bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainable and feasible reagent-free electro-Fenton via sequential dual-cathode electrocatalysis
Authors: Wang Jiabei , Li Shizhen , Qin Qiyue , Peng Chuang
Published: August 2021

Significance

Remediation of environmental pollution usually involves use of chemical reagents, making the process costly whilst generating secondary pollution. Catalysis instead of stoichiometric chemicals is one of the 12 principles in green chemistry. The current work demonstrates a process to achieve radical-based advanced oxidation using only air and electricity, offering a more-sustainable route to pollution control. There is an ongoing “appeal to nano” fallacy that is dominating the research area of energy and environmental chemistry. This trend leads researchers to focus only on the fancy materials rather than fulfillment of the goals in a commercially viable way. This study gives an authentic example to achieve the same function as, and outperform, nanomaterials using low-cost commercially available materials.
Electrochemical borylation of carboxylic acids
Authors: Barton Lisa M. , Chen Longrui , Blackmond Donna G. , Baran Phil S.
Published: August 2021

Significance

Boronic acids are one of the most useful functional groups in organic chemistry and can be used as intermediates in synthesis or as key motifs in medicines. This work describes an extremely simple and economical way to use electrochemistry to convert carboxylic acids, through the intermediacy of redox-active esters, to boronic acids. The scope of this reaction is broad, the mechanism has been thoroughly studied, and it can be easily scaled up. Finally, application to the synthesis of a complex polycyclopropane natural product is demonstrated.
Molecular basis of cholesterol efflux via ABCG subfamily transporters
Authors: Sun Yingyuan , Wang Jin , Long Tao , Qi Xiaofeng , Donnelly Linda , Elghobashi-Meinhardt Nadia , Esparza Leticia , Cohen Jonathan C. , Xie Xiao-Song , Hobbs Helen H. , Li Xiaochun
Published: August 2021

Significance

Cholesterol is an essential component of animal cell membranes whose level in cells is maintained within a narrow range. Cholesterol is actively excreted from cells by two ATP-binding cassette (ABC) transporters, ABCG5–ABCG8 (G5G8) in the liver and gut and ABCG1 (G1) in macrophages. The mechanism(s) by which these proteins translocate rigid, planar sterol molecules across the membrane bilayer remain unknown. Here, we report the structure of human G1 and G5G8 in their unbound and cholesterol-bound states. We also determined the structure of G1 bound to ATP. These structures, together with functional studies in model organisms and biochemical studies, identify the binding site for cholesterol and provide the basis for a model of cholesterol transport by ABC transporters.
Atomic view of cosolute-induced protein denaturation probed by NMR solvent paramagnetic relaxation enhancement
Authors: Okuno Yusuke , Yoo Janghyun , Schwieters Charles D. , Best Robert B. , Chung Hoi Sung , Clore G. Marius
Published: August 2021

Significance

The cosolvent effect alters the equilibrium between native and unfolded states of a protein, with denaturant cosolutes shifting the equilibrium toward the latter and osmolyte cosolutes stabilizing the former. Quantitative characterization of the strength of cosolute–protein interactions at atomic resolution is experimentally challenging as these interactions are highly transient and occur at low occupancy. Here, we make use of paramagnetic cosolutes and NMR solvent paramagnetic relaxation enhancement measurements to quantify the interaction of cosolutes with drkN SH3, a metastable protein domain that exists in dynamic equilibrium between native and unfolded states. The current study shows that destabilization of the native state is largely attributable to preferential cosolute interactions with the unfolded state.
Polar answers and epistemic stance in Greek conversation
Authors: Alvanoudi Angeliki
Published: August 2021

This conversation analytic study examines the linguistic resources for indexing epistemic stance in second position in question sequences in Greek conversation. It targets three formats for providing affirming/confirming answers to polar questions: unmarked and marked positive response tokens, and repetitions. It is shown that the three formats display different functional distributions. Unmarked response tokens do ‘simple’ answering, marked response tokens provide overt confirmations, and repetitional answers assert the respondent’s epistemic authority besides confirming the question’s proposition. Unmarked and marked response tokens accept the questioner’s epistemic stance, whereas repetitional answers may accept or resist the epistemic terms of the question, depending on the action being implemented by the question. This study sheds light on the organization of questioning and answering in Greek conversation and the role of epistemics in the design of polar answers.
Pex30-like proteins function as adaptors at distinct ER membrane contact sites
Authors: Ferreira Joana Veríssimo , Carvalho Pedro
Published: August 2021

