bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort
Authors: Salle Romain , Tubach Florence , Arlegui Hugo , Curmin Raphaëlle , Viguier Manuelle , Beylot-Barry Marie , Dupuy Alain , Beneton Nathalie , Joly Pascal , De Rycke Yann , Jullien Denis , Mahé Emmanuel , Paul Carle , Richard Marie-Aleth , Bachelez Hervé , Zago Marilyn , Chosidow Olivier , Sbidian Émilie ,   PsoBioTeq
Published: July 2023

Background

Little is known about phototype and the response to systemic treatment in psoriasis.

Objectives

To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype.

Methods

We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1.

Results

Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I–II, III–IV and V–VI groups, respectively. The V–VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V–VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups.

Conclusions

Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V–VI group less frequently switched treatments than did the other groups when the response was not efficient.
Acute kidney injury associated with nephrotoxic drugs in critically ill patients: a multicenter cohort study using electronic health record data
Authors: Yasrebi-de Kom Izak A R , Dongelmans Dave A , Abu-Hanna Ameen , Schut Martijn C , de Lange Dylan W , van Roon Eric N , de Jonge Evert , Bouman Catherine S C , de Keizer Nicolette F , Jager Kitty J , Klopotowska Joanna E ,   the RESCUE Study Group, ten Cate J , Schutte P F , van Balen D , Hendriks S , Lau C , Vermeijden W J , Beishuizen A , Masselink J B , Spronk P E , van Kan H J M , van den Bergh W M , Renes M H , Bult W , Hoeksema M , Wesselink E , Purmer I M , Bosma B E , van Bree S H W , Wierenga P C , Bosman R J , Franssen E J F , Karakus A , Sigtermans M , Kuck E M
Published: July 2023

Background

Nephrotoxic drugs frequently cause acute kidney injury (AKI) in adult intensive care unit (ICU) patients. However, there is a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI. Importantly, AKI risk factors may also be indications or contraindications for drugs and thereby confound the associations. Here, we aimed to estimate the associations between commonly administered (potentially) nephrotoxic drug groups and AKI in adult ICU patients whilst adjusting for confounding.

Methods

In this multicenter retrospective observational study, we included adult ICU admissions to 13 Dutch ICUs. We measured exposure to 44 predefined (potentially) nephrotoxic drug groups. The outcome was AKI during ICU admission. The association between each drug group and AKI was estimated using etiological cause-specific Cox proportional hazard models and adjusted for confounding. To facilitate an (independent) informed assessment of residual confounding, we manually identified drug group-specific confounders using a large drug knowledge database and existing literature.

Results

We included 92 616 ICU admissions, of which 13 492 developed AKI (15%). We found 14 drug groups to be associated with a higher hazard of AKI after adjustment for confounding. These groups included established (e.g. aminoglycosides), less well established (e.g. opioids) and controversial (e.g. sympathomimetics with α- and β-effect) drugs.

Conclusions

The results confirm existing insights and provide new ones regarding drug associated AKI in adult ICU patients. These insights warrant caution and extra monitoring when prescribing nephrotoxic drugs in the ICU and indicate which drug groups require further investigation.
Incidence of hypoxic hepatitis in patients with cardiogenic shock and association with mortality
Authors: Beer Benedikt N , Besch Lisa , Weimann Jessica , Surendra Kishore , Roedl Kevin , Grensemann Jörn , Sundermeyer Jonas , Dettling Angela , Kluge Stefan , Kirchhof Paulus , Blankenberg Stefan , Scherer Clemens , Schrage Benedikt
Published: July 2023

Aims

Shock of any cause leads to end-organ damage due to ischaemia, especially in perfusion-sensitive organs such as the liver. In septic shock, hypoxic hepatitis (S-HH) is defined as the 20-fold increase of the upper normal limit of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) and is associated with a mortality of up to 60%. However, as pathophysiology, dynamics, and treatment differ between septic and cardiogenic shock (CS), the S-HH definition may not be suitable for CS. Therefore, we aim to evaluate if the S-HH definition is applicable in CS patients.

Methods and results

This analysis was based on a registry of all-comer CS patients treated between 2009 and 2019 at a tertiary care centre with exclusion of minors and patients without all necessary ASAT and ALAT values. N = 698. During in-hospital follow-up, 386 (55.3%) patients died. The S-HH was not significantly associated with in-hospital mortality in CS patients. To define HH among patients with CS (C-HH), optimal cut-off values were found to be ≥1.34-fold increase for ASAT and ≥1.51-fold increase for ALAT in serial measurements. The incidence of C-HH was 254/698 patients (36%) and C-HH showed a strong association with in-hospital mortality (odds ratio 2.36, 95% confidence interval: 1.61, 3.49).

