bluuebunny/crossref_metadata_2025 huggingface dataset:
Entomological survey of sibling species in the Anopheles funestus group in Tanzania confirms the role of Anopheles parensis as a secondary malaria vector
Authors: Mapua Salum Abdallah , Samb Badara , Nambunga Ismail Hassan , Mkandawile Gustav , Bwanaly Hamis , Kaindoa Emmanuel Wilson , Odero Joel Ouma , Masalu John Paliga , Kahamba Najat Feruz , Hape Emmanuel Elirehema , Govella Nicodem James , Okumu Fredros Oketch , Tripet Frederic
Published: June 2024

Background

Malaria transmission in Tanzania is driven by mosquitoes of the Anopheles gambiae complex and Anopheles funestus group. The latter includes An. funestus s.s., an anthropophilic vector, which is now strongly resistant to public health insecticides, and several sibling species, which remain largely understudied despite their potential as secondary vectors. This paper provides the initial results of a cross-country study of the species composition, distribution and malaria transmission potential of members of the Anopheles funestus group in Tanzania.

Methods

Mosquitoes were collected inside homes in 12 regions across Tanzania between 2018 and 2022 using Centres for Disease Control and Prevention (CDC) light traps and Prokopack aspirators. Polymerase chain reaction (PCR) assays targeting the noncoding internal transcribed spacer 2 (ITS2) and 18S ribosomal DNA (18S rDNA) were used to identify sibling species in the An. funestus group and presence of Plasmodium infections, respectively. Where DNA fragments failed to amplify during PCR, we sequenced the ITS2 region to identify any polymorphisms.

Results

The following sibling species of the An. funestus group were found across Tanzania: An. funestus s.s. (50.3%), An. parensis (11.4%), An. rivulorum (1.1%), An. leesoni (0.3%). Sequencing of the ITS2 region in the nonamplified samples showed that polymorphisms at the priming sites of standard species-specific primers obstructed PCR amplification, although the ITS2 sequences closely matched those of An. funestus s.s., barring these polymorphisms. Of the 914 samples tested for Plasmodium infections, 11 An. funestus s.s. (1.2%), and 2 An. parensis (0.2%) individuals were confirmed positive for P. falciparum. The highest malaria transmission intensities [entomological inoculation rate (EIR)] contributed by the Funestus group were in the north-western region [108.3 infectious bites/person/year (ib/p/y)] and the south-eastern region (72.2 ib/p/y).

Conclusions

Whereas An. funestus s.s. is the dominant malaria vector in the Funestus group in Tanzania, this survey confirms the occurrence of Plasmodium-infected An. parensis, an observation previously made in at least two other occasions in the country. The findings indicate the need to better understand the ecology and vectorial capacity of this and other secondary malaria vectors in the region to improve malaria control.

Graphical Abstract
Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers
Authors: Krieg Stephan , Rohde Thomas , Rausch Tobias , Butthof Luise , Wendler-Link Lena , Eckert Christoph , Breuhahn Kai , Galy Bruno , Korbel Jan , Billmann Maximilian , Breinig Marco , Tschaharganeh Darjus F.
Published: June 2024

Background

Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.

Methods

We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.

Results

We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.

Conclusions

Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.
Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study
Authors: Engels-Domínguez Nina , Koops Elouise A. , Hsieh Stephanie , Wiklund Emma E. , Schultz Aaron P. , Riphagen Joost M. , Prokopiou Prokopis C. , Hanseeuw Bernard J. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I. L.
Published: June 2024

Background

Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.

Methods

A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.

Results

Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.

Conclusions

Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
AI-2 quorum sensing-induced galactose metabolism activation in Streptococcus suis enhances capsular polysaccharide-associated virulence
Authors: Gao Shuji , Mao Chenlong , Yuan Shuo , Quan Yingying , Jin Wenjie , Shen Yamin , Zhang Xiaoling , Wang Yuxin , Yi Li , Wang Yang
Published: June 2024

