bluuebunny/crossref_metadata_2025 huggingface dataset:
PP82 Comparison Between Informal Caregiver Burden Of Patients With Alzheimer’s Disease Versus Other Chronic Diseases
Authors: Demirbas Murat , Hahn-Pedersen Julie Hviid , Jørgensen Henrik Løvendahl
Published: December 2023

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease with progressive neuropsychiatric symptoms. Patient care is often provided by informal caregivers similarly to various other chronic diseases. This targeted literature review assessed the difference in burden experienced by caregivers of people with AD in comparison to other chronic diseases.

Methods

Two separate search strings were developed to identify (i) caregiver burden in AD and (ii) caregiver burden in other chronic diseases using PubMed. Studies published in English (January 2012-October 2022) were included. Comparison of the caregiver burden was done using the weighted mean values (MV) of several questionnaires including the Zarit Burden Interview (ZBI), a 22-item self-report questionnaire for caregivers ranging from 0 to 88 points. ZBI is stratified into four categories of caregiving burden: Little or no burden (0 to 21), mild to moderate burden (22 to 40), moderate to severe burden (41 to 60) and severe burden (61 to 88).

Results

ZBI was the most frequently used questionnaire; 13 studies reported data on caregiver burden in AD and 39 studies reported data on 20 other chronic diseases. The caregiver burden ranged from 18 to 48 in AD, measured by ZBI. The MV of AD burden was 36 based on a total of 1,703 participants. The caregiver burden in other chronic diseases ranged from MV of 5 (chronic musculoskeletal pain) to 59 (bipolar disorder).

Measured by ZBI, AD burden on caregivers (MV: 36, range: 18-48) was greater than heart failure (MV: 27, range: 16-29) and type 2 diabetes (MV: 26, range: Not reported) but lesser than schizophrenia (MV: 56, range: 52-65) and bipolar disorder (MV: 59, range: Not reported).

Conclusions

AD has a significant burden on caregivers. When assessing the value of interventions targeting AD, the impact of AD on caregivers should be considered in addition to the impact of AD on patients. Further studies are required to assess the informal care burden in AD and other chronic diseases.
PP87 Glecaprevir/pibrentasvir (Maviret®) Remains A Cost-effective Treatment For Chronic Hepatitis C Virus Infection After Changes To The Treated Population
Authors: Castles Belinda , Warren Emma , Sharratt Gillian , Arteaga Aitor
Published: December 2023

Introduction

The first direct-acting antiviral (DAA) therapies for chronic Hepatitis C virus (HCV) infection were reimbursed via Australia’s Pharmaceutical Benefits Scheme (PBS) in March 2016. This was based on the recommendation from the Pharmaceutical Benefits Advisory Committee (PBAC) that the regimens would be acceptably cost-effective at an incremental cost-effectiveness ratio (ICER) of AUD15,000/quality-adjusted life-year (QALY). Broad access to DAA therapies has been a key strategy in driving a national health goal to eliminate viral hepatitis as a major health threat by 2030. Since the initial PBS listings for DAA therapies and subsequent listings of newer DAA treatments such as Maviret, the demographics and disease characteristics of currently treated patients have markedly changed. The aim of our analysis was to reassess the cost-effectiveness of Maviret, accounting for the changes of the treated population characteristics and retreatment in first-line failures and reinfected individuals.

Methods

To assess the cost-effectiveness six years after initial listing of Maviret, an update was made to the Markov model used to achieve PBS reimbursement for Viekira-Pak® in May 2016. Amendments to the Viekira-Pak model include: changes to baseline age and fibrosis distribution of treated patients, and incorporation of retreatment of first-line failures (those not achieving a sustained virologic response (SVR)) and reinfected individuals. Treatment-related inputs including SVR response rates, adverse events, treatment-related disutility and discontinuations were sourced from pivotal glecaprevir/pibrentasvir clinical trials.

Results

Using the published price of Maviret, the ICER is above AUD15,000/QALY but well below the commonly used ICER threshold in other chronic diseases (AUD45,000/QALY). When the confidential effective price is used, the ICER is under the AUD15,000/QALY cost-effectiveness threshold set by the PBAC for DAA therapies.

Conclusions

Despite substantial changes to the population seeking treatment in Australia since reimbursement in 2016, Maviret remains a cost-effective treatment for chronic HCV infection.
PP98 Phelan-McDermid syndrome: Methodology For Creating A Patient Adapted Version Of A Clinical Practice Guideline
Authors: Dominguez Josune , López-Argumedo Marta , Carmona-Hidalgo Beatriz , Gaasterland Charlotte , Klein Mirthe , Blasco Juan Antonio
Published: December 2023

Introduction

Phelan-McDermid syndrome (PMS) is a chromosomal disorder caused by the loss of the end of chromosome 22, that is manifested as a neurodevelopmental disorder. Providing an adapted version of a guideline was seen as essential, as currently, there are no such booklets based on an international guideline for PMS patients, families and caregivers. The European Reference Networks (ERN) Guidelines programme results from a call for proposals funded (DG SANTE/2018/B3/030) for the development of Clinical Practice Guidelines (CPG) and Clinical Decision Tools in the area of rare diseases. Based on this European consortium, the purpose of this study is to describe how two Spanish HTA agencies, OSTEBA-BIOEF (Basque Office for Health Technology Assessment) and AETSA (Andalusian Health Quality Assessment Department) methodologically support the ERN-ITHACA (Rare malformation syndromes and rare intellectual and neurodevelopmental disorders) in the development of a comprehensive patient booklet based on a CPG to be used as an adjunct in the management of PMS syndrome that will be published in 2023.