Membrane lipids and proteins synthesized in the ER are used for de novo assembly of organelles, such as lipid droplets and peroxisomes. After assembly, the growth of these organelles is supported by ER-derived lipids transferred at membrane contact sites (MCSs). How ER sites for organelle biogenesis and lipid transfer are established and regulated is unclear. Here, we investigate how the ER membrane protein Pex30 and its family members Pex28, Pex29, Pex31, and Pex32 target and function at multiple MCSs. We show that different Pex30 complexes function at distinct ER domains and MCSs. Pex30 targets ER–peroxisome MCSs when bound to Pex28 and Pex32, organizes the nuclear–vacuolar junction when bound to Pex29, and promotes the biogenesis of lipid droplets independently of other family members. Importantly, the reticulon homology domain (RHD) mediates the assembly of the various Pex30 complexes. Given the role of RHD in membrane shaping, our findings offer a mechanistic link between MCS and regulation of membrane curvature.
The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination
Authors: Beilinson Helen A. , Glynn Rebecca A. , Yadavalli Anurupa Devi , Xiao Jianxiong , Corbett Elizabeth , Saribasak Huseyin , Arya Rahul , Miot Charline , Bhattacharyya Anamika , Jones Jessica M. , Pongubala Jagan M.R. , Bassing Craig H. , Schatz David G.
Published: August 2021

Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1–383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.
Charge transport in single crystal CVD diamond studied at high temperatures
Authors: Crnjac Andreo , Ramos Mauricio R , Skukan Natko , Pomorski Michal , Jakšić Milko
Published: August 2021

The capability of single crystal diamonds to maintain their unique electronic properties even at high temperatures is, in particular, relevant for its applications as a radiation detector. In order to explore characteristics of charge transport at high temperatures (up to 450 ∘C), diamond was exposed to MeV energy ions, both, to induce radiation damage and to probe subsequent influence on detector’s properties. Dependence of mobility-lifetime product with temperature has been obtained for electrons and holes. For holes, mu-tau displays a linear degradation with rising temperature, while for electrons, change with temperature is less evident. Furthermore, deep trapping levels induced in the material by radiation damage, were studied through time-resolved charge signals. Detrapping time was extracted from this data. Hole trap level, with the activation energy of 0.53 ± 0.01 eV has been detected in the regions of the diamond detector previously irradiated by 5 MeV damaging proton beam, but not in the pristine regions. This indicates that the trap was formed due to defect induction during radiation damage exposure. Activation of this deep level is important for charge transport performance in diamond detectors operating at high temperatures and high radiation conditions.
Zero-error attack against coherent-one-way quantum key distribution
Authors: Trényi Róbert , Curty Marcos
Published: August 2021

Coherent-one-way (COW) quantum key distribution (QKD) held the promise of distributing secret keys over long distances with a simple experimental setup. Indeed, this scheme is currently used in commercial applications. Surprisingly, however, it has been recently shown that its secret key rate scales at most quadratically with the system’s transmittance and, thus, it is not appropriate for long distance QKD transmission. Such pessimistic result was derived by employing a so-called zero-error attack, in which the eavesdropper does not introduce any error, but still the legitimate users of the system cannot distill a secure key. Here, we present an improved zero-error attack against COW-QKD that significantly outperforms previous approaches, and provides stronger restrictions on its maximum achievable distance in the absence of errors. This translates into an upper bound on its secret key rate that is more than an order of magnitude lower than previously known upper bounds.
The Oxford Encyclopedia of LGBT Politics and Policy
Authors: Haider-Markel Donald P.
Published: August 2021

This encyclopedia reviews and interprets a broad array of social science and humanities research on LGBT people, politics, and public policy around the world. The articles are organized around six major themes of the study of identity politics, with a focus on movement politics, public attitudes, political institutions, elections, and the broader context of political theory. Under the editorial directorship of Donald P. Haider-Markel and associate editors Carlos Ball, Gary Mucciaroni, Bruno Perreau, Craig A. Rimmerman, and Jami K. Taylor, this publication brings together peer-reviewed contributions by leading researchers and offers a the most comprehensive view of research on LGBT politics and policy to date. As a result, the Oxford Encyclopedia of LGBT Politics and Policy is a necessary resource for students and as well as both new and established scholars.
The Concise Oxford Dictionary of Archaeology
Authors: Darvill Timothy
Published: August 2021

Over 4,500 entries

This dictionary is the most wide-ranging and comprehensive of its kind, covering the essential vocabulary for everyday archaeological work in the English language. There is coverage of principles, theories, techniques, artefacts, materials, people, places, monuments, equipment, and descriptive terms.

The dictionary focuses especially on Europe, the Old World, and the Americas, and covers legislation relating to the United Kingdom and the USA, though this third edition does add a fair number of entries relating to the Near East and Asia. These include Angara Style, Donghulin Culture, Hasanlu, Samarra Culture, and Tel Tsaf, as well as a new appendix listing Chinese rulers and dynasties.

