bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep molecular dreaming: inverse machine learning for de-novo molecular design and interpretability with surjective representations
Authors: Shen Cynthia , Krenn Mario , Eppel Sagi , Aspuru-Guzik Alán
Published: June 2021

Computer-based de-novo design of functional molecules is one of the most prominent challenges in cheminformatics today. As a result, generative and evolutionary inverse designs from the field of artificial intelligence have emerged at a rapid pace, with aims to optimize molecules for a particular chemical property. These models ‘indirectly’ explore the chemical space; by learning latent spaces, policies, and distributions, or by applying mutations on populations of molecules. However, the recent development of the SELFIES (Krenn 2020 Mach. Learn.: Sci. Technol.
1 045024) string representation of molecules, a surjective alternative to SMILES, have made possible other potential techniques. Based on SELFIES, we therefore propose PASITHEA, a direct gradient-based molecule optimization that applies inceptionism (Mordvintsev 2015) techniques from computer vision. PASITHEA exploits the use of gradients by directly reversing the learning process of a neural network, which is trained to predict real-valued chemical properties. Effectively, this forms an inverse regression model, which is capable of generating molecular variants optimized for a certain property. Although our results are preliminary, we observe a shift in distribution of a chosen property during inverse-training, a clear indication of PASITHEA’s viability. A striking property of inceptionism is that we can directly probe the model’s understanding of the chemical space on which it is trained. We expect that extending PASITHEA to larger datasets, molecules and more complex properties will lead to advances in the design of new functional molecules as well as the interpretation and explanation of machine learning models.
Hospital variation in sphincter-preservation rates in rectal cancer treatment: results of a population-based study in the Netherlands
Authors: Koëter T , de Nes L C F , Wasowicz D K , Zimmerman D D E , Verhoeven R H A , Elferink M A , de Wilt J H W
Published: June 2021

Background

This study aimed to examine the sphincter-preservation rate variations in rectal cancer surgery. The influence of hospital volume on sphincter-preservation rates and short-term outcomes (anastomotic leakage (AL), positive circumferential resection margin (CRM), 30- and 90-day mortality rates) were also analysed.

Methods

Non-metastasized rectal cancer patients treated between 2009 and 2016 were selected from the Netherlands Cancer Registry. Surgical procedures were divided into sphincter-preserving surgery and an end colostomy group. Multivariable logistic regression models were generated to estimate the probability of undergoing sphincter-preserving surgery according to the hospital of surgery and tumour height (low, 5 cm or less, mid, more than 5 cm to 10 cm, and high, more than 10 cm). The influence of annual hospital volume (less than 20, 20–39, more than 40 resections) on sphincter-preservation rate and short-term outcomes was also examined.

Results

A total of 20 959 patients were included (11 611 sphincter preservation and 8079 end colostomy) and the observed median sphincter-preservation rate in low, mid and high rectal cancer was 29.3, 75.6 and 87.9 per cent respectively. After case-mix adjustment, hospital of surgery was a significant factor for patients’ likelihood for sphincter preservation in all three subgroups (P < 0.001). In mid rectal cancer, borderline higher rates of sphincter preservation were associated with low-volume hospitals (odds ratio 1.20, 95 per cent c.i. 1.01 to 1.43). No significant association between annual hospital volume and sphincter-preservation rate in low and high rectal cancer nor short-term outcomes (AL, positive CRM rate and 30- and 90-day mortality rates) was identified.

Conclusion

This population-based study showed a significant hospital variation in sphincter-preservation rates in rectal surgery. The annual hospital volume, however, was not associated with sphincter-preservation rates in low, and high rectal cancer nor with other short-term outcomes.
Determination of Phthalate Esters in Cosmetics and Baby Care Products by a Biosorbent Based on Lawsone Capped Chitosan and Followed by Liquid Chromatography
Authors: Samadi Fatemeh , Es’haghi Zarrin
Published: June 2021

This research presents a green synthetic pathway for the preparation of a new biosorbent and eco-friendly extraction process of three phthalate esters: dimethyl phthalate, di-butyl phthalate and benzyl butyl phthalate, from cosmetics and baby care products. Dispersive solid-phase extraction was used based on a new core-shell biomass/sorbent; chitosan-loaded lawsone. The proposed method provides fortunate trapping of phthalate esters in a one-step extraction. Under the optimized extraction conditions, the current work was presented low detection limits (0.03–0.15 ng. g−1), limits of quantification (0.1–0.5 ng·g−1) and reasonable linearity (0.1–10 000 ng. g−1). The applicability of the method was estimated by recovery experiments at different spiking levels (n = 5) for phthalate esters in the real samples.
Unraveling the acetals as ageing markers of Chinese Highland Qingke Baijiu using comprehensive two-dimensional gas chromatography–time-of-flight mass spectrometry combined with metabolomics approach
Authors: Wang Xinlei , Song Xuebo , Zhu Lin , Geng Xiaojie , Zheng Fuping , Zhao Qiangzhong , Sun Xiaotao , Zhao Dongrui , Feng Shengbao , Zhao Mouming , Sun Baoguo
Published: June 2021

Objectives

The ageing process has a significant impact on the aroma of Chinese Baijiu, which could strengthen the desirable flavor characteristics and reduce the undesirable ones. The aim of this study was to observe the initiation of meaningful changes in volatile fraction and locate the ageing markers during ageing storage of Chinese Highland Qingke Baijiu.