Conclusion

The C-HH is a frequent and relevant comorbidity in patients with CS, although its definition varies from the established definition of HH in patients with septic shock. As C-HH contributed to excess mortality risk, these findings emphasize the need for further investigation of therapies reducing the occurrence of C-HH and also improving the associated outcome.
Investigation of factors determining haemodynamic relevance of leaflet thrombosis after transcatheter aortic valve implantation
Authors: Soschynski Martin , Hein Manuel , Capilli Fabio , Hagar Muhammad Taha , Ruile Philipp , Breitbart Philipp , Westermann Dirk , Taron Jana , Schuppert Christopher , Schlett Christopher L , Bamberg Fabian , Krauss Tobias
Published: July 2023

Aims

To determine the conditions under which early hypoattenuated leaflet thickening (HALT) after transcatheter aortic valve implantation (TAVI) becomes haemodynamically relevant.

Methods and results

The study included 100 patients (age: 81.5 ± 5.5 years; female 63%), thereof 50 patients with HALT. After anonymization and randomization, blinded readers measured maximum thrombus thickness per prosthesis (MT_pr) and movement restriction (MR_pr) on electrocardiogram (ECG)-gated whole heart cycle computed tomography angiography. These measurements were compared with echocardiographic mean pressure gradient (mPG), its increase from baseline (ΔmPG), and Doppler velocity index (DVI). Haemodynamic valve deterioration (HVD) was defined as mPG > 20 mmHg. Age, body mass index, valve type, valve size, left ventricular ejection fraction, and atrial fibrillation were considered as influencing factors. Multiple regression analysis revealed that only valve size (P = 0.001) and MT_pr (P = 0.02) had a significant influence on mPG. In an interaction model, valve size moderated the effect of MT_pr on mPG significantly (P = 0.004). Sub-group analysis stratified by valve sizes showed a strong correlation between MT_pr and echocardiographic parameters for 23 mm valves (mPG: r = 0.57, ΔmPG: r = 0.68, DVI: r = 0.55, each with P < 0.001), but neither for 26 nor 29 mm valves (r < 0.2, P > 0.2 for all correlations). Six of seven prostheses with HVD had a 23 mm valve diameter, while one had 29 mm (P = 0.02).

Conclusion

Early HALT rarely causes significant mPG increase. Our study shows that valve size is a key factor influencing the haemodynamic impact of HALT. In small valve sizes, mPG is more likely to increase. Our study is the first to offer in vivo evidence supporting previous in vitro findings on this topic.
Outcomes of out-of-hospital cardiac arrest in adult congenital heart disease: a Danish nationwide study
Authors: Barcella Carlo Alberto , Christensen Daniel Mølager , Idorn Lars , Mudalige Nishan , Malmborg Morten , Folke Frederik , Torp-Pedersen Christian , Gislason Gunnar , El-Chouli Mohamad
Published: July 2023

Aims

The risk, characteristics, and outcome of out-of-hospital cardiac arrest (OHCA) in patients with congenital heart disease (CHD) remain scarcely investigated.

Methods and results

An epidemiological registry-based study was conducted. Using time-dependent Cox regression models fitted with a nested case–control design, hazard ratios (HRs) with 95% confidence intervals of OHCA of presumed cardiac cause (2001–19) associated with simple, moderate, and severe CHD were calculated. Moreover, using multiple logistic regression, we investigated the association between pre-hospital OHCA characteristics and 30-day survival and compared 30-day survival in OHCA patients with and without CHD. Overall, 43 967 cases (105 with simple, 144 with moderate, and 53 with severe CHD) and 219 772 controls (median age 72 years, 68.2% male) were identified. Any type of CHD was found to be associated with higher rates of OHCA compared with the background population [simple CHD: HR 1.37 (1.08–1.70); moderate CHD: HR 1.64 (1.36–1.99); and severe CHD: HR 4.36 (3.01–6.30)]. Pre-hospital cardiopulmonary resuscitation and defibrillation were both associated with improved 30-day survival in patients with CHD, regardless of CHD severity. Among patients with OHCA, simple, moderate, and severe CHD had a similar likelihood of 30-day survival compared with no CHD [odds ratio 0.95 (0.53–1.69), 0.70 (0.43–1.14), and 0.68 (0.33–1.57), respectively].

Conclusion

A higher risk of OHCA was found throughout the spectrum of CHD. Patients with and without CHD showed the same 30-day survival, which relies on the pre-hospital chain of survival, namely cardiopulmonary resuscitation and defibrillation.
Unpacking the lifelong secrets of little penguins: individual quality, energy allocation, and stochasticity in defining fitness
Authors: Joly Nicolas , Chiaradia Andre , Georges Jean-Yves , Saraux Claire
Published: July 2023

While the heterogeneity among individuals of a population is more and more documented, questions on the paths through which it arises, particularly whether it is linked to fixed heterogeneity or chance alone, are still widely debated. Here, we tested how individual quality, energy allocation trade-offs, and environmental stochasticity define individual fitness. To do so, we simultaneously investigated the contribution of 18 life-history traits to the fitness of breeding little penguins (Eudyptula minor), using a structural equation model. Fitness was highly variable amongst the 162 birds monitored over their entire lifespan. It increased with the individual penguin’s ability to increase (a) the number of breeding events (i.e., living longer, breeding younger, breeding more often, and producing more second clutches) and (b) the breeding success per event through increased foraging performances (i.e., mass gained at sea). While all three processes (stochasticity, individual quality, and allocation trade-offs) affected fitness, interindividual variability in fitness was mainly driven by individual quality, birds consistently breeding earlier in the season and displaying higher foraging efficiency exhibiting higher fitness. Why some birds consistently can perform better at sea and breed earlier remains a question to investigate to understand how selection applies to these traits.
The impact of drug palatability on prescribing and dispensing of antibiotic formulations for paediatric patients: a cross-sectional survey of general practitioners and pharmacists
Authors: Elgammal Ayat , Ryan Joseph , Bradley Colin , Crean Abina , Bermingham Margaret
Published: July 2023

