bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of a fluid balance control strategy in critically ill patients: POINCARE-2 trial process evaluation
Authors: Buzzi Marie , Ricci Laetitia , Gibot Sébastien , Argaud Laurent , Badie Julio , Bruel Cédric , Charpentier Claire , Outin Hervé , Louis Guillaume , Monnier Alexandra , Quenot Jean-Pierre , Schneider Francis , Minary Laetitia , Agrinier Nelly
Published: July 2024

Background

POINCARE-2 trial aimed to assess the effectiveness of a strategy designed to tackle fluid overload through daily weighing and subsequent administration of treatments in critically ill patients. Even in highly standardized care settings, such as intensive care units, effectiveness of such a complex intervention depends on its actual efficacy but also on the extent of its implementation. Using a process evaluation, we aimed to provide understanding of the implementation, context, and mechanisms of change of POINCARE-2 strategy during the trial, to gain insight on its effectiveness and inform the decision regarding the dissemination of the intervention.

Methods

We conducted a mixed-method process evaluation following the Medical Research Council guideline. Both quantitative data derived from the trial, and qualitative data from semi-structured interviews with professionals were used to explain implementation, mechanisms of change of the POINCARE-2 strategy, as well as contextual factors potentially influencing implementation of the strategy.

Results

Score of actual exposure to the strategy ranged from 29.1 to 68.2% during the control period, and from 61.9 to 92.3% during the intervention period, suggesting both potential contamination and suboptimal fidelity to the strategy. Lack of appropriate weighing devices, lack of human resources dedicated to research, pre-trial rooted prescription habits, and anticipated knowledge of the strategy have been identified as the main barriers to optimal implementation of the strategy in the trial context.

Conclusions

Both contamination and suboptimal fidelity to POINCARE-2 strategy raised concerns about a potential bias towards the null of intention-to-treat (ITT) analyses. However, optimal fidelity seemed reachable. Consequently, a clinical strategy should not be rejected solely on the basis of the negativity of ITT analyses’ results. Our findings showed that, even in highly standardized care conditions, the implementation of clinical strategies may be hindered by numerous contextual factors, which demonstrates the critical importance of assessing the viability of an intervention, prior to any evaluation of its effectiveness.

Trial registration

Number NCT02765009
Healthcare leaders’ experiences of implementing artificial intelligence for medical history-taking and triage in Swedish primary care: an interview study
Authors: Siira Elin , Tyskbo Daniel , Nygren Jens
Published: July 2024

Background

Artificial intelligence (AI) holds significant promise for enhancing the efficiency and safety of medical history-taking and triage within primary care. However, there remains a dearth of knowledge concerning the practical implementation of AI systems for these purposes, particularly in the context of healthcare leadership. This study explores the experiences of healthcare leaders regarding the barriers to implementing an AI application for automating medical history-taking and triage in Swedish primary care, as well as the actions they took to overcome these barriers. Furthermore, the study seeks to provide insights that can inform the development of AI implementation strategies for healthcare.

Methods

We adopted an inductive qualitative approach, conducting semi-structured interviews with 13 healthcare leaders representing seven primary care units across three regions in Sweden. The collected data were subsequently analysed utilizing thematic analysis. Our study adhered to the Consolidated Criteria for Reporting Qualitative Research to ensure transparent and comprehensive reporting.

Results

The study identified implementation barriers encountered by healthcare leaders across three domains: (1) healthcare professionals, (2) organization, and (3) technology. The first domain involved professional scepticism and resistance, the second involved adapting traditional units for digital care, and the third inadequacies in AI application functionality and system integration. To navigate around these barriers, the leaders took steps to (1) address inexperience and fear and reduce professional scepticism, (2) align implementation with digital maturity and guide patients towards digital care, and (3) refine and improve the AI application and adapt to the current state of AI application development.

Conclusion

The study provides valuable empirical insights into the implementation of AI for automating medical history-taking and triage in primary care as experienced by healthcare leaders. It identifies the barriers to this implementation and how healthcare leaders aligned their actions to overcome them. While progress was evident in overcoming professional-related and organizational-related barriers, unresolved technical complexities highlight the importance of AI implementation strategies that consider how leaders handle AI implementation in situ based on practical wisdom and tacit understanding. This underscores the necessity of a holistic approach for the successful implementation of AI in healthcare.
Time-dependent analysis of erectile dysfunction in kidney transplant recipients: insights from four distinct time periods
Authors: Pan Jiashan , Zheng Zhenming , Wang Wenbo , Hu Dekai , Yao Rui , Chen Yiding , Ding Handong , Zhong Jinbiao , Hao Zongyao , Liao Guiyi
Published: July 2024

Background and intention

Erectile dysfunction (ED) is an underappreciated clinical condition in men. This study aims to compare the dynamic changes in the distribution of ED among male kidney transplant recipients (mKTRs) in four epochs: end-stage renal disease period (ESRDp), early post-transplant period (EPTP), pre-COVID-19, and post-COVID-19.