Materials and Methods

Samples of Chinese Qingke Baijiu were aged for 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 months before analysis. The samples were isolated by liquid–liquid extraction and then analyzed by comprehensive two-dimensional gas chromatography–time-of-flight mass spectrometry. The acquired data were processed by untargeted and targeted metabolomics approach to locate the ageing markers.

Results

The untargeted metabolomics analysis (hierarchical clustering analysis, HCA) shows that the chemical composition of Qingke Baijiu presents a statistically significant deviation from the reference scenario after 5 months. Subsequently, supervised statistics analysis (orthogonal partial least squares discrimination analysis) was performed to locate the markers, which changed significantly during ageing. Fifteen markers were located, and seven of them were acetals. Notably, 1,1-diethoxy-propane, 1,1-diethoxy-butane, and 1,1-diethoxy-3-methyl-butane are important contributors to the flavor of Chinese Baijiu. The identified markers were applied for the untargeted metabolomics (HCA), and the results revealed that these markers could divide the Qingke Baijiu into two ageing stages, 0–5 months and 6–11 months.

Conclusion

The results suggest that it is a valuable tool for monitoring the changes of volatile compounds and locating the age markers in Chinese Baijiu.
A novel mitigator of enzymatic browning—hawthorn leaf extract and its application in the preservation of fresh-cut potatoes
Authors: Qiao Liping , Wang Hailin , Shao Jinsheng , Lu Laifeng , Tian Jinhu , Liu Xia
Published: June 2021

Objectives

The purpose of this study was to evaluate the antibrowning functions of hawthorn leaf extract on fresh-cut potato and its possible mechanism.

Materials and Methods

Fresh-cut potatoes were treated with different concentrations (0.01%, 0.05%, and 0.1%) of hawthorn leaf extract and preserved at 4 ℃ for 8 days. The appearance and colour of potato slices were evaluated, along with the content of the phenol, malondialdehyde (MDA), and hydrogen peroxide (H2O2) during cold storage. Meanwhile, the activities of polyphenol oxidase (PPO), peroxidase (POD), phenylalanine ammonia-lyase (PAL), lipoxygenase (LOX), catalase (CAT), superoxide dismutase (SOD), and the antioxidant capacity were determined. Furthermore, the composition of hawthorn leaf extract was analyzed by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS).

Results

The addition of hawthorn leaf extract effectively delayed the browning process. It not only enhanced the CAT activity and antioxidant capacity but also reduced the LOX activity and accumulation of MDA and H2O2. Meanwhile, the activities of PPO, POD, and PAL as well as the content of phenol were controlled. Additionally, 25 phenols, 34 flavonoids, and 5 proanthocyanidins were identified through high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS), including caffeic acid, quercetin and catechol.

Conclusion

Hawthorn leaf extract significantly alleviated the browning of fresh-cut potato. It could serve as a natural antibrowning alternative by stabilizing the membrane and modulating reactive oxygen species and redox reactions.
Immunomodulatory Effect of Serum Exosomes From Crohn Disease on Macrophages via Let-7b-5p/TLR4 Signaling
Authors: Gong Lingqi , Xiao Jintao , Yi Jun , Xiao Junbo , Lu Fanggen , Liu Xiaowei
Published: June 2021

Background

Exosomes are extensively reported to be strongly associated with many immunologic diseases, including Crohn disease (CD). Meanwhile, the dysfunction of macrophage activation has been proposed to be critical for the pathogenesis of CD. However, it is an unsettled issue whether serum exosomes from CD could activate macrophages and participate in its pathogenesis. Our study intended to clarify the role of CD-derived exosomes on macrophages to elucidate a novel mechanism and possible diagnostic and therapeutic strategies.

Methods

Serum exosomes were isolated and identified. Functional assays in vitro were performed on Raw264.7 macrophages, followed by exosomal microRNA (miRNA) profiling and bioinformatics analyses via high-throughput sequencing. In animal experiments, exosomes were intraperitoneally injected into dextran sulfate sodium–induced colitis.

Results

In vitro CD-derived exosomes induced proinflammatory cytokine expression and increased macrophage counts. Meanwhile, the intervention of exosomes from CD with epithelial cells led to increased permeability of the intestinal epithelial barrier. In vivo, CD-derived exosomes could circulate into the intestinal mucosa and significantly aggravate colitis. Furthermore, CD changed the miRNA profile of exosomes and further analysis revealed a differential expression of let-7b-5p. Mechanistically, the let-7b-5p/TLR4 pathway was recognized as a potential contributor to macrophage activation and inflammatory response. Furthermore, serum exosome–mediated let-7b-5p mimic delivery alleviated colitis significantly.