Background

Palatability is a key element of paediatric acceptability for medicines. Many patient and drug factors are considered when choosing an antibiotic for a child. Pharmacists report that they receive questions about the palatability of oral liquid antibiotics for children. This study aimed to explore the experiences of GPs and pharmacists concerning palatability of oral liquid antibiotics for children.

Methods

A questionnaire about the impact of palatability on the choice of antibiotic formulation for children was emailed to all community pharmacists in Ireland and to GPs and trainee GPs in the Cork region and posted on social media. Survey items were not compulsory; therefore, percentage responses were calculated based on the number of responses to that item. GP and pharmacist responses were analysed independently.

Results

Responses were received from 244 participants (59 GPs, 185 pharmacists). Clinical guidelines and availability of supply were the most important factors considered when choosing an oral liquid antibiotic formulation for children by GP (79.7%) and pharmacist (66.5%) respondents respectively. Forty GP respondents (76.9%) reported ensuring adherence was the most common palatability-related reason leading to deviation from guidelines. Pharmacist respondents (52%) reported advising a parent/caregiver to manipulate the required antibiotic dose to improve acceptability. The least palatable oral liquid antibiotics reported were flucloxacillin (16% GPs, 18% pharmacists) and clarithromycin (17% of each profession).

Conclusion

This study identified palatability issues associated with oral liquid antibiotics for children reported by GPs and pharmacists. Pharmaceutical approaches to adapting oral liquid antibiotic formulations must be developed to improve palatability and thus paediatric acceptability.
Contributions of declining mortality, overall and from HIV, TB and malaria, to reduced health inequality and inequity across countries
Authors: Haacker Markus
Published: July 2023

The objective to reduce global health inequalities and inequities is integral to the global development agenda, from the Universal Declaration of Human Rights to the sustainable development goals and the ongoing response to coronavirus disease. Yet, summary measures of global health gains or of the cost-effectiveness of global health programmes barely capture how well they improve the lives of the most disadvantaged populations. This paper instead explores the distribution of global health gains across countries and the implications for health inequality and inequity (here referring to health disadvantages that reinforce economic disadvantage, and vice versa) across countries. Specifically, it studies the distribution of gains in life expectancy across countries (overall and owing to reduced mortality from HIV, TB and malaria), using the Gini index and a concentration index ranking countries by gross domestic product (GDP) per capita as indicators of health inequality and inequity. By these counts, global inequality in life expectancy across countries declined by one-third between 2002 and 2019. Reduced mortality from HIV, TB and malaria accounted for one-half of this decline. Fifteen countries in sub-Saharan Africa, containing 5% of the global population, accounted for 40% of the global decline in inequality, with nearly six-tenth of this contribution coming from HIV, TB and malaria. Inequity in life expectancy across countries declined by nearly 37%, with a contribution from HIV, TB and malaria of 39% of this gain. Our findings show how simple indicators on the distribution of health gains across countries usefully complement aggregate measures of global health gains and underscore their positive contribution to the global development agenda.
Mediation and moderation of genetic risk of obesity through eating behaviours in two UK cohorts
Authors: Begum Shahina , Hinton Eleanor C , Toumpakari Zoi , Frayling Timothy M , Howe Laura , Johnson Laura , Lawrence Natalia
Published: July 2023

Background

The mechanisms underlying genetic predisposition to higher body mass index (BMI) remain unclear.

Methods

We hypothesized that the relationship between BMI-genetic risk score (BMI-GRS) and BMI was mediated via disinhibition, emotional eating and hunger, and moderated by flexible (but not rigid) restraint within two UK cohorts: the Genetics of Appetite Study (GATE) (n = 2101, 2010–16) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 1679, 2014–18). Eating behaviour was measured by the Adult Eating Behaviour Questionnaire and Three-Factor Eating Questionaire-51.

Results

The association between BMI-GRS and BMI were partially mediated by habitual, emotional and situational disinhibition in the GATE/ALSPAC meta-mediation [standardized betaindirect 0.04, 95% confidence interval (CI) 0.02–0.06; 0.03, 0.01–0.04; 0.03, 0.01–0.04, respectively] external hunger and internal hunger in the GATE study (0.02, 0.01–0.03; 0.01, 0.001–0.02, respectively). There was evidence of mediation by emotional over/undereating and hunger in the ALSPAC study (0.02, 0.01–0.03; 0.01, 0.001–0.02; 0.01, 0.002–0.01, respectively). Rigid or flexible restraint did not moderate the direct association between BMI-GRS and BMI, but high flexible restraint moderated the effect of disinhibition subscales on BMI (reduction of the indirect mediation by -5% to -11% in GATE/ALSPAC) and external hunger (-5%) in GATE. High rigid restraint reduced the mediation via disinhibition subscales in GATE/ALSPAC (-4% to -11%) and external hunger (-3%) in GATE.