Written by a leading authority, the dictionary’s detailed but clear entries provide an essential reference source for students, teachers, professionals, and enthusiasts alike.
The Erasure of Intersex, Transgender, Nonbinary, and Agender Experiences Through Misuse of Sex and Gender in Health Research
Authors: Morrison Tessalyn , Dinno Alexis , Salmon Taurica
Published: August 2021

Conflation of the terms and concepts of “sex” and “gender” continues to perpetuate the invisibility of sex and gender minorities and obscure information about the ways in which biological sex and gender affect health. The misuse of sex and gender terms and the sex and gender binaries can yield inaccurate results but also, more importantly, contributes to the erasure of intersex, transgender, nonbinary, and agender health experiences. In this article, we discuss ways in which public health researchers can use sex and gender terms correctly and center the health experiences of intersex, transgender, nonbinary, and agender individuals. This includes promoting sensitivity in approaching sex and gender minority communities, improving survey questions, and collaborating with GSM communities to improve research quality and participant experiences. Improving our standards for the quality of sex and gender term usage and centering sex and gender minorities in public health research are imperative to addressing the health inequalities faced by sex and gender minorities.
Tolerance of four grain legume species to waterlogging, hypoxia and anoxia at germination and recovery
Authors: Wiraguna Edi , Malik Al Imran , Colmer Timothy David , Erskine William
Published: August 2021

Legume seeds, when relay sown following rice, may suffer from soil waterlogging and the associated hypoxia or even anoxia. This study evaluated the tolerance of grain legume species, grass pea (three genotypes), lentil (two genotypes), faba bean (two genotypes) and field pea (one genotype), to soil waterlogging in a glasshouse, to anoxia and hypoxia in temperature-controlled room at germination and seedling stages. Changes in oxygen in the surface layers of soil, with time after waterlogging, were measured by microelectrode profiling. The soil profiling showed that soil oxygen declined and then stabilized by the fourth day after waterlogging and oxygen was not detected at 8 mm below the soil surface. Germination of seeds under waterlogging for up to 12 days and seedling survival after the soil was drained for up to 36 days were measured in pot experiments. Seed germination and/or survival in anoxia (N2-flushed solutions) and hypoxia (1.0 and 2.5 kPa oxygen) were evaluated, and so were post-anoxia or post-hypoxia recoveries, all in comparison with aerated controls. Lentil had higher seedling emergence (55 %) than the other species during soil waterlogging. However, lentil had lower seedling survival (9 %) than grass pea (28 %) during recovery following soil drainage. Grass pea seeds were more tolerant of anoxia and of hypoxia than the seeds of the three other species. In conclusion, grass pea, with higher percent germination and seedling survival during recovery, is more tolerant to waterlogging and subsequent soil drainage than the three other grain legume species. Grass pea was also more tolerant of hypoxia and of anoxia at the seed germination stage. These findings demonstrate the superior waterlogging tolerance of grass pea in relay sowing, as compared with the other grain legumes.
ksrates: positioning whole-genome duplications relative to speciation events in KS distributions
Authors: Sensalari Cecilia , Maere Steven , Lohaus Rolf
Published: August 2021

We present ksrates, a user-friendly command-line tool to position ancient whole-genome duplication events with respect to speciation events in a phylogeny by comparing paralog and ortholog KS distributions derived from genomic or transcriptomic sequences, while adjusting for substitution rate differences among the lineages involved.

Availability and implementation

ksrates is implemented in Python 3 and as a Nextflow pipeline. The source code, Singularity and Docker containers, documentation and tutorial are available via https://github.com/VIB-PSB/ksrates.

Supplementary information

Supplementary data are available at Bioinformatics online.
Subclinical Tuberculosis in Children: Diagnostic Strategies for Identification Reported in a 6-year National Prospective Surveillance Study
Authors: Fritschi Nora , Wind Ante , Hammer Jürg , Ritz Nicole
Published: August 2021

Background

Subclinical tuberculosis (TB) is well recognized and defined as a disease state with absent or nonrecognized symptoms. The study identifies factors associated with subclinical TB and diagnostic strategies in a low-burden, high-resource country.

Methods

Data were collected between December 2013 and November 2019 through the Swiss Pediatric Surveillance Unit (SPSU). Children with culture/molecular confirmed TB, or who were treated with ≥3 antimycobacterial drugs, were included.

Results

A total of 138 (80%) children with TB disease were included in the final analysis, of which 43 (31%) were subclinical. The median age of children with subclinical compared to symptomatic TB was 3.7 (interquartile range [IQR] 2.2–7) and 9.7 (IQR 2.7–14.3) years, respectively (P = .003). The cause of investigation for TB was recorded in 31/43 (72.1%) of children with subclinical TB and included contact exposure in 25 (80.6%) of children. In children with subclinical TB, diagnosis was made by a combination of the following abnormal/confirming results: culture/molecular + immunodiagnostic + chest radiography in 12 (27.9%) cases, immunodiagnostic + chest radiography in 19 (44.2%) cases, culture/molecular + chest radiography in 2 (4.7%) cases, culture + immunodiagnostic in 1 (2.3%) case, chest radiography only in 8 (18.6%) cases, and immunodiagnostic only in 1 (2.3%) case.

