bluuebunny/crossref_metadata_2025 huggingface dataset:
Interspecific interactions disrupted by roads
Authors: Quiles Pablo , Barrientos Rafael
Published: February 2024

Roads have pervasive impacts on wildlife, including habitat loss and fragmentation, road mortality, habitat pollution and increased human use of habitats surrounding them. However, the effects of roads on interspecific interactions are less understood. Here we provide a synthesis of the existing literature on how species interactions may be disrupted by roads, identify knowledge gaps, and suggest avenues for future research and conservation management. We conducted a systematic search using the Web of Science database for each species interaction (predation, competition, mutualism, parasitism, commensalism and amensalism). These searches yielded 2144 articles, of which 195 were relevant to our topic. Most of these studies focused on predation (50%) or competition (24%), and less frequently on mutualism (17%) or, parasitism (9%). We found no studies on commensalism or amensalism. Studies were biased towards mammals from high‐income countries, with most conducted in the USA (34%) or Canada (18%). Our literature review identified several patterns. First, roads disrupt predator–prey relationships, usually with negative impacts on prey populations. Second, new disturbed habitats created in road corridors often benefit more competitive species, such as invasive species, although some native or endangered species can also thrive there. Third, roads degrade mutualistic interactions like seed dispersal and pollination. Fourth, roads can increase parasitism rates, although the intensity of the alteration is species specific. To reduce the negative impacts of roads on interspecific interactions, we suggest the following management actions: (i) verges should be as wide and heterogenous as possible, as this increases microhabitat diversity, thus enhancing ecosystem services like pollination and seed dispersal; (ii) combining different mowing regimes can increase the complexity of the habitat corridor, enabling it to act as a habitat for more species; (iii) the use of de‐icing salts should be gradually reduced and replaced with less harmful products or maintenance practices; (iv) wildlife passes should be implemented in groups to reduce animal concentrations inside them; (v) periodic removal of carcasses from the road to reduce the use of this resource by wildlife; and (vi) implementation of traffic‐calming schemes could enhance interspecific interactions like pollination and avoid disruption of predator–prey relationships.
International trade fluctuations: Global versus regional factors
Authors: Beck Krzysztof , Jackson Karen
Published: February 2024

This paper examines the relative importance of global, regional, country and idiosyncratic factors as well as the determinants that underpin fluctuations in international trade flows across different regions of the world. Our analysis starts by using a Bayesian dynamic latent factor model (BDFM) to simultaneously estimate the four dynamic factors, followed by the application of Bayesian model averaging to identify the variables that explain the shares of variance. Our key findings are: (i) international factors are the most important in explaining fluctuations in international trade, suggesting that the interconnections between economies and policies/shocks at the regional and global level tend to be more important than country‐level factors and (ii) regional integration, particularly when the agreement goes beyond trade in goods, is positively related to the share of the regional factor and inversely related to the importance of the global factor. Furthermore, the regional factor is more important in the case of economically large trade blocks. Overall, our analysis illustrates the usefulness of applying a BDFM model to study the co‐movements of international trade series.
EGFR amplification indicated poor prognosis in EGFR‐mutated lung cancer with leptomeningeal metastases
Authors: Geng Di , Niu Ruina , Li Jinghong , Guo Sanxing , Guo Qianqian , Huang Siyuan , Wang Yurong
Published: February 2024

Background

Leptomeningeal metastasis (LM) is a lethal complication of advanced lung cancer, and due to limited access to the leptomeningeal lesion, we explored the potential role of cerebrospinal fluid (CSF) as a source for liquid biopsy in LM patients of lung cancer with EGFR mutation.

Materials and Methods

From August 2018 to June 2021, we collected CSF samples of lung cancer patients at First Affiliated Hospital of Zhengzhou University. Next‐generation sequencing was performed to detect the mutations in EGFR genes, and 38 patients detected with EGFR mutations were finally enrolled in further clinical analyses.

Results

TP53 missense mutation (50%) was the most frequently detected concurrent gene in CSF. In those 10 patients whose CSF was obtained upon resistance to first TKI, TP53 missense mutation (40%, n = 4) and EGFR copy number amplification (40%, n = 4) was detected with high frequency; meanwhile, T790M mutation was found only in two patients. Known mechanisms of acquired resistance to third EGFR‐TKIs were found in 31.8% of cases. C797S or C797G mutation was identified in three patients. Possible EGFR‐independent resistant mechanism included MET amplification (4.5%), RET gene fusion (4.5%), PIK3CA missense mutation (4.5%) and CDK4 amplification (4.5%). The median OS was 55 months, the median OSLM was 38 months. EGFR amplification was associated with shortened OS in these EGFR‐mutated lung cancer with leptomeningeal metastases.

