable, and Reuseable (FAIR) guiding principles, a ready-to-publish bundle is created that contains the research data together with their semantic documentation.

Results

While the manual modelling efforts serve as proof of concept by employing one protocol, the automated structure-based approach demonstrates the potential generalisation with seven ELN protocols. For each of those protocols, a ready-to-publish bundle is created and, by employing the SPARQL query language, it is illustrated that questions about the processes and the obtained research data can be answered.

Conclusions

The semantic documentation of research data obtained from the ELN protocols allows for the representation of the retrospective provenance of research data in a machine-interpretable way. Research Object Crate (RO-Crate) bundles including these models enable researchers to easily share the research data including the corresponding documentation, but also to search and relate the experiment to each other.
Rural and urban differences in undersupply of buprenorphine provider availability in the United States, 2018
Authors: Conway Kevin P. , Khoury Dalia , Hilscher Rainer , Aldridge Arnie P. , Parker Stephanie J. , Zarkin Gary A.
Published: January 2022

Background

Medications to treat opioid use disorder (OUD) including buprenorphine products are evidence-based and cost-effective tools for combating the opioid crisis. However, limited availability to buprenorphine is pervasive in the United States (US) and may serve to exacerbate the deadly epidemic. Although prior research points to rural counties as especially needy of strategies that improve buprenorphine availability, it is important to investigate the availability of waivered providers according to treatment need as defined by the county-level rate of opioid-overdose deaths (OOD). This study examined differences in buprenorphine provider availability relative to treatment need among rural and urban counties in the US.

Methods

Buprenorphine provider availability relative to need in each county was defined as the number of waivered providers divided by the rate of OODs (i.e., number of OODs/100,000 population), according to 2018 data. Counties with ratios in the bottom tertile of their state were classified as buprenorphine undersupplied. We estimated logit models to statistically test the association of rurality and state main effects and their interaction terms (independent variables) and the county classified as buprenorphine undersupplied (dependent variable).

Results

A total of 38 states and 2595 counties had sufficient non-suppressed data to remain in the analysis. A larger percent of urban counties (36.43%) than rural counties (32.01%) were classified as buprenorphine undersupplied (p  = 0.001). The likelihood of a rural county being undersupplied varied considerably by state (Chi Square  = 82.88, p  = 0.000). All states with significant (p  < 0.05 or p  < 0.10) interaction terms showed lower likelihood of buprenorphine undersupply in rural counties.

Conclusions

The rural–urban distribution in undersupply of waivered buprenorphine providers relative to need varied markedly by state. Strategies for improving access to buprenorphine-waivered providers should be state-centric and informed by county-specific indicators of need.
Rationale, design and methods of VA-BRAVE: a randomized comparative effectiveness trial of two formulations of buprenorphine for treatment of opioid use disorder in veterans
Authors: Petrakis Ismene , Springer Sandra A. , Davis Cynthia , Ralevski Elizabeth , Gu Lucy , Lew Robert , Hermos John , Nuite Melynn , Gordon Adam J. , Kosten Thomas R. , Nunes Edward V. , Rosenheck Robert , Saxon Andrew J. , Swift Robert , Goldberg Alexa , Ringer Robert , Ferguson Ryan
Published: January 2022

Background

To address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges.

Methods

This 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included.

Discussion

The evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost.

Trial registration Registered at Clinicaltrials.gov NCT04375033
In-situ sequencing reveals the effect of storage on lacustrine sediment microbiome demographics and functionality
Authors: Tennant Richard K. , Power Ann L. , Burton Sara K. , Sinclair Norman , Parker David A. , Jones Richard T. , Lee Rob , Love John
Published: January 2022