Methods

A preliminary booklet was created by HTA agencies using the new European guideline for PMS and a Dutch guideline. The booklet structure is an adaptation based on a European Commission template with the guidance of the methodological Handbook#11.

Results

Through a comprehensive adaptation, following the PMS guideline and the Handbook #11, a booklet is developed for the PMS patients. Composed by 28 pages in DIN A5 format were introduction, diagnosis, treatment, pregnancy, do’s, supportive care, social networks (including a QR code) and a glossary are included. The selection of a symbol, colors at a chromatic level, a typography and graphical elements as illustrations were created as a corporate identity. Clinical experts and patient representatives that have participated in the creation of the guideline will assess and validate the booklet.

Conclusions

Collaboration between agencies, clinicians and patients is critical to obtain evidence-based products adapted to the needs of patients and people involved in their care.
PP121 Assessment Of Heart Rate Characteristics Analysis
Authors: Kim Yoo Jin , Lee Worl Sook
Published: December 2023

Introduction

The heart rate characteristics (HRC) analysis is a technique for predicting and monitoring neonatal infectious diseases in infants with a risk for infectious disease, such as sepsis, using the HRC index based on the electrocardiogram (ECG) data transmitted from a HeRO® device connected to an ECG monitor.

Methods

The assessments were performed via a systematic review. Searching five databases (KoreaMed, Ovid-MEDLINE, Ovid-EMBASE, and Cochrane) yielded 284 related studies. Two reviewers independently assessed the quality of these studies, using the Scottish Intercollegiate Guidelines Network checklist and the assessment results were described based on the results of the quality appraisal and level of evidence.

Results

The safety and effectiveness of the technique were assessed based on eight non-Korean studies (one randomized controlled trial (RCT), five cohort studies, one case-control study, one case series). The four studies that reported area under the curve (AUC) values, the timing of the analysis and AUC values (0.67– 0.75) were inconsistent among the studies. The elevation of the HRC index prior to the diagnosis of an infectious disease was not observed for meningitis or for multiple infectious diseases. In addition, although the group with additional monitoring using the technique had a significantly lower mortality rate, whether the HRC index had a direct impact on the infection prevention activities and the possibility of bias arising from the researchers’ precautionary treatment based on the clinical symptoms and other test results as well as the actual time of disease onset are unknown.

Conclusions

Therefore, the committee presented the following recommendations based on the available evidence and expert opinion. HRC analysis is a safe technique for predicting and monitoring neonatal infectious diseases in infants with a risk for infectious disease, such as sepsis, using the HRC index based on the ECG data transmitted from a HeRO® device connected to an ECG monitor; however, further research is needed to determine its effectiveness (Level of evidence C, Technology category II-a).
PP129 Health Technology Assessment Adaptation: Pharyngolaryngeal Biopsies (OLB) For People with Suspected Head and Neck Cancer in the Outpatient Setting
Authors: Bowles Charlotte , Boyce Rebecca , Hopkin Gareth , Prettyjohns Matthew , Hughes Sophie , Hasler Elise , McDermott Katie , Myles Susan
Published: December 2023

Introduction

In the UK over 12,400 yearly cases of head and neck cancers are reported (2021). Pharyngolaryngeal biopsies (OLB) may improve the speed of diagnosis and treatment of head and neck cancers under local anesthetic. The Scottish Health Technologies Group (SHTG) published advice on this technology in 2018. Since this, additional evidence has been published to warrant a health technology assessment (HTA) for Wales. The aim of this review was to provide update on the clinical and cost-effectiveness of OLB when compared to undergoing biopsy in an operating theatre (OTB) under general anesthetic to inform decision making in Wales.

Methods

A rapid review was undertaken of relevant databases since 2018 of the clinical evidence, health economics and patient perspectives relevant to Wales. Health Technology Wales (HTW) developed a de-novo cost-utility analysis comparing OLB to OTB over a lifetime horizon. Inputs were sourced from the SHTG budget impact analysis, updated with values more relevant to a Welsh setting.

Results

From consultation to biopsy procedure, the mean number of days was 1.3 for OLB compared to 17.4 days under OTB (p < 0.05). The mean time from consultation to start of treatment was 27 days for OLB compared to 41.5 days for OTB (p < 0.05). The economic analysis found a resulting ICER of GBP21,011 (EUR23,824.23) in a population with 2,183 at risk patients. As OLB was associated with lower costs (GBP816 per person) (EUR925.26) and fewer quality adjusted life years than OTB (-0.04), this ICER corresponds to OLB being considered a cost-effective diagnostic strategy.