Conclusions

Our study indicated that serum exosomes can circulate into the intestinal mucosa to aggravate colitis by regulating macrophage activation and epithelial barrier function. In addition, CD showed altered exosomal miRNA profiles. Furthermore, serum exosome–mediated let-7b-5p-mimic delivery may significantly alleviate colitis, providing potential novel insight into an exosome-based strategy for the diagnosis and treatment of CD.
Overview of the United States’ Immunization Program
Authors: Roper Lauren , Hall Mary Ann Kirkconnell , Cohn Amanda
Published: June 2021

This manuscript describes the history, background, and current structure of the United States Immunization Program, founded upon public- and private-sector partnerships that include federal agencies, state and local health departments, tribal nations and organizations, healthcare providers, vaccine manufacturers, pharmacies, and a multitude of additional stakeholders. The Centers for Disease Control and Prevention sets the U.S. adult and childhood immunization schedules based on recommendations from the Advisory Committee on Immunization Practices. We review the current immunization schedules; describe the set of surveillance and other systems used to monitor the health impact, coverage levels, and safety of recommended vaccines; and note significant challenges. Vaccines have reduced the incidence of many diseases to historic lows in the US, and have potential to further reduce the burden of respiratory and other infectious diseases in the United States. Though the United States vaccination program has had notable successes in reducing morbidity and mortality from infectious disease, challenges—including disparities in access and vaccine hesitancy—remain. Supporting access to and confidence in vaccines as an essential public health intervention will not only protect individuals from vaccine-preventable diseases; it will also ensure the country is prepared for the next pandemic.
Nasal Lavage Fluid as a Biomedical Sample for Verification of Chlorine Exposure
Authors: Lindén Pernilla , Jonasson Sofia , Hemström Petrus , Ålander Lovisa , Larsson Andreas , Ågren Lina , Elfsmark Linda , Åstot Crister
Published: June 2021

Chlorine is a toxic chemical that has been used as a chemical warfare agent in recent armed conflicts. There is an urgent need for methods to verify alleged uses of chlorine, and phospholipid chlorohydrins (PL-HOCl) derived from the pulmonary surfactant of exposed victims have previously been proposed as biomarkers of chlorine exposure. Here, we describe an improved protocol for the chemical analysis of these biomarkers and its applicability to biomedical samples from chlorine-exposed animals. By the use of a polymeric solid-phase-supported transesterification of PL-HOCl using ethanolamine, a common biomarker, oleoyl ethanolamide chlorohydrin (OEA-HOCl), was derived from all the diverse oleoyl PL-HOCl that may be formed by chlorine exposure. Compared to native lipid biomarkers, OEA-HOCl represents a larger biomarker pool and is better suited for nano-liquid chromatography--tandem mass spectrometry (nLC–MS-MS analysis), generating 3 amol Limit of Detection (LOD) and a reduced sample carry-over. With the improved protocol, significantly elevated levels of OEA-HOCl were identified in bronchoalveolar lavage fluid (BALF) of chlorine-exposed rats, 2–48 hours after exposure. The difficulty of BALF sampling from humans limits the methods usefulness as a verification tool of chlorine exposure. Conversely, nasal lavage fluid (NLF) is readily collected without advanced equipment. In NLF from chlorine-exposed rats, PL-HOCl were identified and significantly elevated levels of the OEA-HOCl biomarker were detected 2–24 hours after exposure. In order to test the potential of NLF as a biomedical sample for verification of human exposure to chlorine, in-vitro chlorination of human NLF samples was performed. All human in-vitro chlorinated NLF samples exhibited elevated OEA-HOCl biomarker levels, following sample derivatization. These data indicate the potential of human NLF as a biomedical sample for the verification of chlorine exposure, but further work is required to develop and validate the method for the use on real-world samples.
Physical and Psychological Recovery Following Toxic Epidermal Necrolysis: A Patient Survey
Authors: DeNiro Katherine L , Honari Shari , Hippe Dan S , Dai Andrea , Pham Tam N , Caceres Maria , Mandell Samuel P , Duong Phi Q , McMullen Kara A , Gibran Nicole S
Published: June 2021