Bacteria utilize intercellular communication to orchestrate essential cellular processes, adapt to environmental changes, develop antibiotic tolerance, and enhance virulence. This communication, known as quorum sensing (QS), is mediated by the exchange of small signalling molecules called autoinducers. AI-2 QS, regulated by the metabolic enzyme LuxS (S-ribosylhomocysteine lyase), acts as a universal intercellular communication mechanism across gram-positive and gram-negative bacteria and is crucial for diverse bacterial processes. In this study, we demonstrated that in Streptococcus suis (S. suis), a notable zoonotic pathogen, AI-2 QS enhances galactose utilization, upregulates the Leloir pathway for capsular polysaccharide (CPS) precursor production, and boosts CPS synthesis, leading to increased resistance to macrophage phagocytosis. Additionally, our molecular docking and dynamics simulations suggest that, similar to S. pneumoniae, FruA, a fructose-specific phosphoenolpyruvate phosphotransferase system prevalent in gram-positive pathogens, may also function as an AI-2 membrane surface receptor in S. suis. In conclusion, our study demonstrated the significance of AI-2 in the synthesis of galactose metabolism-dependent CPS in S. suis. Additionally, we conducted a preliminary analysis of the potential role of FruA as a membrane surface receptor for S. suis AI-2.
Rapid reconstitution of ubiquitinated nucleosome using a non-denatured histone octamer ubiquitylation approach
Authors: Li Weijie , Cao Peirong , Xu Pengqi , Sun Fahui , Wang Chi , Zhang Jiale , Dong Shuqi , Wilson Jon R. , Xu Difei , Fan Hengxin , Feng Zhenhuan , Zhang Xiaofei , Zhu Qingjun , Fan Yingzhi , Brown Nick , Justin Neil , Gamblin Steven J , Li He , Zhang Ying , He Jun
Published: June 2024

Background

Histone ubiquitination modification is emerging as a critical epigenetic mechanism involved in a range of biological processes. In vitro reconstitution of ubiquitinated nucleosomes is pivotal for elucidating the influence of histone ubiquitination on chromatin dynamics.

Results

In this study, we introduce a Non-Denatured Histone Octamer Ubiquitylation (NDHOU) approach for generating ubiquitin or ubiquitin-like modified histone octamers. The method entails the co-expression and purification of histone octamers, followed by their chemical cross-linking to ubiquitin using 1,3-dibromoacetone. We demonstrate that nucleosomes reconstituted with these octamers display a high degree of homogeneity, rendering them highly compatible with in vitro biochemical assays. These ubiquitinated nucleosomes mimic physiological substrates in function and structure. Additionally, we have extended this method to cross-linking various histone octamers and three types of ubiquitin-like proteins.

Conclusions

Overall, our findings offer an efficient strategy for producing ubiquitinated nucleosomes, advancing biochemical and biophysical studies in the field of chromatin biology.
Unlocking digital performance: exploring the mediating role of employee competitive attitudes, behaviors, and dynamic capabilities in Chinese SMEs under high-involvement human resource management practice
Authors: Wang Guifang , Mansor Zuraina Dato , Leong Yee Choy
Published: June 2024

Digital technology has already permeated the production and operations of organizations, with many incorporating it into employee performance evaluations. However, there remains a research gap in identifying effective approaches to achieving digital performance. Furthermore, while scholars have often mentioned the differences in employee attitudes, and employee dynamic capability (EDC) in the dynamic digital market, empirical evidence supporting this notion is scarce. This paper investigates the influence of high-involvement human resource management practices (HI-HRMPs) on employee digital performance (EDP) within Chinese small and medium-sized enterprises (SMEs), focusing on specific cultural regions in China. Using purposive sampling, four representative regions (Guangzhou, Shanghai, Guizhou, and Anhui) were selected for Survey. Structural equation modeling (AMOS) was employed to examine the relationships between HI-HRMPs as the independent variable and employee competitive attitudes, employee competitive behaviors, and employee dynamic capabilities as mediating variables, with a focus on their impact on employee digital performance. Contrary to direct effects, the study reveals that HI-HRMPs do not directly influence employee digital performance. Instead, employee competitive attitudes and behaviors, along with their dynamic capabilities, emerge as significant mediating variables in this relationship. Specifically, employee competitive attitudes and behaviors, as well as employee dynamic capabilities, play crucial roles in mediating the relationship between HI-HRMPs and employee digital performance. Furthermore, the findings indicate that employee dynamic capabilities exhibit greater influence on employee digital performance compared to employee competitive attitudes and behaviors, particularly in the context of a rapidly evolving digital marketplace. These results underscore the importance of fostering employee dynamic capabilities within SMEs to enhance digital performance in the ever-changing business landscape.
Rubber plantations are impermeable to an avian understory specialist in Sri Lanka
Authors: Dayananda Salindra K. , Athukorala Harsha F. , Peabotuwage Indika , Kumara Chandralal , Ranasinghe Tharindu , Samarasinghe Dhammithra , Gouveia Ana , Kotagama Sarath W. , Mammides Christos , Jiang Aiwu , Goodale Eben
Published: June 2024

Background

Understanding how landscape characteristics affect animal movement is essential for conservation in human-dominated habitats. A fundamental question is how monoculture agroforests, including rubber and tea plantations, affect wildlife and its movement. Experimental translocations represent an important technique to assess animals’ habitat selection while moving through agricultural matrices, especially when complemented with observations of birds’ natural movements, and with “control” translocations, in which birds are moved within their natural habitat such as forest. Yet, experimental translocations have been little used for birds outside the Western Hemisphere.