Conclusions

HTW guidance was able to recommend use of OLB within the diagnostic pathway for head and neck cancers within Wales. For people with a positive test, OLB is sufficient to confirm a diagnosis but should not be used to rule out a diagnosis due to the potential in reducing the time to diagnosis and treatment in a cost-saving way.
PP147 What Does Real World Evidence (RWE) Offer Health Technology Assessment (HTA) Procedures In Australia?
Authors: Challis Gabrielle , Hill Michelle , Strachan Liesl , King Kate , Shawon Shajedur Rahman , Sotade Oluwadamisola , Jorm Louisa
Published: December 2023

Introduction

Medical device health technology assessment (HTA) in Australia is largely coordinated by the Medical Services Advisory Committee (MSAC). Its remit to improve the public’s health by deciding where to allocate public healthcare funding, can be enhanced by considering real world evidence (RWE). Existing data sources have limitations that can be addressed through RWE, including coverage of Australian patient populations who may not meet trial eligibility criteria, and long-term follow-up through data linkage and datasets. We partnered with a university to explore what information could be gained from an analysis of linked administrative patient data, with a view to addressing current evidence gaps and/or limitations. The findings can be used as a source of local data to define patient populations, estimate actual costs of care, and enable more comprehensive economic modeling to inform medical device HTA.

Methods

The University-developed New South Wales Cardiovascular Cohort dataset, comprising person-level longitudinal NSW administrative data for all patients admitted to hospital with a cardiovascular diagnosis from 2001 onwards, linked to national Medicare Benefits Schedule and Pharmaceutical Benefits Scheme claims data, was interrogated.

Results

Working with RWE is resource intensive in terms of time and costs. The potential of these data was revealed as the research progressed. It was possible to continually refine the data analyzed and reported,as well as expand the data requested. Varied expertise is required to accurately analyze the administrative datasets, particularly clinical classification skills and expertise in methods for causal inference using observational data. Findings from this study will enable the refinement of information for MSAC submissions, including identifying the most relevant patient population and reporting comprehensive costs, beyond an admitted hospital setting. The data will enhance engagement with clinicians and refine messaging, for example regarding patient risk factors.

Conclusions

RWE enhances Australian HTA applications. Local data, extended periods of time and insights not apparent from a focus on admitted hospital episodes can be revealed. Data can be refined during the process for specificity and applicability.
PP149 Reengineering Of Processes For The Elaboration Of Health Technology Assessment Reports In Catalonia
Authors: Estrada Maria-Dolors , Ruiz-Baena Jessica , Pastells-Peiró Roland , Gallastegui-Calvache Edurne , Godo Anna , Llinàs-Mallol Laura , Martinez-Diaz Pablo , Mestre-Lleixà Berta , Moltó-Puigmartí Carolina , Pérez-Troncoso Daniel , Ramos-Masdeu Laia , Segur-Ferrer Joan , Solís-Díez Gerard , Vivanco-Hidalgo Rosa Maria
Published: December 2023

Introduction

In order to increase the value of its services and activities, the Agency for Health Quality and Assessment of Catalonia (AQuAS) has incorporated in its strategic plan the commitment to improve the processes, quality and people, while ensuring transparency, independence, rigor and efficiency following the guidelines of the European Foundation for Quality Management. We aim to present the standardization processes to improve the efficiency in elaborating health technology assessment (HTA) reports at AQuAS.

Methods

Process standardization has been developed in seven stages: (i) definition of scope, objectives and creation of working groups; (ii) mapping and analysis of all ongoing processes to determine whether they needed improvement or were already optimal; (iii) creation of new processes by evaluating the inclusion of automatic tools and their possible digitization; (iv) creation of the process map; (v) communication to the team for its implementation after training; (vi) dissemination on corporate website; (vii) monitoring and evaluation of their impact.

Results

The creation of AQuAS’ HTA report development process map has involved 14 people over the past two years. After an initial two-day workshop, the team was organized in working groups of two to three people, with regular monitoring and the creation of a specific knowledge management unit led by the AQuAS’ evaluation manager. The process map was configured based on three axes. The strategic axis contains legal frameworks, ethical principles, good practices and methodological frameworks (29 specific for HTA reports). The key axis presents in an integrated way the process and methodology followed from the request of the HTA report to the final product’s dissemination. The support axis includes, among other, the management of 31 requests, information specialist processes (37 searches), training (51 courses) and 6 internal procedures with their corresponding 26 templates and 27 tools.