The sediment microbiome is a demographically diverse and functionally active biosphere. Ensuring that data acquired from sediment is truly representative of the microbiome is critical to achieving robust analyses. Sample storage and the processing and timing of nucleic acid purification after environmental sample extraction may fundamentally affect the detectable microbial community and thereby significantly alter resultant data. Direct sequencing of environmental samples is increasingly commonplace due to the advent of the portable Oxford Nanopore MinION sequencing device. Here we demonstrate that storing sediment subsamples at − 20 °C or storing the cores at 4 °C for 10 weeks prior to analysis, has a significant effect on the sediment microbiome analysed using sedimentary DNA (sedDNA), especially for Alpha-, Beta- and Deltaproteobacteria species. Furthermore, these significant differences are observed regardless of sediment type. We show that the taxa which are predominantly affected by storage are Proteobacteria, and therefore recommend on-site purifications are performed to ensure an accurate representation of these taxa are observed in the microbiome. Comparisons of sedimentary RNA (sedRNA) analyses, revealed substantial differences between samples purified and sequenced immediately on-site, samples that were frozen before transportation, and cores that were stored at 4 °C prior to analysis. Our data therefore suggest that a more accurate representation of the sediment microbiome demography and functionality may be achieved by environmental sequencing as rapidly as possible to minimise confounding effects of storage.
Selective spinal anesthesia with hyperbaric prilocaine provides better perioperative pain control than local anesthesia for ambulatory inguinal hernia repair without affecting discharging time: a randomized controlled trial
Authors: Costa Fabio , Pascarella Giuseppe , Luffarelli Paolo , Strumia Alessandro , Biondo Gaspare , Piliego Chiara , Alloni Rossana , Agrò Felice E.
Published: January 2022

Purpose

Local anesthesia is the most used anesthetic technique for inguinal hernia repair, despite its unpredictability. Selective spinal anesthesia with a short-term local anesthetic guarantees rapid recovery, predictable duration and low incidence of side effects. We tried to assess the efficacy of this neuraxial technique in ambulatory setting.

Methods

One hundred thirty-two ASA I–III, aged > 18 patients scheduled for inguinal hernia repair have been randomized into two groups receiving unilateral spinal anesthesia with 40 mg of hyperbaric prilocaine (group A) or local anesthesia with mepivacaine (group B). Primary endpoint: intraoperative and post-operative NRS. Other outcomes: sensory block onset, need for opiates and deep sedation, surgery duration, and time to discharge.

Results

Group A: intraoperative NRS was 0 in 100% of patients; post-operative maximum NRS was > 3 in 12.12% of patients. Group B: mean intraoperative NRS was 4; mean post-operative NRS was 2.5. Spinal anesthesia resulted superior in controlling both intraoperative and post-operative pain (p < 0.00001; p = 0.008). Mean time of the motor block resolution in group A was 98 ± 2 min. Mean time to discharge was not significantly different between groups. Surgical time was significantly different between the two groups (mean time of 37 ± 3.2 min group A; 54 ± 6 min group B—p < 0.00001).

Conclusion

Spinal anesthesia group patients had significantly less pain than local anesthesia group, both intraoperatively and post-operatively, without differences in time to discharge, incidence of complications and with improvement of surgical time. More randomized controlled trials are needed to confirm this hypothesis.

Trial registration

NCT05136534. Registered November 29, 2021—Retrospectively registered
Integrating Critical Approaches into Quantitative STEM Equity Work
Authors: Pearson Meaghan I. , Castle Sarah D. , Matz Rebecca L. , Koester Benjamin P. , Byrd W. Carson
Published: January 2022

A primer of reflective questions to assist researchers with framing, analysis, and interpretation of student-level data frequently used to identify disparities and assess course-level and programmatic interventions is provided to support the scientific community with enhancing how we understand and address systemic inequity in STEM fields.
An optimized staggered-grid finite-difference operator for seismic wave simulation in poroelastic media
Authors: Anthony Emmanuel , Vedanti Nimish
Published: January 2022