Conclusions

Genetic predisposition to a higher BMI was partly explained by disinhibition and hunger in two large cohorts. Flexible/rigid restraint may play an important role in moderating the impact of predisposition to higher BMI.
Application of nanomaterials for emission reduction from diesel engines powered with waste cooking oil biodiesel
Authors: Sharma Prabhakar , Paramasivam Prabhu , Bora Bhaskor J , Sivasundar Vijayakumar
Published: July 2023

Diesel engines that predominantly run on fossil-based diesel fuel emit harmful emissions. Biofuels such as biogas and biodiesel are potential alternatives. However, many biofuels have poor heating values and supply inconsistencies. The use of nanoparticles (NPs) offers an appealing alternative for enhancing the combustion and emission reduction. This study aimed to improve the emission performance of biodiesel produced from waste cooking oil biodiesel (WCOB) by adding titanium oxide (TiO2) NPs. Tests were conducted in the diesel-powered engine at varying load levels using fuel mixtures of B1 (100% diesel), B2 (80% diesel + 20% WCOB) and B3 (80% diesel + 20% WCOB with the addition of 200 mg/l TiO2 NPs). In comparison with the diesel mode, the average reduction in carbon monoxide emissions was 8.92% for the B2 blend and 25% for the TiO2 NP-based B3 blend. For the B2 blend and TiO2-based B3 blend, the mean reduction in hydrocarbon emissions was 5.6 and 16.6%, respectively, when compared with diesel mode. When comparing B3 blends with B2 blends, the average reduction in nitrogen oxide emissions was 3.75%. In conclusion, adding NPs to engine fuel is a viable solution for reducing emissions.
On the Cohomology of Torelli Groups. II
Authors: Randal-Williams Oscar
Published: July 2023

We describe the ring structure of the rational cohomology of the Torelli groups of the manifolds $\#^g S^n \times S^n$ in a stable range, for $2n \geq 6$. Some of our results are also valid for $2n=2$, where they are closely related to unpublished results of Kawazumi and Morita.
Integrons as the potential targets for combating multidrug resistance inEnterobacteriaceaeusing CRISPR- Cas9 technique
Authors: Shetty Varsha Prakash , Akshay Sadanand Dangari , Rai Praveen , Deekshit Vijaya Kumar
Published: July 2023

The emergence of multi-drug resistance (MDR) to pan-drug resistance (PDR) in Enterobacteriaceae has made treatment extremely challenging. Genetic mutations and horizontal gene transfer (HGT) through mobile genetic elements (MGEs) were frequently associated mechanisms of drug resistance in pathogens. However, transposons, plasmids, and integrons transfer MDR genes in bacterium via HGT much faster. Integrons are dsDNA segment that plays a crucial role in the adaptation and evolution of bacteria. They contain multiple gene cassettes that code for antibiotic resistance determinants that are expressed by a single promoter (Pc). Integrons are the cause of drug resistance in Enterobacteriaceae. Although alternatives to antibiotics such as bacteriophages, phage proteins, antimicrobial peptides, and natural compounds have been widely used to treat MDR infections, there have been limited efforts to reverse the antibiotic resistance ability of bacteria. Thus, silencing the genes harboured on MGEs achieved by Gene Editing Techniques (GETs) might prevent the spread of MDR. One such GETs, which has a simple design, good repeatability, low cost, and high efficiency, is CRISPR- Cas9 system. Thus, this review is a first of the kind that focuses on utilizing the structure of an integron to make it an ideal target for GETs like CRISPR- Cas9 systems.
Soil microarthropod distribution on the urban–rural gradient of Riga city: a study with robust sampling method application
Authors: Grina Vendija , Kagainis Ugis , Jucevica Edite , Salmane Ineta , Melecis Viesturs
Published: July 2023

To address the new challenge of bringing more nature into the urban environment and developing adequate green infrastructure management methods, it is necessary to clarify the regularities of the distribution of the main ecosystem components—soil organism communities on the urban gradient. Microarthropods—collembolans and mites—are the most diverse soil animals and bioindicators of soil conditions. However, no suitable approaches exist so far to help reduce the high workload of soil zoological studies and make the data acquisition for soil assessment faster. To get closer to a solution to this problem, we propose a robust sampling approach using one pooled sample per site with surface area 58 cm2. This was tested in a microarthropod distribution study on the urban gradient of Riga city (Latvia) in six urban habitat types at 21 sites. The use of classical statistical methods for the processing of soil microarthropod data is limited because these data do not meet model requirements on which classical methods are based, first of all, conformity to the normal distribution. These problems are circumvented by bootstrapping methodology, which thanks to increasing computer performance now is implemented in the most modern program packages. We tested a set of such methods: one-way bootstrap-based analysis of variance, nonmetric multidimensional scaling (NMS), nonparametric multiplicative regression (NPMR), multi-response permutation procedure and Chao bootstrap-based rarefaction curves. NMS in combination with NPMR gave the best results providing statistically significant species distribution curves along the urban gradient which were broadly in line with species traits found by other studies.
New foundations for the physical mechanism of variable chlorophyll a fluorescence. Quantum efficiency versus the light-adapted state of photosystem II
Authors: Garab Győző , Magyar Melinda , Sipka Gábor , Lambrev Petar H
Published: July 2023