Conclusions

With a process reengineering approach, HTA reporting has become more efficient. We believe this approach can help other agencies improve their internal processes and subsequently improve team and customer satisfaction.
Oscar DePriest and Black Agency in American Politics, 1928–1934
Authors: TEAGUE GREYSON
Published: December 2023

Currently, much of the literature surrounding Black politics in the 1920s and 1930s understates the role that Black citizens and politicians played in challenging Jim Crow and white supremacy at the national level. Instead, different factors like the “cage” that white Southerners placed on Civil Rights legislation or the influence that New Deal programs had on electoral decisions in the Black community. After realignment, Black Americans and their allies were then able to launch more effective challenges against white supremacy. Although these narratives contain much explanatory power, oftentimes they overlook critical aspects of Black politics during this period that complicate this narrative. Examining the career of Oscar DePriest, the first Black congressman elected in the twentieth Century, this article argues that Black citizens and their representatives were able to explicitly affect politics at the local, state, and federal levels through DePriest’s career prior to realignment.
Variational inequalities arising from credit rating migration with buffer zone
Authors: Chen Xinfu , Liang Jin
Published: December 2023

In Chen and Liang previous work, a model, together with its well-posedness, was established for credit rating migrations with different upgrade and downgrade thresholds (i.e. a buffer zone, also called dead band in engineering). When positive dividends are introduced, the model in Chen and Liang (SIAM Financ. Math.12, 941–966, 2021) may not be well-posed. Here, in this paper, a new model is proposed to include the realistic nonzero dividend scenarios. The key feature of the new model is that partial differential equations in Chen and Liang (SIAM Financ. Math.12, 941–966, 2021) are replaced by variational inequalities, thereby creating a new free boundary, besides the original upgrading and downgrading free boundaries. Well-posedness of the new model, together with a few financially meaningful properties, is established. In particular, it is shown that when time to debt paying deadline is long enough, the underlying dividend paying company is always in high grade rating, that is, only when time to debt paying deadline is within a certain range, there can be seen the phenomenon of credit rating migration.
Different interlocutors, different EFL interactional strategies: A case study of intercultural telecollaborative projects in secondary classrooms
Authors: Chimeva Yordanka , Trenchs-Parera Mireia
Published: December 2023

The purpose of this article is to investigate the interactional strategies that secondary school EFL learners use during telecollaboration with interlocutors from a different cultural and linguistic background. Its novelty lies in the educational level and cultural contexts explored as well as in the goal of examining whether frequency of strategy use may depend on the interlocutor and, if so, what the relevant factors are for such variation. The study focuses on two projects in which 10 participants from one Bulgarian school and 18 partners from two schools in Spain took part in dyadic synchronous videoconferences discussing culture-related topics. Data were collected via video recordings, field observations, semi-structured interviews, and questionnaires. The article presents both descriptive statistics and qualitative analysis of the communicative behavior of three case study students interacting with different telecollaborative partners. We found that the participants demonstrate differences in interactional behavior and utilize strategies with varying frequency depending on their interlocutor. The results also reveal crucial factors in the design of telecollaborative educational projects if learners are to successfully implement skills of discovery and interaction in real time.
Astroecology: bridging the gap between ecology and astrobiology
Authors: Meurer Juliana Campos , Haqq-Misra Jacob , Mendonça Milton de Souza
Published: December 2023

Although astrobiology studies how life functions and evolves, ecology is still largely overlooked in astrobiology research. Here we present an argument for astroecology, a merger of ecology and astrobiology, a self-aware scientific endeavour. Ecology is rarely mentioned in influential documents like the NASA Astrobiology Strategy (2015), and terms such as ‘niche’ can end up being used in a less precise fashion. As ecology deals with sequential levels of organization, we suggest astrobiologically-relevant problems for each of these levels. Organismal ecology provides ecological niche modelling, which can aid in evaluating the probability that Earth-like life would survive in extraterrestrial environments. Population ecology provides a gamut of models on the consequences of dispersal, and if lithopanspermia can be validated as a form of space dispersal for life, then metabiospheres and similar astrobiological models could be developed to understand such complex structure and dynamics. From community ecology, the discussion of habitability should include the concept of true vacant habitats (a misnomer, perhaps better called ‘will-dwells’) and contributions from the blossoming field of microbial ecology. Understanding ecosystems by focusing on abiotic properties is also key to extrapolating from analogue environments on Earth to extraterrestrial ones. Energy sources and their distribution are relevant for ecological gradients, such as the biodiversity latitudinal gradient – would tropics be species-rich in other inhabited planets? Finally, biosphere ecology deals with integration and feedback between living and non-living systems, which can generate stabilized near-optimal planetary conditions (Gaia); but would this work for other inhabited planets? Are there ‘strong’ (like Earth) and ‘weak’ (perhaps like Mars) biospheres? We hope to show ecology can contribute relevant ideas to the interdisciplinary field of astrobiology, helping conceptualize further levels of integration. We encourage new partnerships and for astrobiologists to take ecology into account when studying the origin, evolution and distribution of life in the universe.
Comparing Local Versus Hemispheric Perspectives of Extreme Heat Events
Authors: Van Loon Senne , Thompson David W. J.
Published: December 2023