Most of the finite-difference methods for simulating seismic wave propagation in poroelastic media compute the spatial derivatives using fixed-length, which is the 2Mth-order operator. An optimized staggered-grid finite-difference (SGFD) method, which uses mixed operator length to approximate spatial derivatives, is derived from Biot’s equations to improve accuracy and stability. The numerical stability and dispersion of our optimized scheme are derived using the dispersion relation for the poroelastic equations. We have compared the dispersion curve plots for the developed and the conventional method. We introduce evidence that the developed scheme is comparatively more stable and accurate than the existing conventional method. The numerical solutions obtained using our optimized scheme closely approximate the analytical solution, and all wave types predicted by Biot’s theory are generated. Our scheme is used to simulate seismic wave propagation in a 2D homogeneous model, a two-layered model, a moderately complex model derived from the Utsira Formation, Sleipner North Sea, where a large amount of CO2 is being sequestrated, and a 3D homogeneous model. The developed scheme takes less computational time than the conventional SGFD method without compromising the accuracy or the stability.
Reconstructing airborne gravity gradient data based on Fourier transform
Authors: Luo Yao , Wu Meiping
Published: January 2022

Reconstructing airborne gravity gradient (AGG) components will improve the signal-to-noise ratio by extracting the coherent signal. Fourier transformations are routinely used to reconstruct a consistent multicomponent AGG data set for noise suppression purposes. The crucial step is calculating the potential from multicomponent data based on the Fourier transform. Given that solving a least-squares (LS) problem is involved in most cases, the methods based on the Fourier transform have no essential difference. However, existing methods ignore the different noise levels of the components. To tackle this problem, we have used a weighted LS method instead and adopted a general expression for calculating the potential from multicomponent data corrupted by noise. With the wavenumber shift technique, this expression, used for AGG reconstruction, achieves the highest accuracy in theory. We finally develop a practical procedure for raw AGG data reconstruction that iteratively evaluates the noise level by updating the weights. In addition, we examine the errors within denoised data, and an improved simulation is adopted to estimate the statistics of noise levels and residual errors after denoising. We evaluate the effectiveness of our approach through synthetic examples, and the results find the ability of noise removal and estimation for data containing noise.
Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage
Authors: Crilly Siobhan , Parry-Jones Adrian , Wang Xia , Selley Julian N. , Cook James , Tapia Victor S. , Anderson Craig S. , Allan Stuart M. , Kasher Paul R.
Published: January 2022

Despite the global health burden, treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive, and translation of specific medical therapies has not been successful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Collection library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified, including two angiotensin-converting enzyme inhibitors (ACE-Is). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. Using the INTERACT2 clinical trial dataset, we demonstrated a significant reduction in the adjusted odds of an unfavourable shift in the modified Rankin scale at 90 days for patients receiving an ACE-I after ICH (versus no ACE-I; odds ratio, 0.80; 95% confidence interval, 0.68-0.95; P=0.009). The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform and has identified therapeutics that may offer neuroprotection.

This article has an associated First Person interview with the first author of the paper.
Fission yeast polycystin Pkd2p promotes cell size expansion and antagonizes the Hippo-related SIN pathway
Authors: Sinha Debatrayee , Ivan Denisa , Gibbs Ellie , Chetluru Madhurya , Goss John , Chen Qian
Published: January 2022

Polycystins are conserved mechanosensitive channels whose mutations lead to the common human renal disorder autosomal dominant polycystic kidney disease (ADPKD). Previously, we discovered that the plasma membrane-localized fission yeast polycystin homolog Pkd2p is an essential protein required for cytokinesis; however, its role remains unclear. Here, we isolated a novel temperature-sensitive pkd2 mutant, pkd2-B42. Among the strong growth defects of this mutant, the most striking was that many mutant cells often lost a significant portion of their volume in just 5 min followed by a gradual recovery, a process that we termed ‘deflation’. Unlike cell lysis, deflation did not result in plasma membrane rupture and occurred independently of cell cycle progression. The tip extension of pkd2-B42 cells was 80% slower than that of wild-type cells, and their turgor pressure was 50% lower. Both pkd2-B42 and the hypomorphic depletion mutant pkd2-81KD partially rescued mutants of the septation initiation network (SIN), a yeast Hippo-related signaling pathway, by preventing cell lysis, enhancing septum formation and doubling the number of Sid2p and Mob1p molecules at the spindle pole bodies. We conclude that Pkd2p promotes cell size expansion during interphase by regulating turgor pressure and antagonizes the SIN during cytokinesis.