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening diseases that cause sloughing of the skin and mucous membranes. Despite improved survival rates, few studies focus on long-term outcomes. We conducted a single-center review of all patients with SJS/TEN admitted from January 2008 to 2014. SJS/TEN survivors were invited to participate in the validated Veterans RAND 12-Item Health Survey (VR-12) to assess health-related quality of life using a mental health composite score and physical health component score (PCS). The sample was compared to U.S. norms using one-sample two-tailed t tests. A second questionnaire addressed potential long-term medical complications related to SJS/TEN. Of 81 treated subjects, 24 (30%) long-term survivors responded. Participants identified cutaneous sequelae most frequently (79%), followed by nail problems (70%), oral (62%), and ocular (58%) sequalae. Thirty-eight percent rated their quality of life to be “unchanged” to “much better” since their episode of SJS/TEN. The average PCS was lower than U.S. population norms (mean: 36 vs 50, P = .006), indicating persistent physical sequelae from SJS/TEN. These results suggest that SJS/TEN survivors continue to suffer from long-term complications that impair their quality of life and warrant ongoing follow-up by a multidisciplinary care team.
Molecular Monitoring of Knockdown Resistance in Head Louse (Phthiraptera: Pediculidae) Populations in Iran
Authors: Ghahvechi Khaligh Fereshteh , Djadid Navid Dinparast , Farmani Mostafa , Asadi Saatlou Zahra , Frooziyan Samira , Abedi Astaneh Fatemeh , Farnoosh Fariba , Sofizadeh Aioub , Naseri Firoozeh , Adib Delnia , Taheri Mohammad , Lalehzari Emran , Pashaei Shabnam , Soltanbeiglou Shadiyeh , Soltani Aboozar , Khooban Hassan , Abbasi Ebrahim , Aivazi Ali-Ashraf , Saeedi Samrand , Taghilou Behrooz , Jafari Abbas , Dashti Khavidak Kamal , Toloza Ariel C , Gholizadeh Saber
Published: June 2021

Knockdown resistance (kdr) is a common mechanism of insecticide resistance in head lice to the conventionally used pyrethroid pediculosis and can be the result of various amino acid substitutions within the voltage-sensitive sodium channel (VSSC). In this study, 54 sequences from varied specimens were investigated to monitor well-known resistance mutations and probable new mutations. The Pediculus humanus capitis de Geer specimens were collected from 13 provinces in Iran. The specimens were stored in 70% ethanol until DNA extraction and PCR amplification of ~900-bp fragment of VSSC. The sequences were analyzed using different bioinformatics software for the detection of well-known kdr substitutions and additional mutations potentially associated with kdr resistance in head lice. There were six new and an old (haplotype I) kdr haplotypes within the Iranian head louse population. K794E, F815I, and N818D amino acid substitutions were reported for the first time. The P813H mutation was the most prevalent amino acid substitution in eight provinces. Among 53 sequences, 26 (49%) were homozygous susceptible, and 27 (51%) were heterozygotes. Thus, 51% of the head lice collected in Iran harbored only the P813H allele. The exact test for the Hardy–Weinberg (H–W) equilibrium showed that genotype frequencies differed significantly from the expectation in East-Azerbaijan and Tehran provinces. Moreover, these populations had an inbreeding coefficient (Fis) <0, indicating the excess of heterozygotes. This observation suggests that the populations of head lice from Iran are currently under active selective pressure. For the rest of the populations, H–W equilibrium and the expectations were significantly in harmony. The results of the current study highlight molecular techniques in the accurate detection of resistance genotypes before their establishment within the head louse population. Accurate detection of resistant genotypes seems to be helpful in decision-making on lice control programs and resistance monitoring and management.
Dominant roles but distinct effects of groundwater depth on regulating leaf and fine-root N, P and N:P ratios of plant communities
Authors: Wang Yin , Wang Jianming , Wang Xiaolin , He Yicheng , Li Guanjun , Li Jingwen
Published: June 2021

Aims

As the determinant of water availability in drylands, groundwater plays a fundamental role in regulating vegetation distribution and ecosystem processes. Although considerable progress has been made over the past years in the relationship between environment stress and plant community-level traits, the potential influence of water stress induced by groundwater changes on plant community-level stoichiometry remains largely unclear. Here, we examined whether belowground and aboveground community-level stoichiometry responded differently to groundwater changes.

Methods

We measured nitrogen (N) and phosphorus (P) concentrations in plant leaves and fine-roots of 110 plots under a broad range of groundwater depths in a typical arid inland river basin. We examined the spatial patterns and drivers of community-level N:P stoichiometry in leaves and fine-roots.

Important Findings

Community-level leaf and fine-root N, P and N:P ratios were mainly determined by groundwater, vegetation types and species composition, among which groundwater played a dominant role. Groundwater indirectly regulated community-level N:P stoichiometry through affecting vegetation types and species composition. Vegetation types and species composition had significant direct influences on community-level N:P stoichiometry. Furthermore, groundwater depth had opposite influences on community-level leaf and fine-root N:P stoichiometry. Groundwater depth regulated vegetation types and further decreased leaf N, P but increased leaf N:P ratios and fine-root N. Groundwater depth had a positive indirect impact on fine-root P but a negative indirect impact on fine-root N:P ratios primarily by affecting species composition. Our findings indicate that groundwater rather than climate conditions effectively regulates community-level N:P stoichiometry, and below- and aboveground N:P stoichiometry has opposite responses to groundwater.
Empirical comparison of genotoxic potency estimations: the in vitro DNA-damage ToxTracker endpoints versus the in vivo micronucleus assay
Authors: Wills John W , Halkes-Wellstead Elias , Summers Huw D , Rees Paul , Johnson George E
Published: June 2021