Conclusion

EGFR amplification indicated poor prognosis in EGFR‐mutated lung cancer with leptomeningeal metastases, providing a novel pathogenesis and treatment direction of these patients.
Age‐ and gender‐adjusted estimated glomerular filtration rate definition reveals hyperfiltration as a risk factor for renal function deterioration in type 2 diabetes
Authors: Wen Wei‐Lun , Lee Yau‐Jiunn , Hwu Der‐Wei , Chang Yu‐Hung
Published: February 2024

Aim

To assess the role of hyperfiltration for diabetic kidney disease (DKD) progression.

Materials and Methods

A retrospective observational cohort study enrolled type 2 diabetes (T2D) patients with an initial estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m2 or higher. Patients were categorized into two groups: hyperfiltration (eGFR exceeding the age‐ and gender‐specific 95th percentile values from a prior national cohort study) and normofiltration. Rapid DKD progression was defined as an eGFR decline of more than 5 mL/min/1.73m2/year. We used a linear mixed effect model and Cox regression with time‐varying covariate model to compare eGFR changes and identify factors associated with rapid DKD progression.

Results

Of the enrolled 7563 T2D patients, 7.2% had hyperfiltration. The hyperfiltration group exhibited a higher rate of eGFR decline compared with the normofiltration group (−2.0 ± 0.9 vs. −1.1 ± 0.9 mL/min/1.73m2/year; P < .001). During an average follow‐up period of 4.65 ± 3.86 years, 24.7% of patients with hyperfiltration experienced rapid DKD progression, compared with 15.7% of patients with normofiltration (P < .001). Cox regression analyses identified that initial hyperfiltration was a significant determinant of rapid DKD progression, with a hazard ratio of 1.66 (95% confidence interval: 1.41‐1.95; P < .001). When combined with albuminuria, the risk of progression was further compounded (hazard ratio 1.76‐3.11, all P < .001).

Conclusions

In addition to using the current Kidney Disease: Improving Global Outcomes CGA classification system, considering glomerular hyperfiltration status can improve the accuracy of predicting DKD progression.
Disseminated intravascular coagulation score evolution in 48 h predicts early death in acute promyelocytic leukemia patients
Authors: Infante Joana Brioso , Esteves Graça Vasconcelos , Raposo João , de Lacerda João Forjaz
Published: February 2024

Introduction

Early death (ED) is the unsolved issue of acute promyelocytic leukemia (APL). The disseminated intravascular coagulation (DIC) score has been proposed as a marker of bleeding and death in APL; whether its temporal evolution predicts outcomes in APL is unknown. We evaluated whether an increasing score 48 h after diagnosis associates with ED.

Methods

Retrospective, single‐center study, including patients with newly diagnosed APL between 2000 and 2023, treated with all‐transretinoic acid (ATRA) plus anthracycline or arsenic trioxide (ATO). “DIC score worsening” was defined as ≥1 point increase in the score after 48 h, and ED as death within 30 days of diagnosis.

Results

Eighty‐six patients were included, with median age of 46 years (17–82). ED patients (26.7%) more frequently had age >60 years and worsening DIC score after 48 h. These were also the only predictors of ED identified in both univariate and multivariate (OR 4.18, p = .011; OR 7.8, p = .005, respectively) logistic regression analysis.

Conclusion

This is the first study on DIC score evolution in APL—a worsening DIC score 48 h after diagnosis is a strong independent predictive factor of ED. We propose a reduction of the DIC score from diagnosis as a new treatment goal in APL care.
Differences in anxiety, depression, and oral health‐related quality of life among dental anxiety patients with and without reported abuse experience
Authors: Aardal Vilde , Willumsen Tiril , Evensen Kjersti Berge
Published: February 2024

This study aimed to explore the differences in anxiety, depression, and oral health‐related quality of life between people with dental anxiety who reported abuse experience (n = 60) and people with dental anxiety who did not report abuse experience (n = 97). Both groups attended a dental service focused on the treatment of dental anxiety intended for people with a history of physiological or psychological trauma, or odontophobia. The participants responded to a questionnaire that included the Hospital Anxiety and Depression Scale (HADS), Oral Impacts on Daily Performance (OIDP), and the Index of Dental Anxiety and Fear (IDAF‐4C+). The differences between groups were tested for statistical significance using Welch's T‐tests, and linear regression was used to adjust for gender. The participants with reported abuse experience expressed greater psychological symptoms of anxiety and poorer oral health‐related quality of life. The participants with reported abuse experience also expressed a higher fear of losing control, as well as feeling shame and disgust. This study shows that individuals with dental anxiety and a history of abuse may face more complex challenges than those with dental anxiety and no history of abuse.
Currency flotation and dividend policies: Evidence from China's central parity reform
Authors: Luo Yilin , Ni Chenkai , Thewissen James
Published: February 2024