Conclusions

A notable proportion of children with TB had subclinical disease. This highlights the importance of non-symptom-based TB case finding in exposed children and refugees from high-TB-prevalence settings. TB screening in these asymptomatic children should therefore include a combination of immunodiagnostic testing and imaging followed by culture and molecular testing.
A Retrospective Test-Negative Case-Control Study to Evaluate Influenza Vaccine Effectiveness in Preventing Hospitalizations in Children
Authors: Yildirim Inci , Kao Carol M , Tippett Ashley , Suntarattiwong Piyarat , Munye Mohamed , Yi Jumi , Elmontser Mohnd , Quincer Elizabeth , Focht Chris , Watson Nora , Bilen Hande , Baker Julia M , Lopman Ben , Hogenesch Elena , Rostad Christina A , Anderson Evan J
Published: August 2021

Background

Vaccination is the primary strategy to reduce influenza burden. Influenza vaccine effectiveness (VE) can vary annually depending on circulating strains.

Methods

We used a test-negative case-control study design to estimate influenza VE against laboratory-confirmed influenza-related hospitalizations among children (aged 6 months–17 years) across 5 influenza seasons in Atlanta, Georgia, from 2012–2013 to 2016–2017. Influenza-positive cases were randomly matched to test-negative controls based on age and influenza season in a 1:1 ratio. We used logistic regression models to compare odds ratios (ORs) of vaccination in cases to controls. We calculated VE as [100% × (1 – adjusted OR)] and computed 95% confidence intervals (CIs) around the estimates.

Results

We identified 14 596 hospitalizations of children who were tested for influenza using the multiplex respiratory molecular panel; influenza infection was detected in 1017 (7.0%). After exclusions, we included 512 influenza-positive cases and 512 influenza-negative controls. The median age was 5.9 years (interquartile range, 2.7–10.3), 497 (48.5%) were female, 567 (55.4%) were non-Hispanic Black, and 654 (63.9%) children were unvaccinated. Influenza A accounted for 370 (72.3%) of 512 cases and predominated during all 5 seasons. The adjusted VE against influenza-related hospitalizations during 2012–2013 to 2016–2017 was 51.3% (95% CI, 34.8% to 63.6%) and varied by season. Influenza VE was 54.7% (95% CI, 37.4% to 67.3%) for influenza A and 37.1% (95% CI, 2.3% to 59.5%) for influenza B.

Conclusions

Influenza vaccination decreased the risk of influenza-related pediatric hospitalizations by >50% across 5 influenza seasons.
Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization
Authors: Fintzi Jonathan , Bonnett Tyler , Sweeney Daniel A , Huprikar Nikhil A , Ganesan Anuradha , Frank Maria G , McLellan Susan L F , Dodd Lori E , Tebas Pablo , Mehta Aneesh K
Published: August 2021

Background

The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death.

Methods

We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient’s clinical course to characterize the effect of remdesivir on progression along the 4 pathways above.

Results

Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]: .59–.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI: .57–.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI: .53–1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline.

Conclusions

Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care.
Incidence and Clinical Characteristics of and Risk Factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Pregnant Individuals in the United States
Authors: Dawood Fatimah S , Varner Michael , Tita Alan , Newes-Adeyi Gabriella , Gyamfi-Bannerman Cynthia , Battarbee Ashley , Bruno Ann , Daugherty Michael , Reichle Lawrence , Vorwaller Kelly , Vargas Celibell , Parks Mickey , Powers Emily , Lucca-Susana Miriam , Gibson Marie , Subramaniam Akila , Cheng Yiling J , Feng Pei-Jean , Ellington Sascha , Galang Romeo R , Meece Jennifer , Flygare Chris , Stockwell Melissa S
Published: August 2021

Background

Data about the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among pregnant individuals are needed to inform infection-prevention guidance and counseling for this population.

Methods

We prospectively followed a cohort of pregnant individuals during August 2020–March 2021 at 3 US sites. The 3 primary outcomes were incidence rates of any SARS-CoV-2 infection, symptomatic infection, and asymptomatic infection, during pregnancy during periods of SARS-CoV-2 circulation. Participants self-collected weekly midturbinate nasal swabs for SARS-CoV-2 reverse transcription–polymerase chain reaction testing, completed weekly illness symptom questionnaires, and submitted additional swabs with coronavirus disease 2019 (COVID-19)–like symptoms. An overall SARS-CoV-2 infection incidence rate weighted by population counts of women of reproductive age in each state was calculated.