Genetic toxicology is an essential component of compound safety assessment. In the face of a barrage of new compounds, higher throughput, less ethically divisive in vitro approaches capable of effective, human-relevant hazard identification and prioritisation are increasingly important. One such approach is the ToxTracker assay, which utilises murine stem cell lines equipped with green fluorescent protein (GFP)-reporter gene constructs that each inform on distinct aspects of cellular perturbation. Encouragingly, ToxTracker has shown improved sensitivity and specificity for the detection of known in vivo genotoxicants when compared to existing ‘standard battery’ in vitro tests. At the current time however, quantitative genotoxic potency correlations between ToxTracker and well-recognised in vivo tests are not yet available. Here we use dose–response data from the three DNA-damage-focused ToxTracker endpoints and from the in vivo micronucleus assay to carry out quantitative, genotoxic potency estimations for a range of aromatic amine and alkylating agents using the benchmark dose (BMD) approach. This strategy, using both the exponential and the Hill BMD model families, was found to produce robust, visually intuitive and similarly ordered genotoxic potency rankings for 17 compounds across the BSCL2-GFP, RTKN-GFP and BTG2-GFP ToxTracker endpoints. Eleven compounds were similarly assessed using data from the in vivo micronucleus assay. Cross-systems genotoxic potency correlations for the eight matched compounds demonstrated in vitro–in vivo correlation, albeit with marked scatter across compounds. No evidence for distinct differences in the sensitivity of the three ToxTracker endpoints was found. The presented analyses show that quantitative potency determinations from in vitro data enable more than just qualitative screening and hazard identification in genetic toxicology.
Efficient multiplexed gene regulation inSaccharomyces cerevisiaeusing dCas12a
Authors: Ciurkot Klaudia , Gorochowski Thomas E , Roubos Johannes A , Verwaal René
Published: June 2021

CRISPR Cas12a is an RNA-programmable endonuclease particularly suitable for gene regulation. This is due to its preference for T-rich PAMs that allows it to more easily target AT-rich promoter sequences, and built-in RNase activity which can process a single CRISPR RNA array encoding multiple spacers into individual guide RNAs (gRNAs), thereby simplifying multiplexed gene regulation. Here, we develop a flexible dCas12a-based CRISPRi system for Saccharomyces cerevisiae and systematically evaluate its design features. This includes the role of the NLS position, use of repression domains, and the position of the gRNA target. Our optimal system is comprised of dCas12a E925A with a single C-terminal NLS and a Mxi1 or a MIG1 repression domain, which enables up to 97% downregulation of a reporter gene. We also extend this system to allow for inducible regulation via an RNAP II-controlled promoter, demonstrate position-dependent effects in crRNA arrays, and use multiplexed regulation to stringently control a heterologous β-carotene pathway. Together these findings offer valuable insights into the design constraints of dCas12a-based CRISPRi and enable new avenues for flexible and efficient gene regulation in S. cerevisiae.
High Cure Rates for Hepatitis C Virus Genotype 6 in Advanced Liver Fibrosis With 12 Weeks Sofosbuvir and Daclatasvir: The Vietnam SEARCH Study
Authors: Flower Barnaby , McCabe Leanne , Le Ngoc Chau , Le Manh Hung , Le Thanh Phuong , Dang Trong Thuan , Vo Thi Thu , Vu Thi Kim Hang , Nguyen Tat Thanh , Phan Thi Hong Dao , Nguyen Thi Chau An , Dinh Thi Tan , Tran Thi Tuyet Nga , Tarning Joel , Kingsley Cherry , Kestelyn Evelyne , Pett Sarah L , Thwaites Guy , Nguyen Van Vinh Chau , Smith David , Barnes Eleanor , Ansari M Azim , Turner Hugo , Rahman Motiur , Walker Ann Sarah , Day Jeremy , Cooke Graham S
Published: June 2021

Background

Genotype 6 is the most genetically diverse lineage of hepatitis C virus, and it predominates in Vietnam. It can be treated with sofosbuvir with daclatasvir (SOF/DCV), the least expensive treatment combination globally. In regional guidelines, longer treatment durations of SOF/DCV (24 weeks) are recommended for cirrhotic individuals, compared with other pangenotypic regimens (12 weeks), based on sparse data. Early on-treatment virological response may offer means of reducing length and cost of therapy in patients with liver fibrosis.

Methods

In this prospective trial in Vietnam, genotype 6-infected adults with advanced liver fibrosis or compensated cirrhosis were treated with SOF/DCV. Day 14 viral load was used to guide duration of therapy: participants with viral load <500 IU/mL at day 14 were treated with 12 weeks of SOF/DCV and those ≥500 IU/mL received 24 weeks. Primary endpoint was sustained virological response (SVR).

Results

Of 41 individuals with advanced fibrosis or compensated cirrhosis who commenced treatment, 51% had genotype 6a and 34% had 6e. The remainder had 6h, 6k, 6l, or 6o. One hundred percent had viral load <500 IU/mL by day 14, meaning that all received 12 weeks of SOF/DCV. One hundred percent achieved SVR12 despite a high frequency of putative NS5A inhibitor resistance-associated substitutions at baseline.