Exploiting the 2015 central parity reform in China, we examine whether and how currency flotation affects corporate payout policies. The reform shifted China's currency regime from a crawling peg to the US dollar to partial flotation, significantly increasing its currency risk. We find that firms with high foreign currency exposures reduced their cash dividends postreform relative to firms with low foreign currency exposures. The dividend reduction is more pronounced for firms with less financial hedging or less financial flexibility before the reform. Firms display asymmetrical responses to foreign exchange gains versus losses. Specifically, while firms cut cash dividends when experiencing foreign exchange losses, they do not increase cash dividends when obtaining foreign exchange gains. A falsification test shows no changes in firms’ stock dividends that do not involve cash flows. Overall, our study shows that currency flotation, through increasing currency risks, dampens firms’ cash dividends.
A review of niche segregation across sympatric breeding seabird assemblages
Authors: Petalas Christina , van Oordt Francis , Lavoie Raphaël A. , Elliott Kyle H.
Published: February 2024

Breeding seabirds challenge the concept of niche segregation among competing species because similar competitors with comparable life histories can coexist in large multi‐species colonies. This makes them an ideal model organism for studying the Hutchisonian niche model, which proposes interspecific niche segregation, across n‐dimensions. Recent advances in assessment of ecological niches have improved our understanding of the mechanisms leading to at‐sea segregation. We examine 152 published studies investigating one or more of three niche spaces in breeding seabirds: dietary items, stable isotopes (isotopic niche) and spatial distribution (horizontal and vertical). Most studies focused on one rather then multiple niche spaces in combination. When multiple niche spaces were combined, higher segregation than overlap was reported, compared with when niche spaces were assessed individually, as is predicted by the n‐dimensional hypervolume concept. Studies investigating vertical (diving) foraging dimensions in addition to the more traditional horizontal (spatial) assessment reported more spatial segregation than overlap, compared with studies focusing only on horizontal or vertical dimensions. Segregation increased with colony size, suggesting an effect of competition. Segregation also increased during chick‐rearing, when taxa were more phylogenetically distant, and when foraging ecology was more similar. To gain a comprehensive understanding of sympatric competitors' interactions and their ecological niche space, it is important to combine approaches and standardize methodologies. Embracing multidimensional approaches to assess niche segregation in seabird species can inform effective conservation and management practices in marine ecosystems.
Effects of dietary fibre source and content and extrusion conditions on the physicochemical composition and physical quality of fibre‐enriched lentil snacks
Authors: Sinaki Nasibeh Y. , Koksel Filiz
Published: February 2024

The growing recognition of the health benefits associated with dietary fibre and the deficit in its daily intake are propelling the food industry to develop a variety of fibre‐enriched products including puffed snacks. Incorporating rich sources of fibre into pulse‐based foods can supplement the insufficient daily dietary fibre intake. To produce fibre‐enriched puffed pulse snacks and ready‐to‐eat breakfast cereals, three different fibre sources, namely carrot powder (CP), wheat bran (WB) and red lentil hulls (LH), were added to red lentil (RL) flour at 0%, 10% and 20% levels (w/w) and extruded at three extrusion moisture contents (MC), i.e., 18%, 20% and 22% (db). Incorporation of all three fibres into RL flour significantly (P ≤ 0.05) increased the total and insoluble dietary fibre contents and hardness and decreased the expansion index, brightness and crispiness of extrudates. Scanning electron microscopy images revealed that the fibre‐enriched extrudates had thicker cell walls with smaller cells when qualitatively compared to RL extrudates with no fibre addition. CP containing extrudates had significantly (P ≤ 0.05) higher soluble dietary fibre (SDF) content compared to extrudates containing WB and LH. WB containing extrudates were significantly (P ≤ 0.05) harder and less expanded than CP and LH containing extrudates at the same MC. The increase in fibre incorporation level increased the hardness of CP and WB containing extrudates but did not affect LH containing extrudates. Fibre incorporation level also increased the colour differences between RL extrudates with and without fibre enrichment. Increasing MC significantly (P ≤ 0.05) increased the SDF and hardness and decreased the expansion index of extrudates. These results can potentially pave the way for the production of fibre‐enriched pulse‐based puffed products, namely, snacks and ready‐to‐eat breakfast cereals, that are texturally and structurally appealing to consumers.
Uncovering the cause of breakup between species' range limits and niche limits under climate warming
Authors: Sánchez‐Castro Darío , Patsiou Theofania‐Sotiria , Perrier Antoine , Schepers Judith , Willi Yvonne
Published: February 2024

Aim

Global climate change has been linked to shifts in species' geographic and elevational distributions, with taxa varying in responsiveness. This variation may be due to a time lag in response or climate alone not being a simple determinant of distribution limits. To tease apart the role of climate in distribution, we compared the temperature response of predicted occurrence revealed by ecological niche modelling (ENM) on historical climate with that of performance in a multi‐population transplant experiment. Congruence would support that climate is a main driver of distribution limits of a species.