Results

Among 1098 pregnant individuals followed for a mean of 10 weeks, 9% (99/1098) had SARS-CoV-2 infections during the study. Population-weighted incidence rates of SARS-CoV-2 infection were 10.0 per 1000 (95% confidence interval, 5.7–14.3) person-weeks for any infection, 5.7 per 1000 (1.7–9.7) for symptomatic infections, and 3.5 per 1000 (0–7.1) for asymptomatic infections. Among 96 participants with SARS-CoV-2 infections and symptom data, the most common symptoms were nasal congestion (72%), cough (64%), headache (59%), and change in taste or smell (54%); 28% had measured or subjective fever. Median symptom duration was 10 (interquartile range, 6–16) days.

Conclusions

Pregnant individuals in this study had a 1% risk of SARS-CoV-2 infection per week, underscoring the importance of COVID-19 vaccination and other prevention measures during pregnancy while SARS-CoV-2 is circulating in the community.
Post-Vaccination Coronavirus Disease 2019: A Case-Control Study and Genomic Analysis of 119 Breakthrough Infections in Partially Vaccinated Individuals
Authors: Baltas Ioannis , Boshier Florencia A T , Williams Charlotte A , Bayzid Nadua , Cotic Marius , Afonso Guerra-Assunção José , Irish-Tavares Dianne , Haque Tanzina , Hart Jennifer , Roy Sunando , Williams Rachel , Breuer Judith , Mahungu Tabitha W
Published: August 2021

Background

Post-vaccination infections challenge the control of the coronavirus disease 2019 (COVID-19) pandemic.

Methods

We matched 119 cases of post-vaccination severe acute respiratory syndrome coronavirus 2 infection with BNT162b2 mRNA or ChAdOx1 nCOV-19 to 476 unvaccinated patients with COVID-19 (September 2020–March 2021) according to age and sex. Differences in 60-day all-cause mortality, hospital admission, and hospital length of stay were evaluated. Phylogenetic, single-nucleotide polymorphism (SNP), and minority variant allele (MVA) full-genome sequencing analysis was performed.

Results

Overall, 116 of 119 cases developed COVID-19 post–first vaccination dose (median, 14 days). Thirteen of 119 (10.9%) cases and 158 of 476 (33.2%) controls died (P < .001), corresponding to the 4.5 number needed to treat (NNT). Multivariably, vaccination was associated with a 69.3% (95% confidence interval [CI]: 45.8 to 82.6) relative risk (RR) reduction in mortality. Similar results were seen in subgroup analysis for patients with infection onset ≥14 days after first vaccination and across vaccine subgroups. Hospital admissions (odds ratio, 0.80; 95% CI: .51 to 1.28) and length of stay (–1.89 days; 95% CI: –4.57 to 0.78) were lower for cases, while cycle threshold values were higher (30.8 vs 28.8, P = .053). B.1.1.7 was the predominant lineage in cases (100 of 108, 92.6%) and controls (341 of 446, 76.5%). Genomic analysis identified 1 post-vaccination case that harbored the E484K vaccine-escape mutation (B.1.525 lineage).

Conclusions

Previous vaccination reduces mortality when B.1.1.7 is the predominant lineage. No significant lineage-specific genomic changes during phylogenetic, SNP, and MVA analysis were detected.
Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria
Authors: Schmitt Esther K , Ndayisaba Gilles , Yeka Adoke , Asante Kwaku Poku , Grobusch Martin P , Karita Etienne , Mugerwa Henry , Asiimwe Stephen , Oduro Abraham , Fofana Bakary , Doumbia Seydou , Su Guoqin , Csermak Renner Katalin , Venishetty Vinay Kumar , Sayyed Sarfaraz , Straimer Judith , Demin Ivan , Barsainya Sarita , Boulton Caroline , Gandhi Preetam
Published: August 2021

Background

Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere).

Methods

This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)–corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed.

Results

All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional.

Conclusions

Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner.

Clinical Trials Registration

ClinicalTrials.gov (NCT03334747).
Clinical Spectrum of Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Protection From Symptomatic Reinfection
Authors: Maier Hannah E , Kuan Guillermina , Saborio Saira , Carrillo Fausto Andres Bustos , Plazaola Miguel , Barilla Carlos , Sanchez Nery , Lopez Roger , Smith Matt , Kubale John , Ojeda Sergio , Zuniga-Moya Julio C , Carlson Bradley , Lopez Brenda , Gajewski Anna M , Chowdhury Mahboob , Harris Eva , Balmaseda Angel , Gordon Aubree
Published: August 2021

Background

There are few data on the full spectrum of disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across the lifespan from community-based or nonclinical settings.

Methods

We followed 2338 people in Managua, Nicaragua, aged <94 years from March 2020 through March 2021. SARS-CoV-2 infection was identified through real-time reverse transcription polymerase chain reaction (RT-PCR) or through enzyme-linked immunosorbent assay. Disease presentation was assessed at the time of infection or retrospectively by survey at the time of blood collection.