Methods

We conducted experimental translocations and home-range measurements on an understory forest specialist, Brown-capped Babbler (BCBA, Pellorneum fuscocapillus), and a forest generalist, Tickell’s Blue Flycatcher (TBFL, Cyornis tickelliae). These species were studied in three rubber plantations, which also included some open areas mostly planted with tea, and in three forest reserves of Sri Lanka.

Results

Four of the five BCBAs translocated within disturbed habitats (rubber plantations) could not return to their capture locations. However, all four individuals within undisturbed habitats (forest reserves) successfully returned to their point of origin within 10.5 daytime hours. In contrast, all TBFLs returned to their capture locations in both disturbed (n = 7) and undisturbed habitats (n = 3) within 11.3 daytime hours. A Cox-proportional survival model demonstrated that the percentage of rubber cover decreased return time, similar to the effect of open-area cover. The home range surveys (n = 13 for BCBA, n = 10 for TBFL) revealed that very little of the birds’ natural home-ranges was covered by rubber (0.2% for BCBA, 13.1% for TBFL at 50% Kernel Density Estimates KDE). Home range size for BCBA was approximately half the size in disturbed habitats compared to undisturbed ones, although there was no significant difference between habitats for TBFL.

Conclusions

We conclude that rubber plantations can be impermeable to understory habitat specialist birds, and even generalist species may avoid them long-term. Our findings highlight the potential utility of strips of native vegetation, particularly those featuring understory layers, as corridors to facilitate the movement of forest specialists in landscapes dominated by rubber plantations and other types of disturbed habitats.
Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems
Authors: Bacioglu Mehtap , Schweighauser Manuel , Gray Derrick , Lövestam Sofia , Katsinelos Taxiarchis , Quaegebeur Annelies , van Swieten John , Jaunmuktane Zane , Davies Stephen W. , Scheres Sjors H. W. , Goedert Michel , Ghetti Bernardino , Spillantini Maria Grazia
Published: June 2024

Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.
Teachers’ and principals’ perceptions of school emphasis on academic success: measurement invariance, agreement, and relations to student achievement
Authors: Ye Wangqiong , Scherer Ronny , Blömeke Sigrid
Published: June 2024

A school’s emphasis on academic success (SEAS) is a crucial aspect of school climate that can be rated by different informants, such as teachers or principals, and with respect to their perception of different groups’ emphasis on academic success, such as parents or students. We know little about whether there is agreement between these ratings. Utilizing Israeli Trends in International Mathematics and Science Study (TIMSS) 2019 data and multilevel structural equation modeling, we examined how teachers and principals rate teachers’, students’, and parents’ emphasis on academic success and how these ratings are related to student achievement. We found that (a) ratings are invariant across informants; (b) teachers and principals agree on parents’ and students’ yet not teachers’ emphasis; (c) teacher ratings explain more variation in student achievement than principal ratings. Since SEAS ratings diverge by informants and relations to student achievement, researchers need to craft validity arguments in their studies.
Novel artificial intelligence algorithms for diabetic retinopathy and diabetic macular edema
Authors: Yao Jie , Lim Joshua , Lim Gilbert Yong San , Ong Jasmine Chiat Ling , Ke Yuhe , Tan Ting Fang , Tan Tien-En , Vujosevic Stela , Ting Daniel Shu Wei
Published: June 2024

Background

Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes of visual impairment that challenge global vision health. New strategies are needed to tackle these growing global health problems, and the integration of artificial intelligence (AI) into ophthalmology has the potential to revolutionize DR and DME management to meet these challenges.