We compare insights provided by local and large‐scale perspectives of extreme heat events in ERA5 near‐surface temperature data. Heat waves where temperatures exceed four standard deviations about the climatological‐mean are expected less than once a century locally but occur roughly once every 10 days somewhere in the Northern Hemisphere midlatitudes. The high frequency of occurrence indicated by the hemispheric perspective is not well represented by normal statistics because it strongly depends on the shapes of the local temperature distributions. The large effective sample size afforded by the hemispheric perspective provides robust evidence of trends in the frequency of occurrence of extreme heat events integrated over the Northern Hemisphere. It also confirms that trends in heat events summed over the hemisphere can be explained by changes in mean temperature alone.
On the Vertical Structure of Mesoscale Eddies in the Kuroshio‐Oyashio Extension
Authors: Yao H. , Ma C. , Jing Z. , Zhang Z.
Published: December 2023

Vertical structure of mesoscale eddies is key to the eddy‐induced heat/material transport that further affects the climate and marine ecosystem. This study explores the vertical structure of mesoscale eddies in the Kuroshio‐Oyashio Extension region (KOE) and its underlying dynamics. By applying the hierarchical ascending classification to the observational and reanalysis data sets, we classify mesoscale eddies with three distinct kinds of vertical structures. Each kind of eddies exhibits clear spatial aggregation along a distinct zonal band. Eddies have core depths of 100–300 m in the northern part of the KOE and core depths of 300–500 m and 0–100 m in the southern. The eddy splitting or merging does not introduce new kind of eddy vertical structure but causes large intra‐kind variability. The different kinds of eddy vertical structures can be partially accounted for by the baroclinic instabilities at the eddy generation sites and local adjustment process.
Equatorial Electrojet (EEJ) Response to Interplanetary (IP) Shocks
Authors: Nilam B. , Tulasi Ram S. , Ankita M. , Oliveira Denny M. , Dimri A. P.
Published: December 2023

Interplanetary (IP) shocks are known to cause significant modifications in Earth's magnetospheric and ionospheric current systems. The sudden enhancement of solar wind dynamic pressure (PDyn) associated with IP shocks could induce convection electric fields at high‐latitude ionosphere which can promptly penetrate to equatorial and low‐latitude regions. Additionally, prompt penetration electric field disturbances may also be induced due to the sudden southward/northward turnings of the Interplanetary Magnetic Field (IMF Bz) (eastward/westward turnings of the interplanetary electric field, IEFy) during IP shocks. The resultant electric field disturbances can significantly alter the ionospheric electrodynamics and equatorial electrojet (EEJ). In this study, the EEJ response to a large number of IP shocks that occurred during 2001–2021 has been investigated. The magnitude of the EEJ response to IP shocks shows a clear local time dependence and varies linearly with the change in solar wind dynamic pressure. The EEJ response is also found to depend considerably on the solar activity (F10.7 solar flux) and the polarity changes in IMF Bz associated with IP shocks. For the first time, an empirical relation is derived that can quantitatively estimate the EEJ response to IP shocks using a large number (306) of events that occurred over a span of two solar cycles. The derived empirical relation is found to be very accurate in predicting the response of the EEJ and exhibits an excellent correlation with observations.
The Effect of Magma Poor and Magma Rich Rifted Margins on Continental Collision Dynamics
Authors: Turino V. , Magni V. , Kjøll H. J. , Jakob J.
Published: December 2023

The transition between non‐rifted continental lithosphere and oceanic lithosphere in rifted margins can display a wide range of characteristics, depending on the regional tectonic evolution. The velocity and duration of the rifting process as well as the geodynamic setting influence the properties and geometry of the margins, which are often grouped into two main categories: magma‐poor and magma‐rich. We show how different types of rifted margins can influence the dynamics of continental collision, focusing on the time and depth of slab break‐off after collision and the fate of margin material. We find that rifted margins have a noticeable impact on subduction dynamics, as we observe large variability in slab break‐off times and depths. In particular, the presence of a rifted margin can delay slab break‐off to up to 60 Myr after the onset of collision. Our results show that a large portion of the weak crust of magma‐poor margins is likely to detach from the subducting plate and accrete to the upper plate, while the dense and strong mafic and ultramafic component of magma‐rich margins causes most of the margin to subduct and be lost into the mantle, leaving only a small fraction of transitional and oceanic crust at the surface. Therefore, the volume of accreted material is much larger when the margin is magma‐poor than magma‐rich, which is consistent with geological observations that fossil magma‐poor rifted margins are preserved in many mountain ranges, whereas remnants of magma‐rich rifted margins are scarce.
High‐Resolution, Multiproxy Speleothem Record of the 8.2 ka Event From Mainland Southeast Asia
Authors: Wood Christopher T. , Johnson Kathleen R. , Lewis Lindsey. E. , Wright Kevin , Wang Jessica K. , Borsato Andrea , Griffiths Michael L. , Mason Andrew , Henderson Gideon M. , Setera Jacob B. , Frisia Silvia , Keophanhya Sengphone , White Joyce C.
Published: December 2023