Photosystem II (PSII) uses solar energy to oxidize water and delivers electrons to fix CO2. Although the structure at atomic resolution and the basic photophysical and photochemical functions of PSII are well understood, many important questions remain. The activity of PSII in vitro and in vivo is routinely monitored by recording the induction kinetics of chlorophyll a fluorescence (ChlF). According to the ‘mainstream’ model, the rise from the minimum level (Fo) to the maximum (Fm) of ChlF of dark-adapted PSII reflects the closure of all functionally active reaction centers, and the Fv/Fm ratio is equated with the maximum photochemical quantum yield of PSII (where Fv=Fm–Fo). However, this model has never been free of controversies. Recent experimental data from a number of studies have confirmed that the first single-turnover saturating flash (STSF), which generates the closed state (PSIIC), produces F1<Fm, and have uncovered rate-limiting steps (Δτ1/2 half-waiting times) in the multi-STSF-induced F1-to-Fm increments that originate from the gradual formation of light-adapted charge-separated states (PSIIL) with significantly increased stability of charges compared to the PSIIC state that is elicited by a single STSF. All the data show that the interpretation of ChlF must be laid on new foundations. Here, we discuss the underlying physical mechanisms and the significance of structural/functional dynamics of PSII as reflected by ChlF and variations in the novel parameter Δτ1/2.
Online social integration of migrants: Evidence from Twitter
Authors: Kim Jisu , Sonne Soazic Elise Wang , Garimella Kiran , Grow André , Weber Ingmar , Zagheni Emilio
Published: July 2023

As online social activities have become increasingly important for people’s lives, understanding how migrants integrate into online spaces is crucial for providing a more complete picture of integration processes. We curate a high-quality data set to quantify patterns of new online social connections among immigrants in the United States. Specifically, we focus on Twitter and leverage the unique features of these data, in combination with a propensity score matching technique, to isolate the effects of migration events on social network formation. The results indicate that migration events led to an expansion of migrants’ networks of friends on Twitter in the destination country, relative to those of similar users who did not move. Male migrants between 19 and 29 years old who actively posted more tweets in English after migration also tended to have more local friends after migration compared to other demographic groups, indicating the impact of demographic characteristics and language skills on integration. The percentage of migrants’ friends from their country of origin decreased in the first few years after migration and increased again in later years. Finally, unlike for migrants’ friends’ networks, which were under their control, we did not find any evidence that migration events expanded migrants’ networks of followers in the destination country. While following users on Twitter in theory is not a geographically constrained process, our work shows that offline (re)location plays a significant role in the formation of online networks.
Materials used to prevent adhesion, growth, and biofilm formation ofCandidaspecies
Authors: Tornero-Gutiérrez Fátima , Ortiz-Ramírez Jorge A , López-Romero Everardo , Cuéllar-Cruz Mayra
Published: July 2023

The species of the Candida genus are opportunistic pathogenic fungi found in humans and are responsible for ∼80% of worldwide fungal infections. Aimed at diminishing and preventing Candida adhesion to cells or implanted devices in the human host, a large diversity of materials has been developed and functionalized that have attracted much interest. Furthermore, these materials have been focused almost exclusively on Candida albicans, followed by C. glabrata, C. parapsilosis, and C. tropicalis. Although an important diversity of materials has been synthesized to prevent adherence and formation of biofilms by Candida species, it is however important to evaluate the capacity of each material in terms of its property to diminish the adherence of Candida. These materials are discussed in this review.
Archaeal Hel308 suppresses recombination through a catalytic switch that controls DNA annealing
Authors: Lever Rebecca J , Simmons Emily , Gamble-Milner Rebecca , Buckley Ryan J , Harrison Catherine , Parkes Ashley J , Mitchell Laura , Gausden Jacob A , Škulj Sanja , Bertoša Branimir , Bolt Edward L , Allers Thorsten
Published: July 2023

Hel308 helicases promote genome stability in archaea and are conserved in metazoans, where they are known as HELQ. Their helicase mechanism is well characterised, but it is unclear how they specifically contribute to genome stability in archaea. We show here that a highly conserved motif of Hel308/HELQ helicases (motif IVa, F/YHHAGL) modulates both DNA unwinding and a newly identified strand annealing function of archaeal Hel308. A single amino acid substitution in motif IVa results in hyper-active DNA helicase and annealase activities of purified Hel308 in vitro. All-atom molecular dynamics simulations using Hel308 crystal structures provided a molecular basis for these differences between mutant and wild type Hel308. In archaeal cells, the same mutation results in 160000-fold increased recombination, exclusively as gene conversion (non-crossover) events. However, crossover recombination is unaffected by the motif IVa mutation, as is cell viability or DNA damage sensitivity. By contrast, cells lacking Hel308 show impaired growth, increased sensitivity to DNA cross-linking agents, and only moderately increased recombination. Our data reveal that archaeal Hel308 suppresses recombination and promotes DNA repair, and that motif IVa in the RecA2 domain acts as a catalytic switch to modulate the separable recombination and repair activities of Hel308.
Glioblastoma modeling with 3D organoids: progress and challenges
Authors: Wang Xin , Sun Yusha , Zhang Daniel Y , Ming Guo-li , Song Hongjun
Published: July 2023

