bluuebunny/crossref_metadata_2025 huggingface dataset:
Conservation genetics of montane willow populations in Scotland—limited natural recovery despite long-distance gene flow and high genetic diversity
Authors: Finger A , Rao S , Cowie N , MacDonell T , Beck A , Denny B
Published: September 2022

Plant species around the world are negatively affected by habitat fragmentation and climate change. Montane willow populations in the UK have declined primarily due to grazing, as well as climate change and muirburn in certain areas. Only small, isolated populations remain, scattered across steep ledges where shrubs escape most grazing animals. We explored the genetic effects of habitat fragmentation on gene flow and genetic diversity in the largest remaining patches in the UK, which lie in Scotland, for two now restricted and rare montane willow species—Salix myrsinites and Salix lapponum. Using ten microsatellite loci and an almost complete genetic inventory in the central Cairngorms area (S. myrsinites n = 186, S. lapponum n = 91) we showed that genetic diversity (heterozygosity and allelic richness) is relatively high in both species, particularly high for the decaploid S. myrsinites, and clonal reproduction low. Historic gene flow between populations could be demonstrated. Significant inbreeding was detected in both species and observed seed set and numbers of juveniles in the field are low, possibly indicating signs of inbreeding depression. Both species have extremely low numbers of individuals at each site, with many being smaller than ten, and in some cases combined with skewed sex-ratios (mainly female biased). This will likely cause more severe reproductive failures in the next generations unless population numbers are increased. Reinforcing populations of both species under low grazing pressure with new, unrelated individuals, as well as creating new stepping-stone populations will be necessary to help the recovery of these species. Results from this study will inform restoration work in Scotland aiming to create continuous woodland habitats from pinewoods at lower altitudes through to higher altitude downy birch woodlands merging with montane willows.
mHapTk: a comprehensive toolkit for the analysis of DNA methylation haplotypes
Authors: Ding Yi , Cai Kangwen , Liu Leiqin , Zhang Zhiqiang , Zheng Xiaoqi , Shi Jiantao
Published: September 2022

Bisulfite sequencing remains the gold standard technique to detect DNA methylation profiles at single-nucleotide resolution. The DNA methylation status of CpG sites on the same fragment represents a discrete methylation haplotype (mHap). The mHap-level metrics were demonstrated to be promising cancer biomarkers and explain more gene expression variation than average methylation. However, most existing tools focus on average methylation and neglect mHap patterns. Here, we present mHapTk, a comprehensive python toolkit for the analysis of DNA mHap. It calculates eight mHap-level summary statistics in predefined regions or across individual CpG in a genome-wide manner. It identifies methylation haplotype blocks, in which methylations of pairwise CpGs are tightly correlated. Furthermore, mHap patterns can be visualized with the built-in functions in mHapTk or external tools such as IGV and deepTools.

Availability and implementation

https://jiantaoshi.github.io/mhaptk/index.html.

Supplementary information

Supplementary data are available at Bioinformatics online.
GBZ file format for pangenome graphs
Authors: Sirén Jouni , Paten Benedict
Published: September 2022

Motivation

Pangenome graphs representing aligned genome assemblies are being shared in the text-based Graphical Fragment Assembly format. As the number of assemblies grows, there is a need for a file format that can store the highly repetitive data space efficiently.

Results

We propose the GBZ file format based on data structures used in the Giraffe short-read aligner. The format provides good compression, and the files can be efficiently loaded into in-memory data structures. We provide compression and decompression tools and libraries for using GBZ graphs, and we show that they can be efficiently used on a variety of systems.

Availability and implementation

C++ and Rust implementations are available at https://github.com/jltsiren/gbwtgraph and https://github.com/jltsiren/gbwt-rs, respectively.

Supplementary information

Supplementary data are available at Bioinformatics online.
Seeded binary segmentation: a general methodology for fast and optimal changepoint detection
Authors: Kovács S , Bühlmann P , Li H , Munk A
Published: September 2022

We propose seeded binary segmentation for large-scale changepoint detection problems. We construct a deterministic set of background intervals, called seeded intervals, in which single changepoint candidates are searched for. The final selection of changepoints based on these candidates can be done in various ways, adapted to the problem at hand. The method is thus easy to adapt to many changepoint problems, ranging from univariate to high dimensional. Compared to recently popular random background intervals, seeded intervals lead to reproducibility and much faster computations. For the univariate Gaussian change in mean set-up, the methodology is shown to be asymptotically minimax optimal when paired with appropriate selection criteria. We demonstrate near-linear runtimes and competitive finite sample estimation performance. Furthermore, we illustrate the versatility of our method in high-dimensional settings.
A scoping review on the approaches for cannulation of reno-visceral target vessels during complex endovascular aortic repair
Authors: Grandi Alessandro , D’Oria Mario , Melloni Andrea , Calvagna Cristiano , Taglialavoro Jacopo , Chiesa Roberto , Lepidi Sandro , Bertoglio Luca
Published: September 2022

OBJECTIVES

The aim of this study was to assess the approaches to reno-visceral target vessels (TVs) cannulation during branched-fenestrated endovascular aortic repair, determine the evidence base that links these approaches to clinical outcomes and identify literature gaps.