Location

North America.

Taxon

Arabidopsis lyrata subsp. lyrata.

Methods

Seeds of 20 populations of North American Arabidopsis lyrata from across the entire range were collected, propagated and then sown along a latitudinal transect across and beyond the species' range. Lifetime performance was related to the main niche‐ and range‐determining climatic variable revealed by ENM.

Results

Lifetime performance did not consistently decline towards the high‐latitude range limit, but it did so towards the low‐latitude range limit. This decline was slightly weaker for low‐latitude populations, indicating divergent climate adaptation. The overall performance curve on the field‐measured minimum temperature in early spring was fairly congruent with the curve of ENM‐predicted suitability on this important niche‐determining variable. ENM‐based projections revealed that the southernmost populations were vulnerable under climate warming.

Main Conclusions

Results verified that ENM based on species occurrences can well‐predict plant performance under field conditions. Congruence teaches us that with the climate change so far, the species exhibits a colonisation deficit in the north. Furthermore, the southernmost populations are vulnerable to extinction. A likely outcome is the shrinking of the species' range.
Artificial Intelligence: The Future of Pedagogy
Authors: Mattalo Brandon
Published: February 2024

While it is important to research the negative impact of generative artificial intelligence on academic integrity, academics should focus most of their efforts on the opportunities these technologies present for improving pedagogical practices. In this note, I attempt to flip the narrative from one of fear to one of opportunity. I suggest that academics should research the use of generative AI to improve teaching effectiveness and efficiency. I offer various practical suggestions on how these tools can be used to advance pedagogical practices, with specific business law examples.
Colorblind racial ideology as an alibi for inaction: Examining the relationship among colorblind racial ideology, awareness of White privilege, and antiracist practices among White people
Authors: Collins Charles R. , Walsh Camille
Published: February 2024

This study examines the relationship among White antiracism, colorblind racial ideology (CBRI), and White privilege awareness. We use Critical Race Theory (CRT) to frame the historical context of racism in the U.S. and the emergence of racist ideologies. We examine the extent to which White privilege awareness mediates the relationship between CBRI and antiracist practices among White people. We found that (1) participants’ antiracist practices were increased the more they rejected power‐evasive forms of CBRI, (2) people who were more aware of their White privilege were also more driven toward antiracist practices, and (3) respondents’ awareness of their White privilege was enhanced as they rejected power evasive forms of CBRI. We also found that White people were more likely to participate in antiracist practices when they rejected power evasion CBRI partly because rejecting CBRI enhanced their awareness of White privilege. Our results suggest that the fight against racism requires White people to acknowledge and dismantle the privileges that come with being a member of a dominant group. We contend that CRT is a powerful framework for psychology because it helps resolve the problem of understanding how structural phenomena become ideologies that shape the way people believe and behave.
Comprehensive lipidomic analysis revealed the effects of fermented Morus alba L. intake on lipid profile in backfat and muscle tissue of Yuxi black pigs
Authors: Hou Junjie , Ji Xiang , Chu Xiaoran , Shi Zhuoyan , Wang Binjie , Sun Kangle , Wei Haibo , Song Zhen , Wen Fengyun
Published: February 2024