Main text

This review discusses the latest AI-driven methodologies in the context of DR and DME in terms of disease identification, patient-specific disease profiling, and short-term and long-term management. This includes current screening and diagnostic systems and their real-world implementation, lesion detection and analysis, disease progression prediction, and treatment response models. It also highlights the technical advancements that have been made in these areas. Despite these advancements, there are obstacles to the widespread adoption of these technologies in clinical settings, including regulatory and privacy concerns, the need for extensive validation, and integration with existing healthcare systems. We also explore the disparity between the potential of AI models and their actual effectiveness in real-world applications.

Conclusion

AI has the potential to revolutionize the management of DR and DME, offering more efficient and precise tools for healthcare professionals. However, overcoming challenges in deployment, regulatory compliance, and patient privacy is essential for these technologies to realize their full potential. Future research should aim to bridge the gap between technological innovation and clinical application, ensuring AI tools integrate seamlessly into healthcare workflows to enhance patient outcomes.
Late-onset lethal complication of non-surgically managed massive gastric conduit necrosis after esophagectomy: a case report
Authors: Takeuchi Hiroshi , Yoshimura Shuntaro , Daimon Mitsuhiro , Sakina Yasunobu , Seki Yusuke , Ishikawa Shintaro , Kouno Yoshiharu , Tashiro Jo , Kawasaki Seiji , Mori Kazuhiko
Published: June 2024

Background

Gastric conduit necrosis (GCN) after esophagectomy is a serious complication that can prove fatal. Herein, we report a rare case of GCN with a severe course that improved with conservative treatment.

Case presentation

We present the case of a 78-year-old male patient who underwent an Ivor Lewis esophagectomy and developed a massive GCN. The patient was critically ill in the initial phase but recovered quickly; he also had a ruptured gallbladder and a bleeding jejunal ulcer. On the 22nd postoperative day, massive GCN was revealed on endoscopy. Considering the recovery course, careful observation with a decompressing nasal gastric tube was the treatment of choice. The GCN was managed successfully, having been completely replaced by fine mucosa within 9 months postoperatively. The patient completed his follow-up visit 5 years after surgery without any evident disease recurrence. Five and a half years after the surgery, the patient presented with progressive weakness and deterioration of renal function. Gastrointestinal endoscopy revealed a large ulcer at the anastomotic site. Three months later, computed tomography revealed a markedly thin esophageal wall, accompanied by adjacent lung consolidation. An esophagopulmonary fistula was diagnosed; surgery was not considered, owing to the patient’s age and markedly deteriorating performance status. He died 2013 days after the diagnosis.

Conclusions

Massive GCN after esophagectomy often requires emergency surgery to remove the necrotic conduit. However, this report suggests that a conservative approach can save lives and preserve the gastric conduit in these cases, thereby augmenting the quality of life.
The discourse and practices of Polish migration policy during the COVID-19 pandemic – economisation as a form of emergency governance
Authors: Jaroszewicz Marta , Krępa Mateusz , Pachocka Marta
Published: June 2024

The existing literature points to securitisation as a dominant form of emergency governance emerging in response to the COVID-19 pandemic, also in relation to migration. However, another important way of framing migration during the pandemic is in terms of economisation. This article aims to analyse the rationale underpinning Polish immigration policy during COVID-19 with a focus on different forms of economisation: macro-economisation, which prioritises economic growth over other socially important issues; and substantive economisation, which centres the needs of a population during a given historical moment. Based on desk and qualitative research, including analysis of official documents and media coverage as well as in-depth expert interviews, we argue that the logics of both kinds of economisation can be discerned in Poland’s immigration policy. Our overall conclusion is that during the COVID-19 pandemic, and despite strong anti-immigrant rhetoric in official political discourse, Poland’s immigration policy prioritised the interests of the national economy and labour market over strategies of security and social control.
Clinical disease activity in autoimmune rheumatic patients receiving COVID-19 vaccines
Authors: Dey Dzifa , Katso Bright , Amoako Emmanuella , Manu Aida , Bediako Yaw
Published: June 2024

Background

Vaccines are a crucial component of the global efforts to control the spread of COVID-19. Very little is known about COVID-19 vaccine responses in patients living with autoimmune rheumatic conditions in Africa. We examined the clinical reaction to COVID-19 vaccinations in Ghanaians diagnosed with autoimmune rheumatic disease.

Methods

This was a hospital-based interventional cohort study of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients recruited via regular face-to-face clinic visits. The systemic lupus erythematosus disease activity index Selena modification (SELENA-SLEDAI) and the disease activity score 28-joint count-erythrocyte sedimentation rate (DAS28-ESR) were used to measure changes in disease activity levels.