The 8.2 ka event is the most significant global climate anomaly of the Holocene epoch, but a lack of records from Mainland Southeast Asia (MSEA) currently limits our understanding of the spatial and temporal extent of the climate response. A newly developed speleothem record from Tham Doun Mai Cave, Northern Laos provides the first high‐resolution record of this event in MSEA. Our multiproxy record (δ18O, δ13C, Mg/Ca, Sr/Ca, and petrographic data), anchored in time by 9 U‐Th ages, reveals a significant reduction in local rainfall amount and weakening of the monsoon at the event onset at ∼8.29 ± 0.03 ka BP. This response lasts for a minimum of ∼170 years, similar to event length estimates from other speleothem δ18O monsoon records. Interestingly, however, our δ13C and Mg/Ca data, proxies for local hydrology, show that abrupt changes to local rainfall amounts began decades earlier (∼70 years) than registered in the δ18O. Moreover, the δ13C and Mg/Ca also show that reductions in rainfall continued for at least ∼200 years longer than the weakening of the monsoon inferred from the δ18O. Our interpretations suggest that drier conditions brought on by the 8.2 ka event in MSEA were felt beyond the temporal boundaries defined by δ18O‐inferred monsoon intensity, and an initial wet period (or precursor event) may have preceded the local drying. Most existing Asian Monsoon proxy records of the 8.2 ka event may lack the resolution and/or multiproxy information necessary to establish local and regional hydrological sensitivity to abrupt climate change.
The intrinsic defects of T cells impact the efficacy of CAR-T therapy in patients with diffuse large B-cell lymphoma
Authors: Zhao Jinrong , Wei Chong , Wang Shuqing , Zhang Yan , Wang Wei , Zhao Danqing , Wang Zi , Zhou Zhipeng , Bai Jing , Zhang Wei , Zhou Daobin
Published: December 2023

CAR-T cell therapy did not achieve the desired efficacy in some patients with diffuse large B-cell lymphoma (DLBCL). We conducted single-cell RNA and TCR sequencing as well as methylation chip profiling of peripheral blood samples in DLBCL patients. Patients who achieved complete remission (CR) showed an upward trend in T-cell levels, especially CD8-effector T cells. The responders exhibited T-cell clone expansion, more active T-cell transformation, and frequent cell communication. Highly expressed genes in the CR group were enriched in functions like leukocyte-mediated cytotoxicity and activation of immune response, while the non-CR group was enriched in pathways related to DNA damage and P53-mediated intrinsic apoptotic. More differentially methylated probes (DMPs) were identified in the baseline of the non-CR group (779 vs 350). GSEA analysis revealed that the genes annotated by DMPs were associated with cellular immune functions in T cells, including the generation of chemokines, leukocyte-mediated cytotoxicity, and cell-killing functions. The genes with low expression in the non-CR group exhibited a high methylation status. There is heterogeneity in the cellular, molecular, and epigenetic characteristics of host T cells in patients with different clinical outcomes. Intrinsic defects in T cells are important factors leading to poor efficacy of CAR-T therapy.
Sensory nerves directly promote osteoclastogenesis by secreting peptidyl-prolyl cis-trans isomerase D (Cyp40)
Authors: Li Junqin , Liu Bin , Wu Hao , Zhang Shuaishuai , Liang Zhuowen , Guo Shuo , Jiang Huijie , Song Yue , Lei Xing , Gao Yi , Cheng Pengzhen , Li Donglin , Wang Jimeng , Liu Yang , Wang Di , Zhan Nazhi , Xu Jing , Wang Lin , Xiao Guozhi , Yang Liu , Pei GuoXian
Published: December 2023

Given afferent functions, sensory nerves have recently been found to exert efferent effects and directly alter organ physiology. Additionally, several studies have highlighted the indirect but crucial role of sensory nerves in the regulation of the physiological function of osteoclasts. Nonetheless, evidence regarding the direct sensory nerve efferent influence on osteoclasts is lacking. In the current study, we found that high levels of efferent signals were transported directly from the sensory nerves into osteoclasts. Furthermore, sensory hypersensitivity significantly increased osteoclastic bone resorption, and sensory neurons (SNs) directly promoted osteoclastogenesis in an in vitro coculture system. Moreover, we screened a novel neuropeptide, Cyp40, using an isobaric tag for relative and absolute quantitation (iTRAQ). We observed that Cyp40 is the efferent signal from sensory nerves, and it plays a critical role in osteoclastogenesis via the aryl hydrocarbon receptor (AhR)-Ras/Raf-p-Erk-NFATc1 pathway. These findings revealed a novel mechanism regarding the influence of sensory nerves on bone regulation, i.e., a direct promoting effect on osteoclastogenesis by the secretion of Cyp40. Therefore, inhibiting Cyp40 could serve as a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.
PDIA6, which is regulated by TRPM2-AS/miR-424-5p axis, promotes endometrial cancer progression via TGF-beta pathway
Authors: Wang Pengling , Zhang Tianli , Jiang Nan , Wang Kun , Feng Liping , Liu Ting , Yang Xingsheng
Published: December 2023