Glioblastoma (GBM) is the most aggressive adult primary brain tumor with nearly universal treatment resistance and recurrence. The mainstay of therapy remains maximal safe surgical resection followed by concurrent radiation therapy and temozolomide chemotherapy. Despite intensive investigation, alternative treatment options, such as immunotherapy or targeted molecular therapy, have yielded limited success to achieve long-term remission. This difficulty is partly due to the lack of pre-clinical models that fully recapitulate the intratumoral and intertumoral heterogeneity of GBM and the complex tumor microenvironment. Recently, GBM 3D organoids originating from resected patient tumors, genetic manipulation of induced pluripotent stem cell (iPSC)-derived brain organoids and bio-printing or fusion with non-malignant tissues have emerged as novel culture systems to portray the biology of GBM. Here, we highlight several methodologies for generating GBM organoids and discuss insights gained using such organoid models compared to classic modeling approaches using cell lines and xenografts. We also outline limitations of current GBM 3D organoids, most notably the difficulty retaining the tumor microenvironment, and discuss current efforts for improvements. Finally, we propose potential applications of organoid models for a deeper mechanistic understanding of GBM and therapeutic development.
Artificial intelligence in orthopaedics: can Chat Generative Pre-trained Transformer (ChatGPT) pass Section 1 of the Fellowship of the Royal College of Surgeons (Trauma & Orthopaedics) examination?
Authors: Cuthbert Rory , Simpson Ashley I
Published: July 2023

Purpose

Chat Generative Pre-trained Transformer (ChatGPT) is a large language artificial intelligence (AI) model which generates contextually relevant text in response to questioning. After ChatGPT successfully passed the United States Medical Licensing Examinations, proponents have argued it should play an increasing role in medical service provision and education. AI in healthcare remains in its infancy, and the reliability of AI systems must be scrutinized. This study assessed whether ChatGPT could pass Section 1 of the Fellowship of the Royal College of Surgeons (FRCS) examination in Trauma and Orthopaedic Surgery.

Methods

The UK and Ireland In-Training Examination (UKITE) was used as a surrogate for the FRCS. Papers 1 and 2 of UKITE 2022 were directly inputted into ChatGPT. All questions were in a single-best-answer format without wording alterations. Imaging was trialled to ensure ChatGPT utilized this information.

Results

ChatGPT scored 35.8%: 30% lower than the FRCS pass rate and 8.2% lower than the mean score achieved by human candidates of all training levels. Subspecialty analysis demonstrated ChatGPT scored highest in basic science (53.3%) and lowest in trauma (0%). In 87 questions answered incorrectly, ChatGPT only stated it did not know the answer once and gave incorrect explanatory answers for the remaining questions.

Conclusion

ChatGPT is currently unable to exert the higher-order judgement and multilogical thinking required to pass the FRCS examination. Further, the current model fails to recognize its own limitations. ChatGPT’s deficiencies should be publicized equally as much as its successes to ensure clinicians remain aware of its fallibility.

Key messages

What is already known on this topic

Following ChatGPT’s much-publicized success in passing the United States Medical Licensing Examinations, clinicians and medical students are using the model increasingly frequently for medical service provision and education. However ChatGPT remains in its infancy, and the model’s reliability and accuracy remain unproven.

What this study adds

This study demonstrates ChatGPT is currently unable to exert the higher-order judgement and multilogical thinking required to pass the Fellowship of the Royal College of Surgeons (FRCS) (Trauma & Orthopaedics) examination. Further, the current model fails to recognize its own limitations when offering both direct and explanatory answers.

How this study might affect research, practice, or policy

This study highlights the need for medical students and clinicians to exert caution when employing ChatGPT as a revision tool or applying it in clinical practice, and for patients to be aware of its fallibilities when using it as a health resource. Future research questions include:
Implementation of chiral two-nucleon forces to nuclear many-body methods with Gaussian-wave packets
Authors: Fukui Tokuro
Published: July 2023

Many-body methods that use Gaussian-wave packets to describe nucleon spatial distribution have been widely employed for depicting various phenomena in nuclear systems, in particular clustering. So far, however, the chiral effective field theory, a state-of-the-art theory of nuclear force, has not been applied to such methods. In this paper, we give the formalism to calculate the two-body matrix elements of the chiral two-nucleon forces using the Gaussian-wave packets. We also visualize the matrix elements and investigate the contributions of the central and tensor forces. This work is a foothold towards an ab initio description of various cluster phenomena in view of nucleons, pions, and many-nucleon forces.
Infection incidence, timing and dose dependency in rheumatoid arthritis patients treated with rituximab: a retrospective cohort study
Authors: Veeken Lara D , Opdam Merel A A , Verhoef Lise M , Popa Calin , van Crevel Reinout , den Broeder Alfons A
Published: July 2023

Objectives

Rituximab (RTX) is a safe and effective treatment for RA. However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion.