Results

There was a large epidemic that peaked between March and August 2020. In total, 129 RT-PCR–positive infections were detected, for an overall incidence rate of 5.3 infections per 100 person-years (95% confidence interval [CI], 4.4–6.3). Seroprevalence was 56.7% (95% CI, 53.5%–60.1%) and was consistent from age 11 through adulthood but was lower in children aged ≤10 years. Overall, 31.0% of the infections were symptomatic, with 54.7% mild, 41.6% moderate, and 3.7% severe. There were 2 deaths that were likely due to SARS-CoV-2 infection, yielding an infection fatality rate of 0.2%. Antibody titers exhibited a J-shaped curve with respect to age, with the lowest titers observed among older children and young adults and the highest among older adults. When compared to SARS-CoV-2–seronegative individuals, SARS-CoV-2 seropositivity at the midyear sample was associated with 93.6% protection from symptomatic reinfection (95% CI, 51.1%–99.2%).

Conclusions

This population exhibited a very high SARS-CoV-2 seropositivity with lower-than-expected severity, and immunity from natural infection was protective against symptomatic reinfection.
Evidence reversals in primary care research: a study of randomized controlled trials
Authors: Ruchon Christian , Grad Roland , Ebell Mark H , Slawson David C , Pluye Pierre , Filion Kristian B , Rousseau Mathieu , Braschi Emelie , Sridhar Soumya , Grover-Wenk Anupriya , Cheung Jennifer Ren-Si , Shaughnessy Allen F
Published: August 2021

Background

Evidence-Based Medicine is built on the premise that clinicians can be more confident when their decisions are grounded in high-quality evidence. Furthermore, evidence from studies involving patient-oriented outcomes is preferred when making decisions about tests or treatments. Ideally, the findings of relevant and valid trials should be stable over time, that is, unlikely to be reversed in subsequent research.

Objective

To evaluate the stability of evidence from trials relevant to primary healthcare and to identify study characteristics associated with their reversal.

Methods

We studied synopses of randomized controlled trials (RCTs) published from 2002 to 2005 as “Daily POEMs” (Patient Oriented Evidence that Matters). The initial evidence (E1) from these POEMs (2002–2005) was compared with the updated evidence (E2) on that same topic in a summary resource (DynaMed 2019). Two physician-raters independently categorized each POEM-RCT as (i) reversed when E1 ≠ E2, or as (ii) not reversed, when E1 = E2. For all “Evidence Reversals” (E1 ≠ E2), we assessed the direction of change in the evidence.

Results

We evaluated 408 POEMs on RCTs. Of those, 35 (9%; 95% confidence interval [6–12]) were identified as reversed, 359 (88%) were identified as not reversed, and 14 (3%) were indeterminate. On average, this represents about 2 evidence reversals per annum for POEMs about RCTs.

Conclusions

Over 12–17 years, 9% of RCTs summarized as POEMs are reversed. Information alerting services that apply strict criteria for relevance and validity of clinical information are likely to identify RCTs whose findings are stable over time.
Identifying hot spots for harm and blind spots across the care pathway from patient complaints about general practice
Authors: O’Dowd Emily , Lydon Sinéad , Lambe Kathryn , Rudland Chris , Hilton Aoife , O’Connor Paul
Published: August 2021

Introduction

Healthcare complaints are underutilized for quality improvement in general practice. Systematic analysis of complaints has identified hot spots (areas across the care pathway where issues occur frequently) and blind spots (areas across the care pathway that cannot be observed by staff) in secondary care. The Healthcare Complaints Analysis Tool (HCAT) has been adapted to the HCAT(GP).

Aims

This study aimed to: (i) assess whether the HCAT(GP) can systematically analyze complaints about general practice; and (ii) identify hot spots and blind spots in general practice.

Methods

GP complaints were sampled. Complaints were coded with the HCAT(GP), classified by HCAT(GP) category (e.g. Safety, Environment, Listening), stage of care (e.g. accessing care, referral/follow-up), severity (e.g. low, medium, high), and harm (e.g. none, major). Descriptive statistics were run to identify discrete issues. A chi-square test of independence identified hot spots, and logistic regression was used for blind spots.

Results

A total of 230 complaints, encompassing 432 issues (i.e. unique problems within complaints), were categorized. Relationship issues (e.g. problems with listening, communication, and patient rights) emerged most frequently (n = 174, 40%). Hot spots were identified in the consultation and the referral/follow-up stages (χ 2(5, n = 432) = 17.931, P < 0.05). A blind spot for multiple issues was identified, with the likelihood of harm increasing with number of issues (odds ratio = 2.02, confidence interval = 1.27–3.23, P < 0.05).