Conclusions

Prescribing 12 weeks of SOF/DCV results in excellent cure rates in this population. These data support the removal of costly genotyping in countries where genotype 3 prevalence is <5%, in keeping with World Health Organization guidelines. NS5A resistance-associated mutations in isolation do not affect efficacy of SOF/DCV therapy. Wider evaluation of response-guided therapy is warranted.
Neck circumference and the burden of metabolic syndrome disease: a population-based sample
Authors: Zanuncio V V , Sediyama C M N O , Dias M M , Nascimento G M , Pessoa M C , Pereira P F , Silva M R I , Segheto K J , Longo G Z
Published: June 2021

Background

This study aims to verify the association between neck circumference (NC) and metabolic syndrome and establish NC cut-off points to predict metabolic syndrome.

Methods

Weight, height, NC, waist circumference, body mass index, fasting plasma glucose, HDL cholesterol, triglycerides and blood pressure were measured in a cross-sectional and population-based study with 966 adults. The association between NC and the burden of metabolic syndrome disease was evaluated by multinomial logistic regression. Receiver operating characteristic curves were used to acquire gender-specific cut-off values and predict metabolic syndrome. The NC is a simple anthropometric measurement, has low evaluation costs, can estimate the subcutaneous fat in the upper body and is related to cardiometabolic risks.

Results

NC is an independent predictor of metabolic syndrome burden with high association to women. The syndrome components stratification indicated that the NC of individuals with one component was lower than those with three or more (P = 0.001). Metabolic syndrome prediction cut-off point was a NC of 39.5 cm for men and 33.3 cm for women.

Conclusions

Increased NC was associated with higher metabolic syndrome risks. This anthropometric parameter can be used as an additional marker for screening cardiovascular risk diseases.
Optimal sleep and work schedules to maximize alertness
Authors: Vital-Lopez Francisco G , Doty Tracy J , Reifman Jaques
Published: June 2021

Study Objectives

Working outside the conventional “9-to-5” shift may lead to reduced sleep and alertness impairment. Here, we developed an optimization algorithm to identify sleep and work schedules that minimize alertness impairment during work hours, while reducing impairment during non-work hours.

Methods

The optimization algorithm searches among a large number of possible sleep and work schedules and estimates their effectiveness in mitigating alertness impairment using the Unified Model of Performance (UMP). To this end, the UMP, and its extensions to estimate sleep latency and sleep duration, predicts the time course of alertness of each potential schedule and their physiological feasibility. We assessed the algorithm by simulating four experimental studies, where we compared alertness levels during work periods for sleep schedules proposed by the algorithm against those used in the studies. In addition, in one of the studies we assessed the algorithm’s ability to simultaneously optimize sleep and work schedules.

Results

Using the same amount of sleep as in the studies but distributing it optimally, the sleep schedules proposed by the optimization algorithm reduced alertness impairment during work periods by an average of 29%. Similarly, simultaneously optimized sleep and work schedules, for a recovery period following a chronic sleep restriction challenge, accelerated the return to baseline levels by two days when compared to the conventional 9-to-5 work schedule.

Conclusions

Our work provides the first quantitative tool to optimize sleep and work schedules and extends the capabilities of existing fatigue-management tools.
Electoral Rules, Nomination Strategies, and Women’s Representation in Japan and Taiwan
Authors: Lin Chao-Chi , YANG Wan-Ying
Published: June 2021

Japan and Taiwan conducted similar electoral reforms in 1994 and 2005. Following the transition from the single nontransferable vote (SNTV) to the mixed-member majoritarian (MMM), at the district level, both countries’ numbers of female representatives have increased, contrary to expectations. What, then, explains the increase in Japan’s and Taiwan’s women’s representation at the district level? We argue that electoral systems can only partly explain the variation in female representation and that the critical factor explaining women’s representation is not the women’s electability, but the earlier stage of nomination. This article examines continuity and change in the candidate selection methods of major parties in Japan and Taiwan and identifies factors that may affect the likelihood of women becoming candidates. Although major parties have adopted different nomination strategies following the reforms, the increase in female representatives has been associated with the centralized process, and whether a woman is an incumbent or not is key to her nomination. Moreover, path dependence matters, and given that Taiwan had more female incumbent representatives than Japan under the SNTV, this might explain the differences in the starting point for female representation between Taiwan and Japan when both switched to the MMM and there was a persistent gap between the two countries.
RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection
Authors: Lewitus Eric , Sanders-Buell Eric , Bose Meera , O’Sullivan Anne Marie , Poltavee Kultida , Li Yifan , Bai Hongjun , Mdluli Thembi , Donofrio Gina , Slike Bonnie , Zhao Hong , Wong Kim , Chen Lennie , Miller Shana , Lee Jenica , Ahani Bahar , Lepore Steven , Muhammad Sevan , Grande Rebecca , Tran Ursula , Dussupt Vincent , Mendez-Rivera Letzibeth , Nitayaphan Sorachai , Kaewkungwal Jaranit , Pitisuttithum Punnee , Rerks-Ngarm Supachai , O’Connell Robert J , Janes Holly , Gilbert Peter B , Gramzinski Robert , Vasan Sandhya , Robb Merlin L , Michael Nelson L , Krebs Shelly J , Herbeck Joshua T , Edlefsen Paul T , Mullins James I , Kim Jerome H , Tovanabutra Sodsai , Rolland Morgane
Published: June 2021