METHODS

A scoping review following the PRISMA Protocols Extension for Scoping Reviews was performed. Available full-text studies published in English (PubMed, Cochrane and EMBASE databases; last queried, 31 June 2022) were systematically reviewed and analysed. Data were reported as descriptive narrative or tables, without any statistical analysis nor quality assessment.

RESULTS

Fourteen retrospective articles were included. Seven articles studied the use of upper extremity access (UEA) during branched-fenestrated endovascular aortic repair, 3 studied the use of steerable sheaths and 4 included both approaches. A left UEA was used in 757 patients (technical success: 99%, stroke rate: 1–3%) and a right UEA in 215 patients (technical success: 92–98%, stroke rate: 0–13%). Seven studies (1066 patients) described a surgical access only (technical success: 80–99%, stroke rate: 0–13%), while 3 studies (146 patients) described a percutaneous access only (technical success: 83–90%, stroke rate: 3%) and lastly 4 studies compared UEA versus use of steerable sheaths from the transfemoral approach (TFA) (UEA: 563 patients, technical success: 95–98%, stroke rate: 1–8%; TFA: 209 patients, technical success: 98–100%, stroke rate: 0–1%).

CONCLUSIONS

Both UEA and TFA as cannulation approaches were associated with high technical success and low perioperative complications. Currently, there is a paucity of high-quality data to provide definitive indication. Optimal UEA in terms of side (left versus right) and approach (surgical versus percutaneous) needs further study.
Rastelli conduit change with the Nuss procedure for relieving compression of extracardiac conduit
Authors: Yi Jung Hoon
Published: September 2022

When Rastelli conduit stenosis occurs concurrently with pectus excavatum, redo Rastelli operation alone may not be sufficient to solve the situation. Therefore, we performed 2 procedures simultaneously: right ventricle to pulmonary artery extracardiac conduit change and the Nuss procedure. The Nuss bar was removed after 4 years.
Who are the loss-averse farmers? Experimental evidence from structurally estimated risk preferences
Authors: Bonjean Isabelle
Published: September 2022

Even though recognised to be of increasing importance, robust estimations of European farmers’ risk preferences are still scarce. Using an incentivised lab-in-the-field experiment with farmers, free of learning bias, this paper analyses the structurally derived parameters of risk preferences based on the cumulative prospect theory. The sector studied is the apple and pear sector in Flanders, Belgium. Farmers are found to be highly risk-averse and to distort probabilities by overweighting a small probability of desirable outcomes. However, there is no evidence of loss aversion on average, unlike previous studies. Moreover, investigating the heterogeneous effects shows that some farmers significantly differ from the representative agent by still being extremely loss-averse. The results of this piece of research prove the need to consider heterogeneity within and across sectors when assessing farmers’ risk preferences.
Linkage between electronic prescribing data and pharmacy claims records to determine primary adherence: the case of antihypertensive therapy in the Lisbon and Tagus Valley Region, Portugal
Authors: Coelho André
Published: September 2022

Background

Hypertension (HT) is highly prevalent and a major risk factor for cardiovascular disease. Over 42% of Portuguese adults have HT. Even though the benefits of antihypertensive (AHT) drugs have been demonstrated, HT control remains inadequate. One major reason is that patients often fail to take their medications as prescribed. This paper aims to determine primary adherence to AHT therapy in newly diagnosed and treated hypertensive patients in Primary Health Care (PHC) units of Lisbon and Tagus Valley Health Region.

Methods

This study reports data from a population-based, retrospective, cohort study from patients diagnosed with HT in PHC units of Lisbon and Tagus Valley Region from 1 January to 31 March 2011, with no prior use of AHT drugs. Primary adherence rate was expressed as number of claims records/total number of prescriptions records. Data were collected from SIARS for each patient during a 2-year period.

Results

Overall primary adherence rate was 58.5%, increasing with age. Rates were higher for men, living in the Lisbon Metropolitan Area and diagnosed with uncomplicated HT. Drugs acting on the renin–angiotensin system had the highest rates, increasing for fixed-dose combinations and diminishing with the increase of cost for the patient.