Conclusions

Complaints are valuable data for improving general practice. This study demonstrated that the HCAT(GP) can support the systematic analysis of general practice complaints, and identify hot spots and blind spots in care.
Revising while playing: development and evaluation of the newly created Microbial Pursuit game as a pedagogical tool in higher education
Authors: Murillo Isabel
Published: August 2021

Playing games is an invaluable and widely used educational tool in both primary and secondary schools and there is an increasing interest in building games into the curricula in the higher education system. This project involves the creation and playing of a board game with questions on a science discipline. Questions and answers are collaboratively made by the students based on the unit material. It is therefore in both the making and the playing of the game that learning takes place. The game contains not only a collaborative element but also an element of competitiveness as the students play with and against their colleagues. Both these elements are designed with the intention of enhancing student engagement with the topic of microbiology. The game, called Microbial Pursuit, represents a versatile tool for converting tutorials and workshops into pedagogical and enjoyable sessions, as well as a promising unit revision tool.
Canadian Exclusion Jurisprudence post-Febles
Authors: Joeck Molly
Published: August 2021

This article examines the state of Canadian refugee law since the decision of the Supreme Court in Febles v Canada (Citizenship and Immigration) [2014] 3 SCR 431. Drawing upon an analysis of a set of decisions of the Immigration and Refugee Board, the administrative tribunal tasked with refugee status determination in Canada, the article seeks to determine whether administrative decision makers are heeding the guidance of Febles when excluding asylum seekers from refugee protection on the basis of serious criminality pursuant to article 1F(b) of the 1951 Convention relating to the Status of Refugees. In doing so, it examines the controversy around article 1F(b) since its inception across various jurisdictions and amongst academic commentators, situating Febles within that controversy in order to demonstrate that the Supreme Court’s reluctance to clearly set out the purpose underlying article 1F(b) is in step with a longstanding tendency to understand the provision as serving a gatekeeping function, that prevents criminalized non-citizens from obtaining membership in our society. It argues that by omitting to set out a clear and principled standard by which asylum seekers can be excluded from refugee protection pursuant to article 1F(b), the Supreme Court failed to live up to a thick understanding of the rule of law. It concludes by calling for a reassertion of the rule of law into exclusion decision making, both nationally and internationally, in order to ensure that the legitimacy of the international refugee law regime is maintained.
Fully oral targeted antibiotic therapy for Gram-positive cocci-related periprosthetic joint infections: a real-life before and after study
Authors: Coehlo Alexandre , Robineau Olivier , Titecat Marie , Blondiaux Nicolas , Dezeque Hervé , Patoz Pierre , Loiez Caroline , Putman Sophie , Beltrand Eric , Migaud Henri , Senneville Eric
Published: August 2021

Background

The optimal length of the intravenous antibiotic treatment of periprosthetic joint infections (PJIs) generally ranges from one to six weeks and is a matter of debate. Most antibiotics active against Gram-positive cocci (GPC) exhibit both high oral bioavailability and bone diffusion. Thus, early oral therapy may be a reasonable option in GPC-related PJIs.

Methods

A 2 year before and after monocentric study that aimed to compare two antibiotic strategies. Empirical intravenous postoperative antibiotic treatment was followed by 7 to 10 days of intravenous targeted therapy (‘before’ group) or by full orally targeted antibiotic treatment (‘after’ group). The primary outcome was a treatment failure during follow-up.

Results

A total of 93 patients were analysed, 43 and 50 in the before and the after groups, respectively. Both groups were comparable in terms of surgical procedures, comorbidities, microbiological documentation and infection site. Antibiotics prescribed to our patients had high oral bioavailability and bone diffusion with rifampicin/fluoroquinolone combinations being the most frequent antibiotic regimens. Both hospital stay and intravenous antibiotic treatment mean durations were shorter in the before group than in the after group [15.0 versus 11.0 days; (P < 0.01) and 13.0 versus 7.0 days; P < 0.001, respectively]. The remission rate assessed after at least a year of follow-up was comparable in the before and the after groups (hazard ratio = 0.70; 95% CI 0.30–1.58).

Conclusions

Full oral targeted antibiotic therapy using a drug regimen with high oral bioavailability and good bone diffusion is an option for the treatment of patients with GPC-related PJIs.
Long-acting antiretrovirals: a new era for the management and prevention of HIV infection
Authors: Thoueille Paul , Choong Eva , Cavassini Matthias , Buclin Thierry , Decosterd Laurent A.
Published: August 2021

The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient’s weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients’ privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current ‘one-size-fits-all’ approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.
Cloning and characterization of Thioredoxin 1 from the Cnidarian Hydra
Authors: Perween Nusrat , Pekhale Komal , Haval Gauri , Mittal Smriti , Ghaskadbi Surendra , Ghaskadbi Saroj S
Published: August 2021

Thioredoxins, small disulphide-containing redox proteins, play an important role in the regulation of cellular thiol redox balance through their disulfide reductase activity. In this study, we have identified, cloned, purified and characterized thioredoxin 1 (HvTrx1) from the Cnidarian Hydra vulgaris Ind-Pune. Bioinformatics analysis revealed that HvTrx1 contains an evolutionarily conserved catalytic active site Cys-Gly-Pro-Cys and shows a closer phylogenetic relationship with vertebrate Trx1. Optimum pH and temperature for enzyme activity of purified HvTrx1 was found to be pH 7.0 and 25°C, respectively. Enzyme activity decreased significantly at acidic or alkaline pH as well as at higher temperatures. HvTrx1 was found to be expressed ubiquitously in whole mount in situ hybridization.