Methods

General information was gathered through interviews, follow-ups, and medical records. The International Index of Erectile Function Questionnaire-5 was used to assess erectile function. The Mann–Whitney U test and chi-square test were used to analyze differences in ED strength. Univariate and logistic regression analyses were conducted to identify risk factors for ED.

Results

The database contains 230 mKTRs. In the ESRDp, 17.0% had normal erectile function, 53.5% had mild ED, 18.3% had moderate ED, and 11.3% had severe ED. In the EPTP, the distribution was 38.2% normal, 42.6% mild, 10.8% moderate, and 8.2% severe. In the pre-COVID-19 period, it was 34.3%, 47.3%, 10.4%, and 7.8%, and in the post-COVID-19 period, it was 23.0%, 45.6%, 21.3%, and 10.0%. Overall, erectile function improved after kidney transplant (KT). However, post-COVID-19, the proportion of erectile function significantly decreased compared to EPTP and pre-COVID-19 periods. Risk factors for post-pandemic ED included degree, Generalized Anxiexy Disorder-7, kidney donor type, postoperative time, hypertension and hemoglobin concentration.

Conclusion

KT improves erectile function in mKTRs within 5 years, but post-SARS-CoV-2 viral infection, ED worsens due to altered risk factors. These findings inform future research for comprehensive ED prevention and management strategies in this population.
Cancer risk following onset of type 2 diabetes in New Zealanders with impaired glucose tolerance over 25 years: a matched prospective cohort study
Authors: Wang Zheng , Yu Dahai , Osuagwu Uchechukwu Levi , Pickering Karen , Baker John , Cutfield Richard , Cai Yamei , Orr-Walker Brandon J. , Sundborn Gerhard , Qu Bingjie , Zhao Zhanzheng , Simmons David
Published: July 2024

Background

In people with prediabetes, the link between developing type 2 diabetes (T2D) and cancer risk among those with impaired glucose tolerance (IGT) remains uncertain. We examined this association in IGT individuals from primary care in South and West Auckland, New Zealand, spanning 1994–2019, assessing 5- and 10-year cancer risks.

Methods

Study cohorts were extracted from the Diabetes Care Support Service in Auckland, New Zealand, linking it with national registries for death, cancer, hospital admissions, pharmaceutical claims, and socioeconomic status. We compared cancer risks in individuals with IGT newly diagnosed with or without T2D within a 1–5-year exposure window. Employing tapered matching and landmark analysis to address potential confounding effects, we formed comparative IGT cohorts. Weighted Cox regression models were then employed to assess the association between T2D onset and 5- and 10-year cancer risks.

Results

The study included 26,794 patients with IGT, with 629 newly diagnosed with T2D within 5 years and 13,007 without such a diagnosis. Those progressing to T2D had similar 5-year cancer risk but significantly higher 10-year risk (HR 1.35; 95% CI 1.09–1.68). This association was stronger in older individuals, the socioeconomically deprived, current smokers, those with worse metabolic measures, and lower renal function. Patients with IGT of NZ European ethnicity had lower 10-year cancer risk.

Conclusions

T2D diagnosis influences cancer risk in individuals with IGT. Developing risk scores for high-risk IGT individuals and implementing cancer screening and structured diabetes prevention, especially in deprived or minority ethnic populations, is essential.
Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials
Authors: Zhan Yanrong , Cheng Xianwen , Mei Pingping , Tan Shufa , Feng Wenzhe , Jiang Hua
Published: July 2024

Objective

To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis.

Methods

The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens.

Results

A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs.

Conclusion

In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.
A comparison between IBEX bone health applied to digital radiographs and dual-energy X-ray absorptiometry at the distal-third and ultra-distal regions of the radius
Authors: Lopez Ben , Meertens Robert , Gundry Mike , Scott Paul , Crone Mr Ben , McWilliam Richard
Published: July 2024

Background

In an ageing population, low impact fragility fractures are becoming increasingly common. However, fracture risk can be reduced where low bone density can be identified at an early stage. In this study we aim to demonstrate that IBEX Bone Health (IBEX BH) can provide a clinically useful prediction from wrist radiographs of aBMD and T-score at the ultra-distal (UD) and distal-third (DT) regions of the radius.

Methods

A 261-participant single-centre, non-randomised, prospective, study was carried out to compare a) IBEX BH, a quantitative digital radiography software device, to b) Dual-energy X-ray Absorptiometry (DXA). A total of 257 participants with wrist digital radiograph (DR), forearm DXA pairs were included in the analysis after exclusions.

Results

The adjusted R2 value for IBEX BH outputs to the radial areal bone mineral density (aBMD) produced by a GE Lunar DXA system for the UD region is 0.87 (99% Confidence Interval (CI) [0.84, 0.89]). The adjusted R2 value for IBEX BH outputs to aBMD for the DT region is 0.88 (99% CI [0.85, 0.90]). The Area Under the Receiver Operating Characteristic curve (AUC) for the forearm T-score ≤  − 2.5 risk prediction model at the UD region is 0.95 (99% CI [0.93, 0.98]). The AUC for the forearm T-score ≤  − 2.5 risk prediction model at the DT region is 0.98 (99% CI [0.97, 0.99]).