Conclusions

Overall, almost 1 out of 2 prescribed AHT drugs were not dispensed. Until this study, little was known in Portugal about primary adherence. Our findings imply that the potential benefits of AHT therapy cannot be fully realized in this population.
Postsecular Pilgrimage in Malek Bennabi’s Lebbeik: pèlerinage de pauvres and Abdelkébir Khatibi’s Pèlerinage d’un artiste amoureux
Authors: Qadiri Sura
Published: September 2022

This paper explores representations of the Islamic pilgrimage to Mecca in two North African literary texts, Malek Bennabi’s Lebbeik (1947) and Abdelkébir Khatibi’s Pèlerinage d’un artiste amoureux (2003). It considers the divergent ways in which pilgrimage is used to explore the place of both literature and religion, as well as their interrelation, when it comes to working out ethics and values on individual and collective levels in Bennabi’s late-colonial Algeria, and Khatibi’s postcolonial Morocco. Drawing on Alain Badiou’s notion of the event as an occurrence that is retrospectively determined to have disrupted the status quo, and contrasting this with Derek Attridge’s idea of literature as a disruptive event with indeterminate outcomes, I consider the different ways in which both the pilgrimage and the narratives representing it can be seen as events, implicitly imparting reflections and even teachings on life and how to approach it in both texts.
Natural Regeneration Dynamics of Longleaf Pine Under Frequent, Low-Intensity Prescribed Fires in Southern Alabama, USA
Authors: Fan Zhaofei , Yang Shoayang , Kush John M , Narine Lana
Published: September 2022

Frequent (≤3 y) prescribed burn has been conducted in the Escambia Experimental Forest in southern Alabama, USA, since 2001.The change in the density of new germinants (≤1 y) and older seedlings and saplings (>1 y) of longleaf pine (Pinus palustris Mill.) from stands of varying conditions was quantified using the locally estimated scatterplot smoothing and spatial statistical methods. A relatively longer fire interval or time since last fire (TSLF) > 600 days favored the recruitment of young seedlings. However, a short fire return interval or TSLF≤ 600 days promoted the recruitment of older seedlings and saplings. Large basal area (BA) and site index (SI) tended to diminish natural regeneration, whereas large quadratic mean diameter (QMD) and age were facilitative. The interactive effect of these factors indicated that a ratio of TSLF/BA of 60 to 120 and QMD/SI of 1.8 to 2.2 would maximize the recruitment of young seedlings. The recruitment of older seedlings and saplings increased linearly with QMD/SI but had no relationship with TSLF/BA. Recruitment was largely absent when QMD/SI was <2.0. As a result, we recommend that QMD/SI be no greater than 2.0 and TSLF/BA range from 60 to 120 to regenerate longleaf pine naturally.
How Shading and Container Type Influence Ilex paraguariensis A.St.-Hil. Seedling Production
Authors: Siqueira Walter Letícia , Melo Moura Marks , Moreno Gabira Mônica , Saudade de Aguiar Natália , Stuepp Carlos André , Kratz Dagma
Published: September 2022

This study aimed to evaluate the influence of containers and shading on Ilex paraguariensis A.St.-Hil (yerba mate) seedling growth. We used a completely randomized design with a 3 × 2 factorial arrangement (containers × shading). We used PlantPaper®, Ellepot® (both biodegradable containers composed of cellulose fibers), and polypropylene tube containers and shaded (75% shading screen) and unshaded (without shading screen) greenhouse environments. We measured height and stem diameter every 30 days and shoot and root dry biomass 210 days after sowing. With these data, we calculated the total dry biomass, Dickson quality index, and height/diameter ratio. The unshaded environment increased yerba mate seedlings growth in height and stem diameter. In unshaded environments, seedlings produced in biodegradable containers had greater growth than those produced in polypropylene tubes. In the shaded environment, however, seedlings produced in polypropylene tubes had better growth. Despite the differences observed between treatments, all seedlings presented adequate growth during the nursery phase. We suggest the use of biodegradable containers to produce yerba mate seedlings in unshaded environments.
The future of fungi: threats and opportunities
Authors: Case Nicola T , Berman Judith , Blehert David S , Cramer Robert A , Cuomo Christina , Currie Cameron R , Ene Iuliana V , Fisher Matthew C , Fritz-Laylin Lillian K , Gerstein Aleeza C , Glass N Louise , Gow Neil A R , Gurr Sarah J , Hittinger Chris Todd , Hohl Tobias M , Iliev Iliyan D , James Timothy Y , Jin Hailing , Klein Bruce S , Kronstad James W , Lorch Jeffrey M , McGovern Victoria , Mitchell Aaron P , Segre Julia A , Shapiro Rebecca S , Sheppard Donald C , Sil Anita , Stajich Jason E , Stukenbrock Eva E , Taylor John W , Thompson Dawn , Wright Gerard D , Heitman Joseph , Cowen Leah E
Published: September 2022