This article has an associated First Person interview with the first author of the paper.
Synthesis of Ketols by Oxidative Dehydrogenation of 1,2-Diols in Water over Pt/Sn-Beta
Authors: Wang Ke , Yang Zhiyun , You Xianfeng , Ma Yangyang , Lu Tianliang , Zhou Lipeng , Yang Xiaomei
Published: January 2022

Oxidative dehydrogenation of 1,2-diols to ketols was realized over Pt supported on Sn-Beta in base-free water. Introduction of Sn improved the catalytic performance of Pt/Sn-Beta dramatically: hydroxyacetone selectivity of 99% was obtained at 1,2-propanediol conversion of 71%. Sn improved the Pt dispersion and facilitated the O2 activation. Meanwhile, the reaction order and the activation energy were determined. In addition, the catalyst had good recyclability and it also showed high selectivity to other ketols from the corresponding 1,2-diols such as hexanediol.
Hydrogenation of Biomass-derived γ-Valerolactone to Form 1,4-Pentanediol over Co/ZrO2 Catalyst
Authors: Zhu Yue , Li Yue , Zhao Shipeng , Jing Ran , Zhang Heqian , Sun Daolai , Sato Satoshi
Published: January 2022

Hydrogenation of γ-valerolactone (GVL) to form 1,4-pentanediol (1,4-PDO) was performed over Co/ZrO2 catalysts with a Co metal loading of 15 wt. %. The calcination of Co/ZrO2 at high temperatures significantly promoted the catalytic activity irrespective of the decrease in the specific surface area. The 750 °C-calcined Co/ZrO2 with Co2+ species exhibited a high catalytic performance: a GVL conversion of 86.1% with a 1,4-PDO selectivity of 97.2% was achieved at 165 °C under 5 MPa H2 pressure.
Extraction of Platinum Hexachloride Anion Using Two Amido Hydrogen Atoms of Secondary Diamides with Different Spacer Length
Authors: Ohto Keisuke , Sato Taisuke , Pang Gehui , Umecky Tatsuya , Morisada Shintaro , Kawakita Hidetaka
Published: January 2022

Three secondary diamides having different space lengths were prepared and their extraction behavior toward Pt(IV) was investigated in acid chloride media. Given 1H NMR investigation, the carbonyl oxygen atoms were not protonated and only NH protons were applied to the solvation extraction of [PtCl6]2−. The effect of spacer length between two NH hydrogen atoms is discussed for s size-discriminating effect of a chlorometalate through the results of the extraction.
Inserção estratégica de unidades de gestão de pessoas em arenas decisórias organizacionais
Authors: Silverio Júlia Cássia dos Santos , Menezes Pedro Paulo Murce
Published: January 2022

Este artigo objetiva revisar a literatura nacional e internacional sobre a inserção estratégica de unidades de gestão de pessoas (GP) em arenas decisórias organizacionais, analisando elementos que influenciam na atuação dessas unidades no processo de tomada de decisão. Dedicando-se à lacuna teórica da dimensão política que permeia a GP, procedeu-se a uma pesquisa bibliográfica sem recorte temporal no portal de periódicos Capes. Como resultado, com base numa análise de conteúdo pós-categórica realizada em 32 artigos, foram identificados quatro elementos que compõem a atuação da área de GP para uma efetiva influência do setor nos negócios organizacionais. São eles: as ações formais e informais, a representação na alta liderança, os papéis dos profissionais e o envolvimento na tomada de decisão. Como limitação, considerando que os modelos de GP se abstêm de estudar modelos políticos, ressalta-se a dificuldade de definição dos descritores para pesquisa bibliográfica.
Ανάπτυξη τροποποιημένων νανοσωματιδίων τιτανίας για φωτοκαταλυτική οξείδωση αέριων ρύπων
Authors: Καραπάτη Σοφία
Published: January 2022