Methods

RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression.

Results

Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared with 1000 mg (adjusted IRR 0.35, 95% CI 0.17, 0.72, P = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared with later on in the treatment cycle, suggesting an association with peak concentration.

Conclusion

Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk.
Metagenomics reveals the structure of Mastrevirus–host interaction network within an agro-ecosystem
Authors: Claverie Sohini , Hoareau Murielle , Chéhida Sélim Ben , Filloux Denis , Varsani Arvind , Roumagnac Philippe , Martin Darren P , Lett Jean-Michel , Lefeuvre Pierre
Published: July 2023

As highly pervasive parasites that sometimes cause disease, viruses are likely major components of all natural ecosystems. An important step towards both understanding the precise ecological roles of viruses and determining how natural communities of viral species are assembled and evolve is obtaining full descriptions of viral diversity and distributions at ecosystem scales. Here, we focused on obtaining such ‘community-scale’ data for viruses in a single genus. We chose the genus Mastrevirus (family Geminiviridae), members of which have predominantly been found infecting uncultivated grasses (family Poaceae) throughout the tropical and sub-tropical regions of the world. We sampled over 3 years, 2,884 individual Poaceae plants belonging to thirty different species within a 2-ha plot which included cultivated and uncultivated areas on the island of Reunion. Mastreviruses were found in ∼8 per cent of the samples, of which 96 per cent did not have any discernible disease symptoms. The multitude of host–virus associations that we uncovered reveals both the plant species that most commonly host mastreviruses and the mastrevirus species (such as maize streak virus and maize streak Reunion virus) that have especially large host ranges. Our findings are consistent with the hypothesis that perennial plant species capable of hosting years-long mixed mastrevirus infections likely play a disproportionately important role in the generation of inter-species and inter-strain mastrevirus recombinants.
IIIMiddle English
Authors: Ash-Irisarri Kate , Atkinson Laurie , Brazil Sarah , Calder Natalie , Finn Andrew , Greene Darragh , Lindstedt Samira , Menmuir Rebecca , Ronan Mark , Sargan J D , Strickland Seth
Published: July 2023

This chapter has twelve sections: 1. Early Middle English (c.1050–1350); 2. Manuscript and Technical Studies; 3. Religious Prose and Verse; 4. Secular Prose; 5. Secular Verse; 6. Piers Plowman; 7. Gower; 8. Older Scots; 9. Drama; 10. The Gawain Poet; 11. Romance: Metrical, Alliterative, Malory; 12. Hoccleve and Lydgate. Section 1 is by Samira Lindstedt; section 2 is by J.D. Sargan; section 3 is by Natalie Calder; section 4 is by Mark Ronan; sections 5, 10, and 11 are by Darragh Greene; section 6 is by Seth Strickland; section 7 is by Rebecca Menmuir; section 8 is by Kate Ash-Irisarri; section 9 is by Sarah Brazil; section 12 is by Laurie Atkinson with assistance from Rebecca Menmuir.
Genistein‐mediated thermogenesis and white‐to‐beige adipocyte differentiation involve transcriptional activation of cAMP response elements in the Ucp1 promoter
Authors: Fuentes‐Romero Rebeca , Velázquez‐Villegas Laura A. , Vasquez‐Reyes Sarai , Pérez‐Jiménez Berenice , Domínguez Velázquez Zuleima N. , Sánchez‐Tapia Mónica , Vargas‐Castillo Ariana , Tobón‐Cornejo Sandra , López‐Barradas Adriana M. , Mendoza Valentín , Torres Nimbe , López‐Casillas Fernando , Tovar Armando R.
Published: July 2023

Genistein is an isoflavone present in soybeans and is considered a bioactive compound due to its widely reported biological activity. We have previously shown that intraperitoneal genistein administration and diet supplementation activates the thermogenic program in rats and mice subcutaneous white adipose tissue (scWAT) under multiple environmental cues, including cold exposure and high‐fat diet feeding. However, the mechanistic insights of this process were not previously unveiled. Uncoupling protein 1 (UCP1), a mitochondrial membrane polypeptide responsible for dissipating energy into heat, is considered the most relevant thermogenic marker; thus, we aimed to evaluate whether genistein regulates UCP1 transcription. Here we show that genistein administration to thermoneutral‐housed mice leads to the appearance of beige adipocyte markers, including a sharp upregulation of UCP1 expression and protein abundance in scWAT. Reporter assays showed an increase in UCP1 promoter activity after genistein stimulation, and in silico analysis revealed the presence of estrogen (ERE) and cAMP (CRE) response elements as putative candidates of genistein activation. Mutation of the CRE but not the ERE reduced genistein‐induced promoter activity by 51%. Additionally, in vitro and in vivo ChIP assays demonstrated the binding of CREB to the UCP1 promoter after acute genistein administration. Taken together, these data elucidate the mechanism of genistein‐mediated UCP1 induction and confirm its potential applications in managing metabolic disorders.
Ophthalmia Neonatorum, Helen Keller, and the Social Dimensions of Eye Disease
Authors: Harman Lynn E. , Margo Curtis E.
Published: July 2023

Purpose:

The aim of this study was to describe how an early 20th-century American celebrity attempted to influence public perception of ophthalmic neonatorum.