The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation. To address this aim, the Canadian Institute for Advanced Research (CIFAR) and the Burroughs Wellcome Fund convened a workshop to unite leading experts on fungal biology from academia and industry to strategize innovative solutions to global challenges and fungal threats. This report provides recommendations to accelerate fungal research and highlights the major research advances and ideas discussed at the meeting pertaining to 5 major topics: (1) Connections between fungi and climate change and ways to avert climate catastrophe; (2) Fungal threats to humans and ways to mitigate them; (3) Fungal threats to agriculture and food security and approaches to ensure a robust global food supply; (4) Fungal threats to animals and approaches to avoid species collapse and extinction; and (5) Opportunities presented by the fungal kingdom, including novel medicines and enzymes.
Exploring Sectoral Reach in Age-Friendly Communities
Authors: Black Kathy , Oh Patricia
Published: September 2022

Background and Objectives

There is growing interest in better understanding the sectoral reach of age-friendly community practice. Action across a wide range of actors is central to achieving age-friendly societal change, according to the World Health Organization and required for governmental participation in its Global Network of Age-Friendly Cities and Communities. However, there is limited knowledge regarding the scope of sectoral reach by age-friendly communities.

Research Design and Methods

We used qualitative inquiry to assess sectoral efforts reported by American age-friendly communities that completed a 5-year cycle of participation (n = 40). We employed directed content analysis using a priori indicators by sectoral actors: public (i.e., government), private (i.e., business), and civil society, including nonprofit organizations and volunteers. We classify sectoral actions by type (i.e., intersectoral and multisectoral) and by clustered domain community foci (i.e., built, social, and service).

Results

Our study identifies the extent and types of sectoral actors and actions reported by age-friendly communities with the greatest efforts reported in the public sector, and while similarly distributed across all the domains, slightly more efforts were noted in the built environment. We also found greater intersectoral efforts (i.e., explicitly working toward shared goals) than multisectoral (i.e., not necessarily in collaboration on shared goals), particularly across government.

Discussion and Implications

While our study substantiates the breadth of actions toward age-friendly change, additional research is needed to examine the ways in which the public and other sectoral actions are further linked to outcomes in communities in the United States and in other countries.
Ulcer Size After Induction Therapy Performs Better Than Symptom Assessment for Prediction of One Year Endoscopic Remission in Crohn’s Disease: A Post Hoc Analysis
Authors: Pray Cara , Wong Emily C L , Aruljothy Achuthan , Dulai Parambir S , Marshall John K , Reinisch Walter , Narula Neeraj
Published: September 2022

Background

We evaluated whether postinduction ulcer size and patient-reported outcome (PRO) severity are associated with the achievement of 1-year endoscopic remission (ER) in patients with Crohn’s disease (CD).

Methods

This post hoc analysis combined data from several clinical trials including 283 patients with baseline ulcers ≥5 mm with repeat endoscopy after ustekinumab or adalimumab induction therapy. Patient-reported outcomes including stool frequency (SF) and abdominal pain (AP) were measured by the Crohn’s Disease Activity Index. Thresholds of SF ≥4 and/or AP ≥2 indicated moderately to severely active CD. Endoscopic remission was defined as Simple Endoscopic Score for CD (SES-CD) <3. Multivariate logistic regression models adjusted for confounders (including disease duration and treatment allocation) evaluated the relationships between postinduction ulcer size, PRO symptoms, and achievement of 1-year ER.

Results

Among the 131 CD patients who continued to have ulcers ≥5 mm after induction therapy, 48 (36.6%) achieved 1-year ER. Patients with postinduction ulcers ≥5 mm were approximately 5 times less likely to achieve 1-year ER than the 152 individuals who had small or no postinduction ulcers (odds ratio [OR], 0.20; 95% CI, 0.08-0.51, P = .001). In patients with ulcers ≥5 mm after induction, postinduction PRO scores (including PRO2 and PRO3) did not predict 1-year ER.

Conclusions

Crohn’s disease patients with ulcers ≥5 mm after induction therapy are less likely to achieve 1-year ER. Postinduction PRO severity does not offer additional prognostic information. This may suggest that objective measures of disease such as endoscopic ulcer size should be considered over symptom assessments for determining clinical response to therapy and utilized in trials for maintenance therapy.
Sex differences in childhood cancer risk among children with major birth defects: a Nordic population-based nested case-control study
Authors: Daltveit Dagrun Slettebø , Klungsøyr Kari , Engeland Anders , Ekbom Anders , Gissler Mika , Glimelius Ingrid , Grotmol Tom , Madanat-Harjuoja Laura , Ording Anne Gulbech , Sørensen Henrik Toft , Troisi Rebecca , Bjørge Tone
Published: September 2022

Background

Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear.