PDIA6 have been reported to be involved in a variety of cancers, however, the underlying role in endometrial cancer is still unclear. In this study, we aimed to study the function of PDIA6 in endometrial cancer. Firstly, we verified that PDIA6 was significantly upregulated in endometrial cancer, which was correlated with the progression of endometrial cancer patients. Furthermore, we identified PDIA6 significantly altered the ability of endometrial cancer cells to proliferate and metastasize. In addition, our result illustrated the oncogene effects of PDIA6 in promoting malignant biological behavior of endometrial cancer cells by regulating TGF-β pathway and being modulated by TRPM2-AS/miR-424-5p axis for the first time. Taken together, this study suggested that PDIA6 may be a new candidate target for endometrial cancer therapy.
The E3 ubiquitin ligase NEDD4 regulates chemoresistance to 5-fluorouracil in colorectal cancer cells by altering JNK signalling
Authors: Anand Sushma , Nedeva Christina , Chitti Sai V. , Fonseka Pamali , Kang Taeyoung , Gangoda Lahiru , Tabassum Nishat I. , Abdirahman Suad , Arumugam Thiruma V. , Putoczki Tracy L. , Kumar Sharad , Mathivanan Suresh
Published: December 2023

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Though chemotherapy is the main treatment option for advanced CRC, patients invariably acquire resistance to chemotherapeutic drugs and fail to respond to the therapy. Although understanding the mechanisms regulating chemoresistance has been a focus of intense research to manage this challenge, the pathways governing resistance to drugs are poorly understood. In this study, we provide evidence for the role of ubiquitin ligase NEDD4 in resistance developed against the most commonly used CRC chemotherapeutic drug 5-fluorouracil (5-FU). A marked reduction in NEDD4 protein abundance was observed in a panel of CRC cell lines and patient-derived xenograft samples that were resistant to 5-FU. Knockout of NEDD4 in CRC cells protected them from 5-FU-mediated apoptosis but not oxaliplatin or irinotecan. Furthermore, NEDD4 depletion in CRC cells reduced proliferation, colony-forming abilities and tumour growth in mice. Follow-up biochemical analysis highlighted the inhibition of the JNK signalling pathway in NEDD4-deficient cells. Treatment with the JNK activator hesperidin in NEDD4 knockout cells sensitised the CRC cells against 5-FU. Overall, we show that NEDD4 regulates cell proliferation, colony formation, tumour growth and 5-FU chemoresistance in CRC cells.
The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression
Authors: Chen Sisi , Zhou Binghai , Huang Wei , Li Qing , Yu Ye , Kuang Xiuqing , Huang Huabin , Wang Wei , Xie Peiyi
Published: December 2023

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin‐specific peptidase 44 (USP44), a member of the deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments. Through quantitative proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression by downregulating the Hedgehog (Hh) signaling pathway. Mechanistically, we found that USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch. These events result in the proteasomal degradation of Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses PDL1 expression and the progression of HCC. Furthermore, the HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. Finally, the Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling, and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients.
A novel circular RNA, circMAML3, promotes tumor progression of prostate cancer by regulating miR-665/MAPK8IP2 axis
Authors: Zhenhao Zeng , Ru Chen , Xiaofeng Cheng , Heng Yang , Gongxian Wang
Published: December 2023

Many studies have now demonstrated that circRNAs are aberrantly expressed in cancer and are involved in the regulation of malignant tumor progression. However, the role of circMAML3 (hsa_circ_0125392) in prostate cancer has not been reported. circMAML3 was selected from public data through screening. The circMAML3 circular characterization was performed using Sanger sequencing, agarose gel electrophoresis assay, RNase R assay and actinomycin D assay. The expression of circMAML3 in prostate cancer tissues and cells was detected by qRT-PCR. In vivo and in vitro experiments were conducted to investigate the biological functions of circMAML3 in prostate cancer. Finally, the underlying mechanism of circMAML3 was revealed by qRT-PCR, luciferase reporter assay, miRNA Pulldown, RNA immunoprecipitation, western blotting, and rescue assay. Compared to normal prostate tissue and prostate epithelial cells, circMAML3 is highly expressed in prostate cancer tissues and cell lines. CircMAML3 overexpression promotes prostate cancer proliferation and metastasis, while knockdown of circMAML3 exerts the opposite effect. Mechanistically, circMAML3 promotes prostate cancer progression by upregulating MAPK8IP2 expression through sponge miR-665. Our research indicates that circMAML3 promotes prostate cancer progression through the circMAML3/miR-665/MAPK8IP2 axis. circMAML3 and MAPK8IP2 are upregulated in prostate cancer expression and play an oncogenic role, whereas miR-665 is downregulated in prostate cancer and plays an oncogenic role. Therefore, CircMAML3 may be a potential biomarker for prostate cancer diagnosis, treatment and prognosis.
Binge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Authors: Ding Chengyi , Ng Fat Linda , Britton Annie , Im Pek Kei , Lin Kuang , Topiwala Anya , Li Liming , Chen Zhengming , Millwood Iona Y. , Bell Steven , Mehta Gautam
Published: December 2023