Methods:

This study reviews the editorial written by Helen Keller in the 1909 Ladies’ Home Journal and related historical documents about the prevention of blindness from neonatal conjunctivitis.

Results:

Although blind, deaf, and nulliparous, Helen Keller at the age of 29 sensed that the newborn children of many American women were being denied preventative treatment for ophthalmia neonatorum. In her editorial in the Ladies’ Home Journal discussing the complications of venereal disease she urged women to become proactive in matters of personal and family health care.

Conclusions:

Helen Keller viewed blindness from ophthalmia neonatorum as a failure of the American health care system. Her solution was to impart women with enough knowledge to seek care from educated medical professionals. The observation that many women and their children were receiving substandard care reflected a fundamental problem with disparities in the delivery of perinatal health care. Her insights are as relevant today as they were in 1909.
Point-of-care Ultrasound to Assess Hemodynamic Contributors to Acute Kidney Injury in Pediatric Patients With Cerebral Malaria: A Pilot Study
Authors: Lintner Rivera Michael , Prager Ross , Gushu Montfort Bernard , June Sylvester , Phiri Tusekile , Salameh Jean-Paul , Johnson Hunter C. , Taylor Terrie , O’Brien Nicole F.
Published: July 2023

Background:

Acute kidney injury is common in severe malaria and is independently associated with mortality. The pathogenesis of acute kidney injury (AKI) in severe malaria remains incompletely understood. Ultrasound-based tools such as point-of-care ultrasound (POCUS), ultrasound cardiac output monitors (USCOMs) and renal arterial resistive index (RRI) can be used to detect hemodynamic and renal blood flow abnormalities contributing to AKI in malaria.

Methods:

We conducted a prospective study of Malawian children with cerebral malaria to determine the feasibility of using POCUS and USCOM to characterize hemodynamic contributors to severe AKI (Kidney Disease: Improving Global Outcomes stage 2 or 3). The primary outcome was feasibility (completion rate of study procedures). We also assessed for differences in POCUS and hemodynamic variables for patients with or without severe AKI.

Results:

We enrolled 27 patients who had admission cardiac and renal ultrasounds and USCOM. Completion rates were high for cardiac (96%), renal (100%) and USCOM studies (96%). Severe AKI occurred in 13 of 27 patients (48%). No patients had ventricular dysfunction. Only 1 patient in the severe AKI group was determined to be hypovolemic (P = 0.64). No significant differences in USCOM, RRI or venous congestion parameters were detected among patients with and without severe AKI. Mortality was 11% (3/27) with the 3 deaths occurring in the severe AKI group (P = 0.056).

Conclusions:

Ultrasound-based cardiac, hemodynamic and renal blood flow measurements appear to be feasible in pediatric patients with cerebral malaria. We were unable to detect hemodynamic or renal blood flow abnormalities contributing to severe AKI in cerebral malaria. Larger studies are needed to corroborate these findings.
Center-based First-line Therapy Is a Significant Predictor for Mortality of Fournier Gangrene
Authors: Rieger Constantin , Hübers Max , Kastner Lucas , Pfister David , Holling Heinz , Heidenreich Axel
Published: July 2023

Introduction:

Fournier gangrene is a life-threatening urological disease that requires rapid surgical intervention. Despite major improvements in medical therapy, the mortality of Fournier gangrene has not changed during the past 25 years. To potentially improve the outcome, we analyzed different medical processes for overall mortality in the treatment of Fournier gangrene.

Methods:

We performed a retrospective single-center study of 21 patients with Fournier gangrene. Patients were grouped according to initial symptoms, first medical advice, blood tests, medical history, and further clinical processes and compared using a t test, χ2 test, or Fisher exact test. A t test for heterogeneous variances was used if a Levene test showed significantly different variances, otherwise a t test for homogeneous variances was used. The log-rank test was applied for survival analysis. Logistic regression was applied to identify potential clinical predictors for mortality. Follow-up was performed until 130 days after the first surgical intervention.

Results:

There were no significant differences in the mortality rate of patients depending on the day and time of presentation in the hospital. Of the patients first consulting a urologist (either outpatient or hospital), no patient died within the first 120 days. By contrast, approximately 70% of patients who were transferred by a hospital without urologic specialization or a nonurologic outpatient clinic (P = .008) died within the first 130 days after surgery. Multivariate survival analysis showed that the type of first doctor's advice could serve as a significant factor in determining patients' mortality (P = .031), which also correlated with a significantly shorter duration of the first surgical procedure (110 vs 54 minutes, P = .019).

Conclusion:

Despite the small cohort, we were able to show a significant correlation between the initial doctor's advice, either by a urologist or nonurologist, and the patient's mortality. Considering the life-threatening potential of Fournier gangrene, professionals should develop strategies to educate nonurologists and raise awareness about this disease and its clinical presentation to optimize rapid intervention and reduce mortality.