Methods

We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0–19 years) and 218 980 matched population controls, born 1967–2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects.

Results

Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6–12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8–2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6–3.1) than males (OR = 2.1, 95% CI = 1.9–2.2, Pinteraction <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, PNIE <0.001), although more at younger ages (10% below years and 28% below 1 year).

Conclusions

The birth defect–cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved.
Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder
Authors: Wang Tzu-Yun , Lu Ru-Band , Lee Sheng-Yu , Chang Yun-Hsuan , Chen Shiou-Lan , Tsai Tsung-Yu , Tseng Huai-Hsuan , Chen Po See , Chen Kao Chin , Yang Yen Kuang , Hong Jau-Shyong
Published: September 2022

Background

Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored.

Methods

We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured.

Results

We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance.

Conclusion

OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.
From Truth Commission to Truth Project: The Evolution of Mississippi’s Incomplete Truth Commission, 2005–2010
Authors: Whitlinger Claire
Published: September 2022

ABSTRACT∞

Just months after the Mississippi Truth Commission’s public launch in 2009, organizers abandoned the Commission despite sufficient funding and growing public support, deciding instead to pursue a statewide oral history project. This study explores why, offering insight into an understudied phenomenon: incomplete truth commissions. Drawing on ethnographic observations, archival documents and interviews with local practitioners, this study highlights several reasons that local organizers changed course. In addition to a shifting cultural context, the Mississippi Truth Commission faced several cognitive challenges. First, local audiences struggled to comprehend the structure and scope of the truth commission model, leading to ‘Transitional Justice 101,’ a perpetual, and ultimately unsuccessful, public education program. Second, local organizers’ visit to South Africa in 2009 cast doubt on the efficacy of truth commissions and caused them to question the metaphoric logic that had constructed Mississippi’s history of racial violence as analogous to South Africa’s, providing implicit justification for the Commission until that point. Thus, alongside economic and political resources, this research suggests that cognitive resources are a critical, and often overlooked, component of truth commissions’ infrastructure. Findings also indicate that incomplete truth commissions can be leveraged to support alternative truth-seeking processes that may be more advantageous in stable democracies.
The Transformation of Lithuanian Memories of Soviet Crimes to Genocide Recognition
Authors: Sagatienė Dovilė
Published: September 2022

ABSTRACT∞

This article examines the transformation of memory regarding Soviet crimes in Lithuania, and more broadly in the Baltics and Eastern Europe, as an interlinked political and legal process. In the Lithuanian context, this transformation was part of a transitional justice effort that resulted in the recovery of European identity and international legal recognition of Soviet genocide against Lithuanian partisans by the European Court of Human Rights.
Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings
Authors: Darlow Christopher A , McEntee Laura , Johnson Adam , Farrington Nicola , Unsworth Jennifer , Jimenez-Valverde Ana , Jagota Bhavana , Kolamunnage-Dona Ruwanthi , Da Costa Renata M A , Ellis Sally , Franceschi François , Sharland Mike , Neely Michael , Piddock Laura , Das Shampa , Hope William
Published: September 2022

Background

Annual mortality from neonatal sepsis is an estimated 430 000–680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting.

Objectives

To assess the pharmacodynamics of flomoxef and amikacin in combination.

Methods

The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs.

Results

Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L.

Conclusions

We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.
Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study
Authors: Aebi-Popp Karoline , Kahlert Christian R , Crisinel Pierre-Alex , Decosterd Laurent , Saldanha Susana Alves , Hoesli Irene , Martinez De Tejada Begona , Duppenthaler Andrea , Rauch Andri , Marzolini Catia ,   Swiss Mother and Child HIV Cohort Study (SHCS), Abela A I , Aebi-Popp K , Anagnostopoulos A , Battegay M , Bernasconi E , Braun D L , Bucher H C , Calmy A , Cavassini M , Ciuffi A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux C A , Günthard H F , Hachfeld A , Haerry D , Hasse B , Hirsch H H , Hoffmann M , Hösli I , Huber M , Kahlert C R , Kaiser L , Keiser O , Klimkait T , Kouyos R D , Kovari H , Kusejko K , Martinetti G , Martinez de Tejada B , Marzolini C , Metzner K J , Müller N , Nemeth J , Nicca D , Paioni P , Pantaleo G , Perreau M , Rauch A , Schmid P , Speck R , Stöckle M , Tarr P , Trkola A , Wandeler G , Yerly S
Published: September 2022

Introduction

In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants.