Mulberry leaf is a widely used protein feed and is often used as a strategy to reduce feed costs and improve meat quality in the livestock industry. However, to date, there is a lack of research on the improvement of meat quality using mulberry leaves, and the exact mechanisms are not yet known. The results showed that fermented mulberry leaves significantly reduced backfat content but had no significant effect on intramuscular fat (IMF). Lipidomic analysis showed that 98 and 303 differential lipid molecules (p < 0.05) were identified in adipose and muscle tissues, respectively, including triglycerides (TG), phosphatidylcholine, phosphatidylethanolamine, sphingolipids, and especially TG; therefore, we analysed the acyl carbon atom number of TG. The statistical results of acyl with different carbon atom numbers of TG in adipose tissue showed that the acyl group containing 13 carbon atoms (C13) in TG was significantly upregulated, whereas C15, C16, C17, and C23 were significantly downregulated, whereas in muscle tissue, the C12, C19, C23, C25, and C26 in TG were significantly downregulated. Acyl changes in TG were different for different numbers of carbon atoms in different tissues. We found that the correlations of C (14–18) in adipose tissue were higher, but in muscle tissue, the correlations of C (18–26) were higher. Through pathway enrichment analysis, we identified six and four metabolic pathways with the highest contributions of differential lipid metabolites in adipose and muscle tissues respectively. These findings suggest that fermented mulberry leaves improve meat quality mainly by inhibiting TG deposition by downregulating medium‐ and short‐chain fatty acids in backfat tissue and long‐chain fatty acids in muscle tissue.
Prevalence of metabolic dysfunction‐associated steatotic liver disease in the Middle East and North Africa
Authors: Younossi Zobair M. , Golabi Pegah , Paik James , Owrangi Soroor , Yilmaz Yusuf , El‐Kassas Mohamed , Alswat Khalid , Alqahtani Saleh A.
Published: February 2024

Background and Aims

Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is common and closely associated with type 2 diabetes (T2D). We assessed the prevalence of NAFLD/MASLD in the general population and among patients with T2D in the Middle East and North Africa (MENA) region.

Methods

We searched PubMed and Embase for English‐language articles published between 1990 and 2023 according to PRISMA. Each country's NAFLD/MASLD prevalence in the general population and in T2D patients was predicted by using a multivariable meta regression model. Input data were extracted from our systematic review, GBD and NCD Risk Factor Collaboration. Confidence intervals were constructed by using prediction intervals with the delta method.

Results

Meta‐analytic pooling estimated the prevalence of NAFLD/MASLD as 39.43% in the general population and 68.71% among T2D patients. NAFLD/MASLD prevalence has increased from 35.42% (2008–2016) to 46.20% (2017–2020). Using GBD‐2019 dataset, it was predicted that there are 141.51 million cases of NAFLD/MASLD in the MENA region. The highest number of NAFLD/MASLD cases were expected in Egypt (25.71 million), followed by Türkiye (23.33 million) and Iran (19.85 million). Estimated NAFLD prevalence exceeded 40% in 10 of 21 countries with the top countries being Kuwait (45.37%), Egypt (45.0%), Qatar (44.4%), and Jordan (43.3%). Furthermore, it was predicted that there are 24.96 million cases of NAFLD/MASLD with T2D in the MENA region.

Conclusions

In the MENA region, prevalence of NAFLD/MASLD is very high and growing, necessitating an urgent need for regional public policy to deal with this growing burden.
Distribution and insecticide resistance profile of the major malaria vectorAnopheles funestusgroup across theAfricancontinent
Authors: Wangrawa Dimitri W. , Odero Joel O. , Baldini Francesco , Okumu Fredros , Badolo Athanase
Published: February 2024

There has been significant progress in malaria control in the last 2 decades, with a decline in mortality and morbidity. However, these gains are jeopardised by insecticide resistance, which negatively impacts the core interventions, such as insecticide‐treated nets (ITN) and indoor residual spraying (IRS). While most malaria control and research efforts are still focused onAnopheles gambiaecomplex mosquitoes,Anopheles funestusremains an important vector in many countries and, in some cases, contributes to most of the local transmission. As countries move towards malaria elimination, it is important to ensure that all dominant vector species, includingAn. funestus, an important vector in some countries, are targeted. The objective of this review is to compile and discuss information related toA. funestuspopulations' resistance to insecticides and the mechanisms involved across Africa, emphasising the sibling species and their resistance profiles in relation to malaria elimination goals. Data on insecticide resistance inAn. funestusmalaria vectors in Africa were extracted from published studies. Online bibliographic databases, including Google Scholar and PubMed, were used to search for relevant studies. Articles published between 2000 and May 2023 reporting resistance ofAn. funestusto insecticides and associated mechanisms were included. Those reporting only bionomics were excluded. Spatial variation in species distribution and resistance to insecticides was recorded from 174 articles that met the selection criteria. It was found thatAn. funestuswas increasingly resistant to the four classes of insecticides recommended by the World Health Organisation for malaria vector control; however, this varied by country. Insecticide resistance appears to reduce the effectiveness of vector control methods, particularly IRS and ITN. Biochemical resistance due to detoxification enzymes (P450s and glutathione‐S‐transferases [GSTs]) inAn. funestuswas widely recorded. However,An. funestusin Africa remains susceptible to other insecticide classes, such as organophosphates and neonicotinoids. This review highlights the increasing insecticide resistance ofAn. funestusmosquitoes, which are important malaria vectors in Africa, posing a significant challenge to malaria control efforts. WhileAn. funestushas shown resistance to the recommended insecticide classes, notably pyrethroids and, in some cases, organochlorides and carbamates, it remains susceptible to other classes of insecticides such as organophosphates and neonicotinoids, providing potential alternative options for vector control strategies. The study underscores the need for targeted interventions that consider the population structure and geographical distribution ofAn. funestus, including its sibling species and their insecticide resistance profiles, to effectively achieve malaria elimination goals.
Stomatal conductance reduction tradeoffs in maize leaves: A theoretical study
Authors: Srivastava Antriksh , Srinivasan Venkatraman , Long Stephen P.
Published: February 2024