Treatment of Hydra with hydrogen peroxide (H2O2), a highly reactive oxidizing agent, led to a significant increase in gene expression and enzyme activity of Trx1. Further experiments using PX12, an inhibitor of Trx1, indicated that Trx1 plays an important role in regeneration in Hydra. Finally, by using growth assay in Escherichia coli and wound healing assay in human colon cancer cells, we demonstrate that HvTrx1 is functionally active in both prokaryotic and eukaryotic heterologous systems.
General Court rules that Guerlain’s shape of Rouge G lipstick enjoys trade mark protection
Authors: Maienza Giulia
Published: August 2021

Guerlain v European Union Intellectual Property Office (EUIPO), T-488/20, EU:T:2021:443

The General Court (‘GC’) has overturned the EUIPO and Board of Appeal decisions, ruling that the shape of a lipstick may be registered as a 3D trade mark insofar as it represents a memorable shape that will be perceived by the relevant public as one that departs significantly from the norms and customs of the cosmetics sector. In its analysis of the distinctive character of the sign, the GC did not take into account the originality of the shape nor the high-quality design or its successful aesthetic appeal. It instead considered the range of different shapes of lipsticks available on the market and focused on the objective and uncommon visual effect of the Guerlain’s shape on the relevant public.
Characterization of growth and development of sorghum genotypes with differential susceptibility to Striga hermonthica
Authors: Kawa Dorota , Taylor Tamera , Thiombiano Benjamin , Musa Zayan , Vahldick Hannah E , Walmsley Aimee , Bucksch Alexander , Bouwmeester Harro , Brady Siobhan M
Published: August 2021

Two sorghum varieties, Shanqui Red (SQR) and SRN39, have distinct levels of susceptibility to the parasitic weed Striga hermonthica, which have been attributed to different strigolactone composition within their root exudates. Root exudates of the Striga-susceptible variety Shanqui Red (SQR) contain primarily 5-deoxystrigol, which has a high efficiency for inducing Striga germination. SRN39 roots primarily exude orobanchol, leading to reduced Striga germination and making this variety resistant to Striga. The structural diversity in exuded strigolactones is determined by a polymorphism in the LOW GERMINATION STIMULANT 1 (LGS1) locus. Yet, the genetic diversity between SQR and SRN39 is broad and has not been addressed in terms of growth and development. Here, we demonstrate additional differences between SQR and SRN39 by phenotypic and molecular characterization. A suite of genes related to metabolism was differentially expressed between SQR and SRN39. Increased levels of gibberellin precursors in SRN39 were accompanied by slower growth rate and developmental delay and we observed an overall increased SRN39 biomass. The slow-down in growth and differences in transcriptome profiles of SRN39 were strongly associated with plant age. Additionally, enhanced lateral root growth was observed in SRN39 and three additional genotypes exuding primarily orobanchol. In summary, we demonstrate that the differences between SQR and SRN39 reach further than the changes in strigolactone profile in the root exudate and translate into alterations in growth and development.
Xylem biomechanics, water storage, and density within roots and shoots of an angiosperm tree species
Authors: Baer Alex B , Fickle Jaycie C , Medina Jackeline , Robles Catherine , Pratt R Brandon , Jacobsen Anna L
Published: August 2021

Xylem is a complex tissue that forms the bulk of tree bodies and has several functions, including to conduct water, store water and nutrients, and biomechanically support the plant body. We examined how xylem functional traits varied at different positions within 9-year-old Populus balsamifera subsp. trichocarpa. Whole trees were excavated, and xylem samples were collected at 1-m increments along the main root-to-shoot axis of six trees, from root tip to shoot tip. We examined biomechanical and water-storage traits of the xylem, including using a non-invasive imaging technique to examine water content within long, intact branches (high-resolution computed tomography; microCT). Xylem density, strength, and stiffness were greater in shoots than roots. Along the main root-to-shoot axis, xylem strength and stiffness were greatest at shoot tips, and the tissue became linearly weaker and less stiff down the plant and through the root. Roots had greater water storage with lower biomechanical support, and shoots had biomechanically stronger and stiffer xylem with lower water storage. These findings support trade-offs among xylem functions between roots and shoots. Understanding how xylem functions differ throughout tree bodies is important in understanding whole-tree functioning and how terrestrial plants endure numerous environmental challenges over decades of growth.