Methods

All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval.

Results

Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs.

Conclusions

ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding.
Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe
Authors: Shortridge Dee , Deshpande Lalitagauri M , Streit Jennifer M , Castanheira Mariana
Published: September 2022

Background

Carbapenem-resistant Enterobacterales (CRE) isolates have disseminated worldwide. CREs usually produce a carbapenemase; however, some isolates are negative for known carbapenemases. In this study, we evaluated the activity of meropenem/vaborbactam and comparators against CREs without a carbapenemase (nonCP CREs) collected from European hospitals from 2016 to 2019.

Materials and methods

23 043 Enterobacterales clinical isolates were collected in 41 hospitals located in 20 countries. Susceptibility (S) testing was performed using the broth microdilution method. CLSI/EUCAST (2021) interpretive criteria were used. 978 CREs were identified with MICs >2 mg/L to meropenem or imipenem. Whole-genome sequencing was performed on each CRE isolate. 125 isolates were negative for carbapenemase genes, including blaKPC, blaNDM, blaIMP, blaVIM and blaOXA-48-like. NonCP CRE isolates were analysed for the presence of other β-lactamases, multilocus sequence types (ST) and mutations in outer membrane protein (OMP) sequences.

Results

Most nonCP CRE were Klebsiella pneumoniae (KPN; n = 97/125). 84.0% of nonCP CRE (n = 105) were from Poland, including 88 KPN. The most common β-lactamase was blaCTX-M-15 in 92/125 isolates. OMP disruptions or alterations were noted among 76 KPN. Among KPN isolates that had MLST typing, 30 belonged to ST11, 18 to ST152 and 17 to ST147, while 13 other STs were observed. Susceptibility to meropenem/vaborbactam was 96.0/97.6% (CLSI/EUCAST) while meropenem was 2.4/8.0%S.

Conclusions

Meropenem/vaborbactam had potent in vitro activity against CRE isolates that lacked known carbapenemases. Resistance mechanisms observed among nonCP CREs included acquired β-lactamases and OMP alterations. These results indicate that meropenem/vaborbactam may be a useful treatment for infections caused by nonCP CREs.
Antibiotic prescribing amongst South African general practitioners in private practice: an analysis of a health insurance database
Authors: Alabi Mobolaji Eniola , Essack Sabiha Yusuf
Published: September 2022

Objectives

To investigate the appropriateness of antibiotic prescribing among GPs in the private primary healthcare sector in South Africa.

Methods

An anonymized national database of claims for antibiotic prescriptions was obtained from a large medical insurer. Antibiotic prescriptions were categorized based on International Classification of Diseases (ICD-10) codes as ‘appropriate’, ‘potentially appropriate’ and ‘inappropriate’ using a classification scheme developed by Chua et al. (BMJ 2019; 364: k5092). Further assessments of antibiotic choice, dosage and duration of treatment were carried out to determine the appropriateness of ‘appropriate’ and ‘potentially appropriate’ prescriptions in comparison with treatment guidelines.

Results

In February 2018, 188 141 antibiotics were prescribed for 174 889 patients who consulted GPs in the private sector. Penicillins were the most frequently prescribed antibiotic class, making up 40.7% of all antibiotics prescribed. Amoxicillin/clavulanic acid was the most frequently prescribed antibiotic, making up 28.6% of all antibiotics prescribed. Diseases of the respiratory system generated the highest number of prescriptions, making up 46.1% of all diagnoses. Of all prescriptions, 8.8% were appropriate, 32.0% were potentially appropriate, 45.4% were inappropriate and 13.8% could not be assessed. Of the appropriately and potentially appropriately prescribed antibiotics, 30.8% were correct antibiotic selections. Of the correctly selected antibiotics for adults, 57.7% had correct doses. Of the antibiotics prescribed with correct doses for adults, 76.7% had correct dosage frequencies and durations of treatment.

Conclusions

The study revealed that antibiotics were frequently prescribed inappropriately by GPs in the private primary healthcare sector. There is thus a need to develop stewardship interventions in the sector.
Validation of the Test Method—Determination of Available Carbohydrates in Cereal and Cereal Products, Dairy Products, Vegetables, Fruit, and Related Food Products and Animal Feeds: Collaborative Study, Final Action 2020.07
Authors: McLoughlin Ciara , McKie Vincent A , McCleary Barry V
Published: September 2022

Background

A simple, accurate, and reliable method to measure available carbohydrate components of food products, including cereal and dairy products, fruits, vegetables, processed food, food ingredients, and animal foods, was developed by Megazyme (product K-AVCHO, Bray, Ireland). A single-laboratory validation of the enzymatic method resulted in First Action status as Official Method of AnalysisSM2020.07.