Στην παρούσα Διδακτορική Διατριβή πραγματοποιήθηκε επεξεργασία νανοσωματιδίων τιτανίας με τροποποιητές διαφορετικής υδροφιλικότητας και υδροφοβικότητας σε μονοφασικό (νερό ή αιθανόλη) και διφασικό (νερό/τολουένιο) σύστημα διαλυτών. Μελετήθηκε, επίσης, η συνεργιστική δράση αυτών των ιδιοτήτων και στις δύο περιπτώσεις. Ως πηγή TiO2 χρησιμοποιήθηκε ο εμπορικός φωτοκαταλύτης της Evonic Degussa, P25. Σημαντικό μέρος των εργασιών αποτέλεσε η μελέτη της συνεργιστικής δράσης των τροποποιημένων φωτοκαταλυτών με δομικά υλικά όπως τσιμέντο και χρώματα. Σε αυτήν την κατεύθυνση παρασκευάστηκε φωτοενεργό λευκό τσιμέντο με συστάσεις 2.5, 1 και 0.5 % w/w, καθώς και σύνθετα φωτοκαταλυτικά χρώματα με έως και 20 % w/w τροποποιημένου και μη φωτοκαταλύτη. Η κατανομή μεγέθους και το επιφανειακό φορτίο των νανοσωματιδίων του τροποποιημένου φωτοκαταλύτη σε υδατικούς ή οργανικούς μη πολικούς διαλύτες και οι πιθανοί δεσμοί τους με τον τροποποιητή προσδιορίστηκαν με διάφορες τεχνικές όπως η Δυναμική Σκέδαση Φωτός (DLS), η Θερμική Ανάλυση (TG/DTA/DTG) και η Φασματοσκοπία Υπερύθρου (FT-IR) αντίστοιχα. Η μορφολογία των σωματιδίων μελετήθηκε με την τεχνική της Ηλεκτρονικής Μικροσκοπίας Διελεύσεως (TEM). Ο υπολογισμός του ενεργειακού χάσματος των υπό εξέταση υλικών πραγματοποιήθηκε μέσω της μεθόδου της Διάχυτης Ανάκλασης (Diffuse Reflectance). Χρησιμοποιήθηκε, επίσης, η πρότυπη μέθοδος ISO/DIS 22197–1:2016 προκειμένου να αξιολογηθεί η φωτοενεργότητα των σύνθετων υλικών ως προς την οξείδωση του αέριου ρύπου NO.Όλα τα τροποποιημένα υλικά παρουσίασαν καλύτερη φωτοκαταλυτική δραστικότητα σε σύγκριση με το Ρ25, τόσο ως προς την οξείδωση του αέριου ρύπου ΝΟ (έως και 5 φορές μεγαλύτερη) όσο και ως προς τον καθαρισμό του αέρα και από τους δύο ρύπους, το ΝΟx και το παραγόμενο ως ενδιάμεσο προϊόν ΝΟ2. Αναλυτικότερα, οι βέλτιστες φωτοκαταλυτικές ιδιότητες παρουσιάζονται για τα σύνθετα υλικά που έχουν τροποποιηθεί με υδρόφιλες επιφανειοδραστικές ουσίες σε μονοφασικό σύστημα με διαλύτη νερό.Η φωτονική αποδοτικότητα των σύνθετων δομικών υλικών τσιμέντου με τιτανία που έχει τροποποιηθεί με συνδυασμό υδρόφοβων και υδρόφιλων ενώσεων σε διφασικό σύστημα διαλυτών νερού/τολουενίου παρουσίασε τη μεγαλύτερη βελτίωση σε σχέση με τη χρήση του εμπορικού φωτοκαταλύτη. Η διερεύνηση της «τοπογραφίας» και της ανάλυσης της σύνθεσης των φωτοκαταλυτικών τσιμεντοειδών υλικών πραγματοποιήθηκε με την τεχνική της Hλεκτρονικής Μικροσκοπίας Σάρωσης Σκεδαζόμενης Ενέργειας Ακτίνων Χ (SEM-EDAX).Επιπροσθέτως, στην περίπτωση των φωτοενεργών χρωμάτων με τροποποιημένη τιτανία με συνδυασμό υδρόφιλων και υδρόφοβων οργανικών ομάδων, παρατηρήθηκε βελτιωμένη μακροπρόθεσμη φωτοκαταλυτική συμπεριφορά συνοδευόμενη από 25 % επιπλέον απομάκρυνση ρύπων ΝΟx σε σχέση με τη χρήση μη τροποποιημένης τιτανίας.