Results

Thirty-eight (38) patients of which 21 (55.3%) were diagnosed with SLE and 17 (44.7%) with RA contributed data for analyses. Most (89.5%) of the patients were females, with a mean age of 37.4 years. The SLE patients experienced a notable increase in severe flares during weeks three and six, as well as the third and sixth months, followed by subsequent decreases in the twelfth month, while remission levels increased throughout the same period. Among RA patients, high disease activity decreased during weeks three and six, as well as the third, sixth, and twelfth months, with remission levels increasing during the same time. A low dose (≥ 50 < 75 mg) dose of azathioprine was at some point associated with having a severe flare among SLE patients. After both vaccine doses, SLE patients were the majority having experienced both local and systemic reactions, all resolving within 24 h. Approximately 73.7% of the patients were COVID-19 negative at baseline. During post-vaccination visits, this increased to 100% by week six, with no positives thereafter.

Conclusion

This study explores COVID-19 vaccine responses in Ghanaian autoimmune rheumatic disease patients, revealing disease activity levels in RA patients improved after vaccination compared to SLE patients. Our findings identify a potential link between low-dose azathioprine and severe flares in SLE patients, particularly evident in the third-week post-vaccination. Further research is warranted to clarify these findings and guide tailored treatment approaches in this medically significant population during pandemics and vaccination efforts.
Early and midterm efficacy of oxiplex gel on postoperative pain intensity, physical disability, and musculoskeletal power in patients undergoing lumbar discectomy
Authors: Tabibkhooei Alireza , Azar Maziar , Nabiuni Mohsen , Jahandideh Javad , Benam Mohsen , Qoorchi Moheb Seraj Farid , Ebrahimnia Feizollah , Moradi Ali
Published: June 2024

Introduction

Carboxymethylcellulose/polyethylene oxide, also known as Oxiplex gel, is commonly used during lumbar discectomy operations. It serves to cover the surgical site, preventing adhesions and providing relief from pain and symptoms. However, there is ongoing debate regarding the extent of its beneficial effects on postoperative pain intensity, level of disability, and overall improvement of musculoskeletal conditions. Therefore, the objective of this study is to evaluate the advantages and limitations of using Oxiplex gel in lumbar laminectomy procedures specifically for herniated discs.

Methods

A randomized controlled trial was conducted on 56 consecutive patients who were candidates for unilateral lumbar discectomy on one lumbar surface. The patients were chosen based on their clinical manifestations and imaging findings. After the initial assessment, the patients underwent either laminectomy or laminotomy surgery. Following the surgery, the patients were randomly assigned to either the intervention group (receiving Oxiplex gel) or the control group. This assignment was done using a computerized random number generator. Assessments were conducted before the operation, as well as 3 and 6 months post-surgery for all patients.

Results

There was no significant difference found between the Oxiplex gel and control groups in terms of radicular and low back pain intensity, as well as disability scores, at different time points after surgery (p = 0.336, p = 0.65, and p = 0.336, respectively). Additionally, there were no significant differences found in the prevalence of sexual or sphincteric disorders between the two groups during postoperative assessments (p = 0.639 and p = 0.15, respectively). Furthermore, no significant differences were observed in the results of the postsurgical neuromuscular evaluation under different lower extremities conditions between the two groups.

Conclusions

Based on our findings, it was observed that Oxiplex gel did not demonstrate any improvement in post-unilateral lumbar discectomy symptoms or musculoskeletal power.
Using neural biomarkers to personalize dosing of vagus nerve stimulation
Authors: Berthon Antonin , Wernisch Lorenz , Stoukidi Myrta , Thornton Michael , Tessier-Lariviere Olivier , Fortier-Poisson Pascal , Mamen Jorin , Pinkney Max , Lee Susannah , Sarkans Elvijs , Annecchino Luca , Appleton Ben , Garsed Philip , Patterson Bret , Gonshaw Samuel , Jakopec Matjaz , Shunmugam Sudhakaran , Edwards Tristan , Tukiainen Aleksi , Jennings Joel , Lajoie Guillaume , Hewage Emil , Armitage Oliver
Published: June 2024

Background

Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies.

Methods

We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses.

Results

Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently.