Objective

A collaborative study was conducted to evaluate the repeatability and reproducibility of Official Method 2020.07 for the measurement of available carbohydrates, including digestible starch, lactose, sucrose, isomaltose, maltose, glucose, fructose, and galactose in a broad range of food and feed products.

Method

Samples are defatted if containing >10% fat content, and incubated with pancreatic α-amylase and amyloglucosidase under conditions that simulate those in the small intestine (pH 6, 37°C, 4 h). The reaction solution is clarified and diluted, and an aliquot is incubated with sucrase, maltase, oligo-1,6-α-glucosidase, and β-galactosidase to hydrolyze sucrose, maltose, isomaltose, and lactose to glucose, fructose, and galactose, which are then measured enzymatically. The multi-laboratory validation (MLV) matrixes included cereal, animal feeds, fruit, vegetables, infant formula, powdered milk drink, a dessert product, and mushrooms. Additional materials were analyzed by collaborators as “practice samples.”

Results

All MLV matrixes resulted in repeatability relative standard deviations (RSDr) <3.91% and reproducibility relative standard deviations (RSDR) ranging from 3.51 to 11.58% with 9 of the 10 matrixes having RSDR of <6.19%. For the practice samples, the RSDR ranged from 2.7 to 11.4% with 7 of the 8 samples having RSDR of <4.4%.

Conclusions

Official Method 2020.07 meets the AOAC requirements for repeatability and reproducibility, and the data support Final Action status.

Highlights

Official Method 2020.07 is a robust, simple to use, and reproducible method for the analysis of available carbohydrates in a wide range of matrixes.
Liquid Chromatography–High-Resolution Mass Spectrometry (LC–HRMS) Analysis Following Voluntary Carvedilol Poisoning in a Subject with Cirrhosis: A Case Report
Authors: Berthier Joseph , Pasquet Agathe , Guerard Pascal , Matheux Alice
Published: September 2022

Accidental or intentional carvedilol poisoning is rarely reported. Here, we describe a case of attempted suicide with a large quantity of immediate-release carvedilol (75 mg) and alcohol. In order to determine the kinetics, liquid chromatography–high-resolution mass spectrometry analyses were performed. The results for the plasma concentration of carvedilol were 906 µg/L 3 h after ingestion, 288 µg/L 12 h after ingestion and 103 µg/L 24 h after ingestion. A one-compartment model with linear and first order best described the elimination of the carvedilol, and the estimated half-life was 5.8 h. The result 3 h after ingestion represented the highest concentration ever observed for this drug. However, the patient was cirrhotic, and liver function was impaired with decreased Factor V (45%) and prothrombin ratio (61%). These conditions may explain the high concentrations of carvedilol. The patient was treated with glucagon and discharged from the hospital the following day.
Compounds in cigarette smoke induce EGR1 expression via the AHR, resulting in apoptosis and COPD
Authors: Hattori Naoko , Nakagawa Takeya , Yoneda Mitsuhiro , Hayashida Hiromi , Nakagawa Kaori , Yamamoto Kazuo , Htun Myo Win , Shibata Yasuaki , Koji Takehiko , Ito Takashi
Published: September 2022

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide, and pulmonary epithelial cell apoptosis is regarded as one of the most important factors in its pathogenesis. Here, we examined the molecular mechanisms of apoptosis caused by cigarette smoke (CS). In the normal bronchial epithelium cell line BEAS-2B, a CS extract markedly induced apoptosis together with transient early growth response 1 (EGR1) protein expression, which is activated over time via the aryl hydrocarbon receptor (AHR). The CS extract–induced apoptosis decreased cell count of BEAS-2B cells and was significantly reversed by knockdown of either EGR1 or AHR. In vivo, the CS extract caused alveolar wall destruction, mimicking COPD, 1 week after intrathoracic injection. Bronchoalveolar lavage fluid (BALF) from the CS extract–treated mice contained massive numbers of apoptotic epithelial cells. Furthermore, it was found that aminoanthracene induced EGR1 expression and cell apoptosis. By contrast, the AHR antagonist stemregenin 1 (SR1) restored apoptosis upon CS treatment. These results suggest that aryl hydrocarbons, such as aminoanthracene, induce EGR1 expression via the AHR, resulting in cell apoptosis and that this can be prevented by administration of an antagonist of AHR.
Do photosynthetic cells communicate with each other during cell death? From cyanobacteria to vascular plants
Authors: Aguilera Anabella , Distéfano Ayelén , Jauzein Cécile , Correa-Aragunde Natalia , Martinez Dana , Martin María Victoria , Sueldo Daniela J
Published: September 2022