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1’s high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.
Human genomics of the humoral immune response against polyomaviruses
Authors: Hodel F , Chong A Y , Scepanovic P , Xu Z M , Naret O , Thorball C W , Rüeger S , Marques-Vidal P , Vollenweider P , Begemann M , Ehrenreich H , Brenner N , Bender N , Waterboer T , Mentzer A J , Hill A V S , Hammer C , Fellay J
Published: June 2021

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
Creative Ways to Enhance and Assess Critical Thinking in Nursing Students
Authors: Parker Kimberly C.
Published: June 2021

Nursing students should be challenged to implement critical thinking decisions regarding conclusions they implement for patient care. This article reinforces common techniques and introduces new practices to teach critical thinking. Many ways are currently recognized utilizing an assortment of techniques. The concepts from an escape room are a great way to deliver opportunities for students to practice this skill and can be provided economically and easily. Being creative in managing these concepts will offer an exciting chance to introduce critical thinking for your students.
Characterizing Health-Related Quality of Life by Ambulatory Status in Patients with Spinal Metastases
Authors: Schoenfeld Andrew J. , Yeung Caleb M. , Tobert Daniel G. , Nguyen Lananh , Passias Peter G. , Shin John H. , Kang James D. , Ferrone Marco L.
Published: June 2021

Study Design.

Retrospective review of prospective longitudinal data.

Objective.

To determine health-related quality of life (HRQL) utilities associated with specific ambulatory states in patients with spinal metastases: independent, ambulatory with assistance, and nonambulatory.

Summary of Background Data.

It is assumed that HRQL is aligned with ambulatory ability in patients with spinal metastases. Few studies have effectively considered these parameters while also accounting for clinical confounders.

Methods.

We used prospective longitudinal data from patients treated at one of three tertiary medical centers (2017–2019). HRQL was characterized using the Euroquol-5-dimension (EQ5D) inventory. We performed standardized estimations of HRQL stratified by ambulatory state using generalized linear modeling that accounted for patient age at presentation, biologic sex, follow-up duration, operative or nonoperative management, and repeated measures within the same participant.

Results.

We evaluated 675 completed EQ5D assessments, with 430 for independent ambulators, 205 for ambulators with assistance, and 40 for nonambulators. The average age of the cohort was 61.5. The most common primary cancer was lung (20%), followed by breast (18%). Forty-one percent of assessments were performed for participants treated surgically. Mortality occurred in 51% of the cohort. The standardized EQ5D utility for patients with spinal metastases and independent ambulatory function was 0.76 (95% confidence interval [CI] 0.74, 0.78). Among those ambulatory with assistance, the standardized EQ5D utility was 0.59 (95% CI 0.57, 0.61). For nonambulators, the standardized EQ5D utility was 0.14 (95% CI 0.09, 0.19).

Conclusion.

Patients with spinal metastases and independent ambulatory function have an HRQL similar to patients with primary cancers and no spinal involvement. Loss of ambulatory ability leads to a 22% decrease in HRQL for ambulation with assistance and an 82% reduction among nonambulators. Given prior studies demonstrate superior maintenance of ambulatory function with surgery for spinal metastases, our results support surgical consideration to the extent that it is clinically warranted.

Level of Evidence: 3
Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial
Authors: Kadry Zakiyah , Stine Jonathan G. , Dohi Takehiko , Jain Ashokkumar , Robyak Kimberly L. , Kwon Osun , Hamilton Christopher J. , Janicki Piotr , Riley Thomas R. , Butt Fauzia , Krok Karen , Schreibman Ian R. , Bezinover Dmitri , Ghahramani Nasrollah , Campos Stalin , Hollenbeak Christopher S.
Published: June 2021

Background.

Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.

Methods.

This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson’s chi-square test for binary outcomes. Effect size was measured using Cohen’s d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test.

Results.

Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months.

Conclusions.

EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.
Bow-tie architecture of gene regulatory networks in species of varying complexity
Authors: Ghosh Roy Gourab , He Shan , Geard Nicholas , Verspoor Karin
Published: June 2021

The gene regulatory network (GRN) architecture plays a key role in explaining the biological differences between species. We aim to understand species differences in terms of some universally present dynamical properties of their gene regulatory systems. A network architectural feature associated with controlling system-level dynamical properties is the bow-tie, identified by a strongly connected subnetwork, the
core
layer, between two sets of nodes, the
in
and the
out
layers. Though a bow-tie architecture has been observed in many networks, its existence has not been extensively investigated in GRNs of species of widely varying biological complexity. We analyse publicly available GRNs of several well-studied species from prokaryotes to unicellular eukaryotes to multicellular organisms. In their GRNs, we find the existence of a bow-tie architecture with a distinct largest strongly connected
core
layer. We show that the bow-tie architecture is a characteristic feature of GRNs. We observe an increasing trend in the relative
core
size with species complexity. Using studied relationships of the
core
size with dynamical properties like robustness and fragility, flexibility, criticality, controllability and evolvability, we hypothesize how these regulatory system properties have emerged differently with biological complexity, based on the observed differences of the GRN bow-tie architectures.
The plate-to-rod transition in trabecular bone loss is elusive
Authors: Felder A. A. , Monzem S. , De Souza R. , Javaheri B. , Mills D. , Boyde A. , Doube M.
Published: June 2021