Conclusion

Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.
Development of a method for Making Optimal Decisions for Intervention Flexibility during Implementation (MODIFI): a modified Delphi study
Authors: Brewer Stephanie K. , Corbin Catherine M. , Baumann Ana A. , Stirman Shannon Wiltsey , Jones Janine M. , Pullmann Michael D. , Lyon Aaron R. ,   MODIFI Expert Panel, Aalsma Matthew , Aldridge William , Arean Patricia , Barnett Maya , Barwick Melanie , Birken Sarah , Brown Jacquie , Bruns Eric , Calloway Amber , Cooper Brittany , Creed Torrey , Darnell Doyanne , Dopp Alex , Escoffery Cam , Green Kelly , Hunter Sarah , Jungbluth Nathaniel , Kopelovich Sarah , Lau Anna , McLeod Bryce , Monroe-DeVita Maria , Moore Julia , Prusaczyk Beth , Shelton Rachel , Stanick Cameo , Williston Michael , Wright Sean , Youn Soo Jeong
Published: June 2024

Background

Intervention adaptation is often necessary to improve the fit between evidence-based practices/programs and implementation contexts. Existing frameworks describe intervention adaptation processes but do not provide detailed steps for prospectively designing adaptations, are designed for researchers, and require substantial time and resources to complete. A pragmatic approach to guide implementers through developing and assessing adaptations in local contexts is needed. The goal of this project was to develop Making Optimal Decisions for Intervention Flexibility during Implementation (MODIFI), a method for intervention adaptation that leverages human centered design methods and is tailored to the needs of intervention implementers working in applied settings with limited time and resources.

Method

MODIFI was iteratively developed via a mixed-methods modified Delphi process. Feedback was collected from 43 implementation research and practice experts. Two rounds of data collection gathered quantitative ratings of acceptability and inclusion (Round 1) and feasibility (Round 2), as well as qualitative feedback regarding MODIFI revisions analyzed using conventional content analysis.

Results

In Round 1, most participants rated all proposed components as essential but identified important avenues for revision which were incorporated into MODIFI prior to Round 2. Round 2 emphasized feasibility, where ratings were generally high and fewer substantive revisions were recommended. Round 2 changes largely surrounded operationalization of terms/processes and sequencing of content. Results include a detailed presentation of the final version of the three-step MODIFI method (Step 1: Learn about the users, local context, and intervention; Step 2: Adapt the intervention; Step 3: Evaluate the adaptation) along with a case example of its application.

Discussion

MODIFI is a pragmatic method that was developed to extend the contributions of other research-based adaptation theories, models, and frameworks while integrating methods that are tailored to the needs of intervention implementers. Guiding teams to tailor evidence-based interventions to their local context may extend for whom, where, and under what conditions an intervention can be effective.
Diverse pharmacological actions of potential carbazole derivatives by influencing various pathways of molecular signaling
Authors: Tiwari Archita , Mishra Bharat
Published: June 2024

Background

Carbazoles are an important class of heterocyclic aromatic compounds that contain nitrogen atom in the ring. They have a large-conjugated system, attractive “electrical and charge-transport properties”, and the ability to efficiently incorporate different functional groups into the structurally inflexible carbazolyl ring.

Main text

Carbazole derivative ECCA acts as an anticancer agent by reactivating the P53 molecular signaling pathway; similarly, some other derivatives of carbazole show antifungal activity by acting on the RAS-MAPK pathway. Carbazole derivatives also show their effect on inflammation by inhibiting the p38 mitogen-activated protein kinase signaling pathway by stopping the conversion of DAXX protein into ASK-1. By modifying the AKT molecular signaling pathway through boosting protein phosphatase activity in the brain, they show anti-Alzheimer’s activity and also by translocating the GLUT4 these are effective against diabetes.

Conclusion

After exploring the literature on carbazole, it was found that carbazole has an immeasurably great potential for the treatment of various diseases as the carbazole nucleus leads to various synthesized derivatives which are used for their pharmacological activities. So there is a need to explore carbazole for some newer drugs.
Hypokalemic paralysis as presenting manifestation of systemic diseases: a case series
Authors: Sheikh Rayees Yousuf , Bhat Nucksheeba Aziz , Mustafa Farhat , Tripathi Puja , Johri Nidhi , Wani Imtiyaz
Published: June 2024

Hypokalemia is a common issue in clinical settings, often indicating underlying systemic conditions that require careful evaluation. This study presents three cases where hypokalemic paralysis served as the initial symptom of systemic diseases. Key evaluation methods included clinical history, physical examination focusing on volume status, and acid–base assessment. The cases highlight the diverse etiologies of hypokalemia, including primary hyperaldosteronism, Sjogren’s syndrome, and Crohn’s disease.
Magnetic procedure for sentinel lymph node detection and evaluation of metastases: design and rationale of the Lowmag trial
Authors: Christenhusz Anke , Dassen Anneriet E. , van der Schaaf Margreet C. , Salamzadeh Sadaf , Brinkhuis Mariël , Haken Bennie ten , Alic Lejla
Published: June 2024