As in metazoans, life in oxygenic photosynthetic organisms relies on the accurate regulation of cell death. During development and in response to the environment, photosynthetic cells activate and execute cell death pathways that culminate in the death of a specific group of cells, a process known as regulated cell death (RCD). RCD control is instrumental, as its misregulation can lead to growth penalties and even the death of the entire organism. Intracellular molecules released during cell demise may act as ‘survival’ or ‘death’ signals and control the propagation of cell death to surrounding cells, even in unicellular organisms. This review explores different signals involved in cell-cell communication and systemic signalling in photosynthetic organisms, in particular Ca2+, reactive oxygen species, lipid derivates, nitric oxide, and eATP. We discuss their possible mode-of-action as either ‘survival’ or ‘death’ molecules and their potential role in determining cell fate in neighbouring cells. By comparing the knowledge available across the taxonomic spectrum of this coherent phylogenetic group, from cyanobacteria to vascular plants, we aim at contributing to the identification of conserved mechanisms that control cell death propagation in oxygenic photosynthetic organisms.
Some applications of Baaz’s generalization method to the study of the factors of Fermat numbers
Authors: Sauras-Altuzarra Lorenzo
Published: September 2022

This paper revisits a method of generalization of proofs of universal sentences that was introduced by Baaz and provides several applications to the study of the factors of Fermat numbers; remarkably an improvement of his sufficient condition for a given value to be one of such factors.
Women of the Gulf War: Understanding Their Military and Health Experiences Over 30 Years
Authors: Lafferty Megan , Winchell Kara , Cottrell Erika , Knight Sara , Nugent Shannon M
Published: September 2022

Introduction

Women Veterans of the Persian Gulf War (GW) expanded the military roles they had filled in previous military eras, with some women engaging in direct combat for the first time. Many GW service members, including women, had unique combat exposures to hazardous agents during deployment, which might have contributed to the development of chronic health problems. This study aims to understand the experiences of women GW Veterans (GWVs) as it is related to their military service and subsequent health in order to better inform and improve their clinical care.

Materials and Methods

We conducted in-depth interviews with 10 women GWVs to understand their experiences and perspectives about how their military service in the Gulf has impacted their lives and health. We used an integrated approach of content analysis and inductive thematic analysis to interpret interview data.

Results

Besides having many of the same war-related exposures as men, women faced additional challenges in a military that was inadequately prepared to accommodate them, and they felt disadvantaged as women within the military and local culture. After service, participants had emergent physical and mental health concerns, which they described as developing into chronic and complex conditions, affecting their relationships and careers. While seeking care and service connection at Veterans Health Administration (VA), women voiced frustration over claim denials and feeling dismissed. They provided suggestions of how VA services could be improved for women and GWVs. Participants found some nonpharmacological approaches for symptom management and coping strategies to be helpful.

Conclusions

Women in the GW encountered challenges in military and healthcare systems that were inadequately prepared to address their needs. Women faced chronic health conditions common to GWV and voiced the desire to be understood as a cohort with unique needs. There is an ongoing need to expand services within the VA for women GWVs, particularly involving psychosocial support and management of chronic illness. While the small sample size can limit generalizability, the nature of these in-depth, minimally guided interviews provides a rich narrative of the women GWVs in this geographically diverse sample.
Investigation of a likely orbital periodicity of Nova Hercules 2021 in X-rays and γ-rays
Authors: Lin Lupin Chun-Che , Fan Jhih-Ling , Hu Chin-Ping , Takata Jumpei , Li Kwan-Lok
Published: September 2022

We report a detection of a ∼0.153 d period in the classical nova V1674 Her using the NICER observations taken within a month since the outburst (i.e. ∼MJD 59405). The X-ray period is consistent with the orbital period previously found in the optical band, strongly suggesting the NICER signal as the X-ray orbital periodicity of the system. A seemingly double-humped profile was obtained by folding the detrended X-ray light curve with the period after removing the rotational X-ray pulsations of the nova. The profile may be caused by occultation by the companion or the accretion disc, possibly indicating a high inclination of the system. The γ-ray emission of V1674 Her with a significance level ≳ 5 σ was detected by Fermi-LAT close to its optical peak and the emission faded away within 1 d, which is the shortest duration known for a γ-ray nova. Folded on 0.153 d, a marginal γ-ray variability can be also seen in the LAT light curve, but without the double-hump feature observed in X-rays. If the γ-ray modulation is real, its origin is probably different from that observed in the X-ray and optical bands.