Changes in trabecular micro-architecture are key to our understanding of osteoporosis. Previous work focusing on structure model index (SMI) measurements have concluded that disease progression entails a shift from plates to rods in trabecular bone, but SMI is heavily biased by bone volume fraction. As an alternative to SMI, we proposed the ellipsoid factor (EF) as a continuous measure of local trabecular shape between plate-like and rod-like extremes. We investigated the relationship between EF distributions, SMI and bone volume fraction of the trabecular geometry in a murine model of disuse osteoporosis as well as from human vertebrae of differing bone volume fraction. We observed a moderate shift in EF median (at later disease stages in mouse tibia) and EF mode (in the vertebral samples with low bone volume fraction) towards a more rod-like geometry, but not in EF maximum and minimum. These results support the notion that the plate to rod transition does not coincide with the onset of bone loss and is considerably more moderate, when it does occur, than SMI suggests. A variety of local shapes not straightforward to categorize as rod or plate exist in all our trabecular bone samples.
Thermoelectric performances for both p- and n-type GeSe
Authors: Fan Qiang , Yang Jianhui , Cao Jin , Liu Chunhai
Published: June 2021

In this paper, the thermoelectric properties of p-type and n-type GeSe are studied systematically by using first principles and Boltzmann transport theory. The calculation includes electronic structure, electron relaxation time, lattice thermal conductivity and thermoelectric transport properties. The results show that GeSe is an indirect band gap semiconductor with band gap 1.34 eV. Though p-type GeSe has a high density of states near Fermi level, the electronic conductivity is relative low because there is no carrier transport pathway along the
a
-axis direction. For n-type GeSe, a charge density channel is formed near conduction band minimum, which improves the electrical conductivity of n-type GeSe along the
a
-axis direction. At 700 K, the optimal ZT value reaches 2.5 at 4 × 10
19
cm
−3
for n-type GeSe, while that is 0.6 at 1 × 10
20
cm
−3
for p-type GeSe. The results show n-type GeSe has better thermoelectric properties than p-type GeSe, indicating that n-type GeSe is a promising thermoelectric material in middle temperature.
The ecological dynamics of the coronavirus epidemics during transmission from outside sources when
R
0
is successfully managed below one
Authors: Engen Steinar , Tian Huaiyu , Yang Ruifu , Bjørnstad Ottar N. , Whittington Jason D. , Stenseth Nils Chr.
Published: June 2021

Since COVID-19 spread globally in early 2020 and was declared a pandemic by the World Health Organization (WHO) in March, many countries are managing the local epidemics effectively through intervention measures that limit transmission. The challenges of immigration of new infections into regions and asymptomatic infections remain. Standard deterministic compartmental models are inappropriate for sub- or peri-critical epidemics (reproductive number close to or less than one), so individual-based models are often used by simulating transmission from an infected person to others. However, to be realistic, these models require a large number of parameters, each with its own set of uncertainties and lack of analytic tractability. Here, we apply stochastic age-structured Leslie theory with a long history in ecological research to provide some new insights to epidemic dynamics fuelled by external imports. We model the dynamics of an epidemic when
R
0
is below one, representing COVID-19 transmission following the successful application of intervention measures, and the transmission dynamics expected when infections migrate into a region. The model framework allows more rapid prediction of the shape and size of an epidemic to improve scaling of the response. During an epidemic when the numbers of infected individuals are rapidly changing, this will help clarify the situation of the pandemic and guide faster and more effective intervention.
Influence of early thermal-oxidative ageing on the structure and properties of polyoxymethylene copolymer
Authors: Pang Yuan-Jin , Xu Wen-Shuai , Yang Ben-Tengzi , Ni Hai-Ying , Chen Jun
Published: June 2021

Thermal-oxidative ageing of polyoxymethylene (POM) copolymer in the oven at 100°C for 1, 2, 3, 5, 7, 10, 14 and 21 days and the influence of early thermal-oxidative ageing on POM structure and properties were studied by means of wide-angle X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and tensile test. Based on the results, we found that the early thermal-oxidative ageing of POM copolymer can be divided into three regions. The region I is the initial 3 days. In this region, some molecular chains rearranged, resulting in internal stress relaxation, increase of crystallinity degree and grain size due to the perfection of crystal structure; both extended chain crystal (ECC) and folded chain crystal (FCC) increased and ECC grew faster than FCC. The region II is from 3 days to 10 days, and in this region, chain scission took place in amorphous region and led to chemi-crystallization. The region III is after 10 days. In this region, the structure and performance of POM copolymer reached a stable situation at this stage. In this work, the difference between skin and core were also analysed.