As the leading global grain crop, maize significantly impacts agricultural water usage. Presently, photosynthesis () in leaves of modern maize crops is saturated with , implying that reducing stomatal conductance () would not affect but reduce transpiration (), thereby increasing water use efficiency (WUE). While reduction benefits upper canopy leaves under optimal conditions, the tradeoffs in low light and nitrogen‐deficient leaves under nonoptimal microenvironments remain unexplored. Moreover, reduction increases leaf temperature () and water vapor pressure deficit, partially counteracting transpiratory water savings. Therefore, the overall impact of reduction on water savings remains unclear. Here, we use a process‐based leaf model to investigate the benefits of reduced in maize leaves under different microenvironments. Our findings show that increases in due to reduction can diminish WUE gains by up to 20%. However, reduction still results in beneficial WUE tradeoffs, where a 29% decrease in in upper canopy leaves results in a 28% WUE gain without loss in . Lower canopy leaves exhibit superior tradeoffs in reduction with 178% gains in WUE without loss in . Our simulations show that these WUE benefits are resilient to climate change.
Microsecond dynamics control the HIV-1 Envelope conformation
Authors: Bennett Ashley L. , Edwards Robert , Kosheleva Irina , Saunders Carrie , Bililign Yishak , Williams Ashliegh , Bubphamala Pimthada , Manosouri Katayoun , Anasti Kara , Saunders Kevin O. , Alam S. Munir , Haynes Barton F. , Acharya Priyamvada , Henderson Rory
Published: February 2024

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.
Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response
Authors: Zhang Wei , Zhang Minjie , Ma Li , Jariyasakulroj Supawadee , Chang Qing , Lin Ziying , Lu Zhipeng , Chen Jian-Fu
Published: February 2024

Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA)
SNORD118
. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of
SNORD118
function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell–based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our
SNORD118
mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.
TFPIα anticoagulant function is highly dependent on protein S in vivo
Authors: Petri Anastasis , Sasikumar Parvathy , Folgado Patricia Badia , Jones David , Xu Yaoxian , Ahnström Josefin , Salles-Crawley Isabelle I. , Crawley James T. B.
Published: February 2024

Tissue factor pathway inhibitor α (TFPIα) is the major physiological regulator of the initiation of blood coagulation. In vitro, TFPIα anticoagulant function is enhanced by its cofactor, protein S. To define the role of protein S enhancement in TFPIα anticoagulant function in vivo, we blocked endogenous TFPI in mice using a monoclonal antibody (14D1). This caused a profound increase in fibrin deposition using the laser injury thrombosis model. To explore the role of plasma TFPIα in regulating thrombus formation, increasing concentrations of human TFPIα were coinjected with 14D1, which dose-dependently reduced fibrin deposition. Inhibition of protein S cofactor function using recombinant C4b-binding protein β chain significantly reduced the anticoagulant function of human TFPIα in controlling fibrin deposition. We report an in vivo model that is sensitive to the anticoagulant properties of the TFPIα-protein S pathway and show the importance of protein S as a cofactor in the anticoagulant function of TFPIα in vivo.
Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8
+
T-myeloid cell networks in melanoma
Authors: Barras David , Ghisoni Eleonora , Chiffelle Johanna , Orcurto Angela , Dagher Julien , Fahr Noémie , Benedetti Fabrizio , Crespo Isaac , Grimm Alizée J. , Morotti Matteo , Zimmermann Stefan , Duran Rafael , Imbimbo Martina , de Olza Maria Ochoa , Navarro Blanca , Homicsko Krisztian , Bobisse Sara , Labes Danny , Tsourti Zoe , Andriakopoulou Charitini , Herrera Fernanda , Pétremand Rémy , Dummer Reinhard , Berthod Gregoire , Kraemer Anne I. , Huber Florian , Thevenet Jonathan , Bassani-Sternberg Michal , Schaefer Niklaus , Prior John O. , Matter Maurice , Aedo Veronica , Dromain Clarisse , Corria-Osorio Jesus , Tissot Stéphanie , Kandalaft Lana E. , Gottardo Raphael , Pittet Mikaël , Sempoux Christine , Michielin Olivier , Dafni Urania , Trueb Lionel , Harari Alexandre , Laniti Denarda Dangaj , Coukos George
Published: February 2024

Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8
+
TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.
Rare and aggressive metastatic pheochromocytoma recurrence in a patient with MEN 2A syndrome
Authors: Hernandez Edrome Ferrer , Nicodemus Nemencio Almare
Published: February 2024

An adult male in his early 30s diagnosed with multiple endocrine neoplasia type 2A syndrome, confirmed through genetic testing, presented as bilateral pheochromocytoma in a metachronous fashion, primary hyperparathyroidism and medullary thyroid carcinoma. Left and right adrenalectomy was done 9 years and 3 years ago, respectively. He was also subjected to total thyroidectomy with neck dissection and left inferior parathyroidectomy. During surveillance monitoring, 24-hour total urine metanephrines were elevated 13.977 mg (Normal value 0–1 mg) 1 year after right adrenalectomy. Adrenal CT scan demonstrated a 2.1 cm ovoid focus in the right suprarenal region, and functional imaging (131I meta-iodobenzylguanidine (MIBG scan) showed an avid uptake on the right frontal bone. Excision of the right adrenal bed and the right frontal bone tumour was performed, and metastatic pheochromocytoma was confirmed histologically. The patient achieved clinical and biochemical remission postoperatively and is currently receiving steroid and thyroxine replacement.
Functional vision disorder: a review of diagnosis, management and costs
Authors: Tao Brendan Ka-Lok , Xie Jim Shenchu , Margolin Edward
Published: February 2024

Functional vision disorder (FVD) is a relatively common diagnosis in ophthalmic practice which can be difficult to make because of clinician’s apprehension to miss organic pathology. We review the diagnostic approach to patients with FVD, organic mimics of FVD, its diagnostic and management strategies and associated cost burden. Patients with FVD typically present with visual acuity and/or field loss. Diagnostic work-up should include patient observation, detailed history, pupillary examination, dilated ophthalmoscopy, visual field testing and ganglion cell analysis of the macular complex. Most common organic mimickers of FVD are amblyopia, cortical blindness, retrobulbar optic neuritis, cone dystrophy and chiasmal tumours; however, all could be ruled out by structured diagnostic approach. For patients with unilateral visual loss, bottom-up refraction, fogging of the well-seeing eye in the phoropter, convex lens and base-down prism tests could aid in diagnosis. For patients claiming binocular vision loss, checking for eye movement during the mirror test or nystagmus elicited by an optokinetic drum can be helpful. Effective management of FVD involves reassurance, stress reduction and, if agreed on, management of comorbid anxiety and/or depression. The social cost of FVD is predominately economic as patients typically meet several healthcare providers over multiple visits and often undergo several neuroimaging studies before neuro-ophthalmology referral. Further, inappropriate granting of disability benefits confers additional stigma to patients with organic vision loss.
Burden of impaired awareness of hypoglycemia in people with diabetes undergoing hemodialysis
Authors: Habte-Asres Hellena Hailu , Jiang Yutong , Rosenthal Miranda , Wheeler David Collins
Published: February 2024

Introduction

Impaired awareness of hypoglycemia (IAH) refers to a diminished capacity to detect hypoglycemia. IAH can result in severe and even life-threatening outcomes for individuals with diabetes, especially those in advanced stages of the disease. This study aimed to assess the prevalence of IAH in people with diabetes on hemodialysis.

Research design and methods

We conducted a single-center audit to assess the prevalence of IAH using the Clarke questionnaire. Simultaneously, we measured fear of hypoglycemia with an adapted version of the Hypoglycemia Survey and recorded the incidence of severe hypoglycemia. Data were presented as mean±SD or counts/percentages. Logistic regression was then employed to analyze the association between IAH and various sociodemographic and clinical factors.

Results

We included 56 participants with diabetes on hemodialysis, with a mean age of 67.2 years (±12.9), of whom 51.8% were male. The ethnic distribution was 23.2% white, 23.2% black, 19.6% Asian, and 33.9% unspecified. The mean HbA1c was 52 mmol/mol (±18.6). The majority (91.1%) had a diagnosis of type 2 diabetes, and 55.4% of those were treated with insulin. The use of diabetes technology was low, with 2.8% of the participants using a continuous glucose monitor. IAH prevalence was 23.2%, and among the 57 participants, 23.6% had a history of severe hypoglycemia, and 60.6% reported fear of hypoglycemia. There were no significant differences in sociodemographic and clinical characteristics between those with IAH and normal hypoglycemia awareness.