Background

Primary tumour biology and axillary lymph node status are key prognostic factors in breast cancer treatment. The LowMag trial introduced a magnetic sentinel lymph node biopsy procedure using a superparamagnetic iron oxide (SPIO) tracer and a handheld magnetometer as a radiation-free alternative for axillary staging. The trial aimed to assess a low-dose magnetic tracer for non-invasive preoperative evaluation of lymph node metastases and intraoperative sentinel lymph node detection.

Methods

Patients with confirmed invasive breast cancer or ductal carcinoma in situ, eligible for sentinel lymph node biopsy, were included in the LowMag trial. The sentinel lymph nodes were detected perioperatively using Sentimag® and inked to maintain spatial orientation between MRI and histopathology. The amount of iron was estimated using two magnetic devices: SPaQ and Sentimag®. Additional ex vivo MRI was performed with a low-field MRI system. After being buffered in formalin, the sentinel lymph nodes were sectioned perpendicular to the MRI planes, consecutively sliced at 2 μm intervals, and stained with H&E, Perls Prussian blue, CK8/18, and CD68.

Results

In an interim assessment of 20 sentinel lymph nodes, two contained metastases. The analysis revealed good concordance in uptake between the magnetic and radioactive tracers, with a median iron content of 19.21 µg. In healthy sentinel lymph nodes, iron particles were found in both the subcapsular space and sinusoids, with macrophages nearby. Healthy regions within metastatic lymph nodes showed similar behaviour to healthy nodes. In metastatic sites, iron pigment presence was reduced, especially in areas occupied by tumour cells. A healthy lymph node with low iron content displayed a large central fatty region without iron uptake but confirmed iron in sinusoidal macrophages. The metastatic lymph node had subcapsular and parenchymal tumour cells in the central region, with limited infiltration into nearby adipose tissue and no local iron enhancement. However, iron deposits were detected within the sinusoids.

Discussion

The MRI images effectively distinguish between fat, nodal tissue, and the SPIO tracer, either through signal intensity or texture. This demonstrates the potential for sentinel lymph node imaging using a low-field MRI system.
Survey on large language model annotation of cellular senescence from figures in review articles
Authors: Yamagata Yuki , Yamada Ryota
Published: June 2024

This study evaluated large language models (LLMs), particularly the GPT-4 with vision (GPT-4 V) and GPT-4 Turbo, for annotating biomedical figures, focusing on cellular senescence. We assessed the ability of LLMs to categorize and annotate complex biomedical images to enhance their accuracy and efficiency. Our experiments employed prompt engineering with figures from review articles, achieving more than 70% accuracy for label extraction and approximately 80% accuracy for node-type classification. Challenges were noted in the correct annotation of the relationship between directionality and inhibitory processes, which were exacerbated as the number of nodes increased. Using figure legends was a more precise identification of sources and targets than using captions, but sometimes lacked pathway details. This study underscores the potential of LLMs in decoding biological mechanisms from text and outlines avenues for improving inhibitory relationship representations in biomedical informatics.
Phase I study of GUCY2C CAR-T therapy IM96 in patients with metastatic colorectal cancer.
Authors: QI Changsong , Liu Chang , Li Jian , Gong Jifang , Wang Xicheng , Wang Zhenghang , Lu Xin-an , He Ting , Ding Yanping , Wu Fei , Liu Dongqun , Shen Lin
Published: June 2024