Alcohol-related liver disease (ARLD) represents a major public health burden. Identification of high-risk individuals would allow efficient targeting of public health interventions. Here, we show significant interactions between pattern of drinking, genetic predisposition (polygenic risk score, PRS) and diabetes mellitus, and risk of incident ARLD, in 312,599 actively drinking adults in UK Biobank. Binge and heavy binge drinking significantly increase the risk of alcohol-related cirrhosis (ARC), with higher genetic predisposition further amplifying the risk. Further, we demonstrate a pronounced interaction between heavy binge drinking and high PRS, resulting in a relative excess risk due to interaction (RERI) of 6.07. Diabetes consistently elevates ARC risk across all drinking and PRS categories, and showed significant interaction with both binge patterns and genetic risk. Overall, we demonstrate synergistic effects of binge drinking, genetics, and diabetes on ARC, with potential to identify high-risk individuals for targeted interventions.
A computational toolbox for the assembly yield of complex and heterogeneous structures
Authors: Curatolo Agnese I. , Kimchi Ofer , Goodrich Carl P. , Krueger Ryan K. , Brenner Michael P.
Published: December 2023

The self-assembly of complex structures from a set of non-identical building blocks is a hallmark of soft matter and biological systems, including protein complexes, colloidal clusters, and DNA-based assemblies. Predicting the dependence of the equilibrium assembly yield on the concentrations and interaction energies of building blocks is highly challenging, owing to the difficulty of computing the entropic contributions to the free energy of the many structures that compete with the ground state configuration. While these calculations yield well known results for spherically symmetric building blocks, they do not hold when the building blocks have internal rotational degrees of freedom. Here we present an approach for solving this problem that works with arbitrary building blocks, including proteins with known structure and complex colloidal building blocks. Our algorithm combines classical statistical mechanics with recently developed computational tools for automatic differentiation. Automatic differentiation allows efficient evaluation of equilibrium averages over configurations that would otherwise be intractable. We demonstrate the validity of our framework by comparison to molecular dynamics simulations of simple examples, and apply it to calculate the yield curves for known protein complexes and for the assembly of colloidal shells.
Dietary circadian rhythms and cardiovascular disease risk in the prospective NutriNet-Santé cohort
Authors: Palomar-Cros Anna , Andreeva Valentina A. , Fezeu Léopold K. , Julia Chantal , Bellicha Alice , Kesse-Guyot Emmanuelle , Hercberg Serge , Romaguera Dora , Kogevinas Manolis , Touvier Mathilde , Srour Bernard
Published: December 2023

Daily eating/fasting cycles synchronise circadian peripheral clocks, involved in the regulation of the cardiovascular system. However, the associations of daily meal and fasting timing with cardiovascular disease (CVD) incidence remain unclear. We used data from 103,389 adults in the NutriNet-Santé study. Meal timing and number of eating occasions were estimated from repeated 24 h dietary records. We built multivariable Cox proportional-hazards models to examine their association with the risk of CVD, coronary heart disease and cerebrovascular disease. In this study, having a later first meal (later than 9AM compared to earlier than 8AM) and last meal of the day (later than 9PM compared to earlier than 8PM) was associated with a higher risk of cardiovascular outcomes, especially among women. Our results suggest a potential benefit of adopting earlier eating timing patterns, and coupling a longer nighttime fasting period with an early last meal, rather than breakfast skipping, in CVD prevention.
Chronic exposure to environmental temperature attenuates the thermal sensitivity of salmonids
Authors: González-Ferreras Alexia M. , Barquín Jose , Blyth Penelope S. A. , Hawksley Jack , Kinsella Hugh , Lauridsen Rasmus , Morris Olivia F. , Peñas Francisco J. , Thomas Gareth E. , Woodward Guy , Zhao Lei , O’Gorman Eoin J.
Published: December 2023

Metabolism, the biological processing of energy and materials, scales predictably with temperature and body size. Temperature effects on metabolism are normally studied via acute exposures, which overlooks the capacity for organisms to moderate their metabolism following chronic exposure to warming. Here, we conduct respirometry assays in situ and after transplanting salmonid fish among different streams to disentangle the effects of chronic and acute thermal exposure. We find a clear temperature dependence of metabolism for the transplants, but not the in-situ assays, indicating that chronic exposure to warming can attenuate salmonid thermal sensitivity. A bioenergetic model accurately captures the presence of fish in warmer streams when accounting for chronic exposure, whereas it incorrectly predicts their local extinction with warming when incorporating the acute temperature dependence of metabolism. This highlights the need to incorporate the potential for thermal acclimation or adaptation when forecasting the consequences of global warming on ecosystems.
Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Authors: Hall Steven R. , Rasmussen Sean A. , Crittenden Edouard , Dawson Charlotte A. , Bartlett Keirah E. , Westhorpe Adam P. , Albulescu Laura-Oana , Kool Jeroen , Gutiérrez José María , Casewell Nicholas R.
Published: December 2023

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.