Conclusions

We observed that 23.2% of individuals with diabetes undergoing hemodialysis had IAH. IAH was more prevalent in people who reported a fear of hypoglycemia and had a history of severe hypoglycemia episode. The study highlights the unmet needs and disparities in access to diabetes technology within this population.
CD, or not CD, that is the question: a digital interobserver agreement study in coeliac disease
Authors: Denholm James , Schreiber Benjamin A , Jaeckle Florian , Wicks Mike N , Benbow Emyr W , Bracey Tim S , Chan James Y H , Farkas Lorant , Fryer Eve , Gopalakrishnan Kishore , Hughes Caroline A , Kirkwood Kathryn J , Langman Gerald , Mahler-Araujo Betania , McMahon Raymond F T , Myint Khun La Win , Natu Sonali , Robinson Andrew , Sanduka Ashraf , Sheppard Katharine A , Tsang Yee Wah , Arends Mark J , Soilleux Elizabeth J
Published: February 2024

Objective

Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of immunoglobulin A tissue transglutaminase (IgA tTG) and haemoglobin (Hb) data improves the interobserver agreement of diagnosis.

Design

We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase 1, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase 2, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data.

Results

We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen’s kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen’s kappa coefficient of 0.67 (±0.09).

Conclusion

We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited interobserver agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the importance of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using artificial intelligence.
Performance of large language models on advocating the management of meningitis: a comparative qualitative study
Authors: Fisch Urs , Kliem Paulina , Grzonka Pascale , Sutter Raoul
Published: February 2024

Objectives

We aimed to examine the adherence of large language models (LLMs) to bacterial meningitis guidelines using a hypothetical medical case, highlighting their utility and limitations in healthcare.

Methods

A simulated clinical scenario of a patient with bacterial meningitis secondary to mastoiditis was presented in three independent sessions to seven publicly accessible LLMs (Bard, Bing, Claude-2, GTP-3.5, GTP-4, Llama, PaLM). Responses were evaluated for adherence to good clinical practice and two international meningitis guidelines.

Results

A central nervous system infection was identified in 90% of LLM sessions. All recommended imaging, while 81% suggested lumbar puncture. Blood cultures and specific mastoiditis work-up were proposed in only 62% and 38% sessions, respectively. Only 38% of sessions provided the correct empirical antibiotic treatment, while antiviral treatment and dexamethasone were advised in 33% and 24%, respectively. Misleading statements were generated in 52%. No significant correlation was found between LLMs’ text length and performance (r=0.29, p=0.20). Among all LLMs, GTP-4 demonstrated the best performance.

Discussion

Latest LLMs provide valuable advice on differential diagnosis and diagnostic procedures but significantly vary in treatment-specific information for bacterial meningitis when introduced to a realistic clinical scenario. Misleading statements were common, with performance differences attributed to each LLM’s unique algorithm rather than output length.

Conclusions

Users must be aware of such limitations and performance variability when considering LLMs as a support tool for medical decision-making. Further research is needed to refine these models' comprehension of complex medical scenarios and their ability to provide reliable information.
Waiting-list interventions for children and young people using child and adolescent mental health services: a systematic review
Authors: Valentine Althea Z , Hall Sophie S , Sayal Kapil , Hall Charlotte L
Published: February 2024

Question

Children and young people experience delays in assessment and/or treatment within mental health services. The objective of this systematic review, funded by the Emerging Minds Network, was to explore the current evidence base for mental health waiting list interventions to support children and young people.

Study selection and analysis

A literature search was conducted in MEDLINE, PsycINFO, Web of Science and the Cochrane databases from 2000 to 2023 (last searched October 2023). Included studies described interventions to support children and young people and/or their family while on a waiting list for child and adolescent mental health services. Titles and abstracts were screened independently by two reviewers, data were extracted by one reviewer, confirmed by a second and a narrative synthesis was provided.

Findings

Eighteen studies including 1253 children and young people were identified. Studies described waiting list interventions for autism spectrum disorders, eating disorders, generic conditions, transgender health, anxiety/depression, self-harm and suicide and behavioural issues. Many interventions were multicomponent; 94% involved psychoeducation, other components included parental support, bibliotherapy and coaching. Duration of the interventions ranged from a single session to over a year; 66% involved face-to-face contact. All studies demonstrated benefits in terms of improved clinical outcomes and/or feasibility/acceptability. Evidence for service outcomes/efficiency was largely unexplored. Limitations of the underpinning research, such as sample size and low-quality papers, limit the findings.

Conclusions

There is limited research exploring waiting list interventions, however, the findings from small-scale studies are promising. Further research using robust study designs and real-world implementation studies are warranted.