2518

Background: The clinical outcomes of metastatic colorectal cancer (mCRC) therapies are limited, especially for liver metastasis. Guanylyl cyclase 2C (GUCY2C) is ectopically expressed in all stages of CRC and intestinally restricted. GUCY2C-targeted CAR-T (IM96) was developed and phase I study was conducted to evaluate the safety and efficacy (NCT05287165). Methods: In this open-label, 3+3 dose-escalation study, IM96 was evaluated in GUCY2C-positive mCRC patients (pts) failed to ≥3 lines of therapies. Pts were pre-treated with fludarabine and cyclophosphamide, and received a single infusion of IM96 at the dose of 3×108 (DL1), 6×108 (DL2), 12×108 (DL3), or 20×108 (DL4) CAR-T cells. Dose-expansion study was performed at DL3. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile. Results: As of December 2023, 20 pts were enrolled and infused with IM96. The follow-up time was 7-19 months for all pts. The median age was 52.5, and 11/20 cases were male. Liver metastasis was found in 11/20 cases (55%), proficient mismatch repair (pMMR) in 20/20 pts (100%), KRAS mutation in 12/20 pts (60.0%), NRAS mutation in 1/20 pts (5.0%), and BRAF mutation in 3/20 pts (15.0%). Bridging therapies were used in 19 pts. Only 1/20 pt (5.0%) showed neurotoxicity and ≥grade 3 cytokine release syndromes (CRS). Grade 1-2 CRS occurred in 16/20 pts (80.0%) with dramatic increase of interleukin-6. Grade 1-3 rash was observed in 14/20 pts (70.0%). Grade 3 diarrhea occurred in 11/20 pts (55.0%), and grade 1-3 oral mucositis appeared in 7/20 pts (35.0%), only in DL2, DL3 and DL4 groups. Dose-limiting toxicity and maximum tolerated dose were not achieved. Among 19 evaluable pts, the disease control rate (DCR) was 73.7%, and the objective response rate (ORR) was 26.3%. In DL3 group, pts showed an ORR of 40.0%, nevertheless of liver metastasis or not. The median progression-free survival time was 7 months, and the median duration of response was 10 months in DL3 group. No responding pts showed disease progression within 6 months. Tumor responses were correlated with significant decreases in carcinoembryonic antigen levels among all pts. Conclusions: This study demonstrated that IM96 has durable efficacy with acceptable safety profile in pMMR mCRC pts, in particularly, showing high therapeutic potential in liver metastasis pts. Clinical trial information: NCT05287165 .
Performance characteristics of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies.
Authors: Liu Geoffrey , Pienkowski Martha , Huang Shao Hui , Ailles Laurie , Rey-McIntyre Katrina , Min Jun , Wang Yarong , Burgener Justin , Jones Joshua T. , Brown Ben , Zhang Junjun , Hall Owen , Shen Shu Yi , Provance Jeremy B. , Sosa Eduardo , Zhang Jing , Licon Abel , Allen Brian , Hartman Anne-Renee , De Carvalho Daniel D.
Published: June 2024

3009

Background: Plasma cell-free DNA (cfDNA) tests have emerged as a promising approach for cancer management. cfDNA methylome approaches are well-suited for molecular residual disease (MRD) detection. Here we present data using a tissue-agnostic, genome-wide methylome enrichment platform based on cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMEDIP-seq) in head and neck cancer (HNC) to predict relapse for purposes of guiding adjuvant therapy after completion of curative-intent treatment and to detect early relapse. Methods: The cohort is comprised of biobanked samples from individuals diagnosed with stage I-IVB human papillomavirus (HPV)-negative and HPV-positive HNC with longitudinal data collection and sampling. The full cohort includes 325 unique patients with 1,155 samples. Samples were split into distinct sets to train and test a classifier consisting of differentially methylated regions. Blood collection time points include at diagnosis, and approximately 3 (landmark), 12 and 24 months after curative intent treatment. 5-10 ng of cfDNA isolated from each plasma sample was used for cfMEDIP-seq. MRD signals were quantified from average normalized counts across informative methylated regions and binarized into a positive (above the threshold) and negative groups. Recurrence-free survival (RFS) was compared for patients who tested positive to those who tested negative at 3 months post-curative treatment (i.e., landmark timepoint) and longitudinally. Results: A total of 196 post-treatment samples from 80 unique patients [stage I (35%), II (15%), III (24%), IV (26%)] were analyzed and correlated with recurrence, in this interim training result. At the landmark timepoint, patients who tested positive showed significantly worse RFS than those who tested negative (Hazard ratio (HR) 9.69; 95% CI, 4.39-21.4, P<0.001). Incorporating serial longitudinal samples, recurrence-free survival was worse in patients who tested positive compared to those that tested negative (HR 14.52; 95% CI, 5.78-36.46, P<0.001). Conclusions: Interim analysis demonstrates that MRD detection with a tissue-agnostic, genome-wide methylome enrichment platform in HNC patients after curative intent treatment correlates strongly with RFS with hazard ratios consistent with tumor-informed assays previously described. Updated analyses from the cohort will be presented at the meeting.