Conclusion

From a DR of the wrist, IBEX BH provides a clinically useful i) estimate of aBMD at the two regions of interest on the radius and ii) risk prediction model of forearm T-score ≤  − 2.5 at the UD and DT regions.
Pregnancies complicated with functioning adrenal adenomas causing severe obstetric outcomes: a 20-year experience at a tertiary center
Authors: Zhu Caixia , Cai Shiqin , Zhong Xue , Huang Linhuan
Published: July 2024

Background

Functioning adrenal adenoma during pregnancy is rare, and the diagnosis is challenging owing to unspecific symptoms and restricted investigations. The obstetric outcomes of patients who undergo surgery during pregnancy or who receive only medical treatment are poorly described.

Objective

The aim was to investigate the associations between functioning adrenal adenomas and obstetric outcomes.

Methods

A retrospective study was performed in a tertiary center over 20 years. The clinical characteristics, management and obstetric outcomes of the diagnosed pregnant women were reviewed.

Results

A total of 12 women were diagnosed with functioning adrenal adenomas during pregnancy from January 2002 to September 2022. Eight women had cortisol-secreting adrenal adenomas, two had excessive catecholamine secretion, and two had primary aldosteronism. The initial symptoms of adrenal adenoma during pregnancy included hypertension or preeclampsia, gestational diabetes mellitus or prepregnancy diabetes mellitus, hypokalemia and ecchymosis. Four women underwent adrenalectomy during pregnancy, while 8 women received only medical therapy. Preterm birth occurred in all patients who received medicine, whereas 1 patient who underwent surgery experienced preterm birth. Among the 8 women in the medical treatment group, 3 had neonates who died.

Conclusions

Once hypertension, hyperglycemia and hypokalemia occur during the 1st or 2nd trimester, pregnant women with adrenal adenomas should be evaluated via laboratory and imaging examinations. The maternal and fetal outcomes were unpredictable owing to the severity of adrenal adenoma, particularly in patients who received only medical treatment. Adrenalectomy should be recommended during pregnancy.
Causal effect of the age at first birth with depression: a mendelian randomization study
Authors: Guo Wanshu , Guo Yuanyuan , Song Shaokang , Huang Xuankai , Zhang Yu , Zhang Aizhen , Meng Fangrong , Chang Minghang , Wang Zhipeng
Published: July 2024

Background

This study aimed to explore the causal relationship between age at first birth (AFB) and depression.

Methods

Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result.

Results

We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 − 0.861; P = 4.51 × 10− 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10− 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10− 3. SE = 6.909 × 10− 3. P = 2.02 × 10− 01) and MR_PRESSO global test (P = 2.03 × 10− 01) indicated there is no pleiotropy.

Conclusion

There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.
Producing recombinant proteins in Vibrio natriegens
Authors: Smith Matthew , Hernández José Sánchez , Messing Simon , Ramakrishnan Nitya , Higgins Brianna , Mehalko Jennifer , Perkins Shelley , Wall Vanessa E. , Grose Carissa , Frank Peter H. , Cregger Julia , Le Phuong Vi , Johnson Adam , Sherekar Mukul , Pagonis Morgan , Drew Matt , Hong Min , Widmeyer Stephanie R. T. , Denson John-Paul , Snead Kelly , Poon Ivy , Waybright Timothy , Champagne Allison , Esposito Dominic , Jones Jane , Taylor Troy , Gillette William
Published: July 2024

The diversity of chemical and structural attributes of proteins makes it inherently difficult to produce a wide range of proteins in a single recombinant protein production system. The nature of the target proteins themselves, along with cost, ease of use, and speed, are typically cited as major factors to consider in production. Despite a wide variety of alternative expression systems, most recombinant proteins for research and therapeutics are produced in a limited number of systems: Escherichia coli, yeast, insect cells, and the mammalian cell lines HEK293 and CHO. Recent interest in Vibrio natriegens as a new bacterial recombinant protein expression host is due in part to its short doubling time of ≤ 10 min but also stems from the promise of compatibility with techniques and genetic systems developed for E. coli. We successfully incorporated V. natriegens as an additional bacterial expression system for recombinant protein production and report improvements to published protocols as well as new protocols that expand the versatility of the system. While not all proteins benefit from production in V. natriegens, we successfully produced several proteins that were difficult or impossible to produce in E. coli. We also show that in some cases, the increased yield is due to higher levels of properly folded protein. Additionally, we were able to adapt our enhanced isotope incorporation methods for use with V. natriegens. Taken together, these observations and improvements allowed production of proteins for structural biology, biochemistry, assay development, and structure-based drug design in V. natriegens that were impossible and/or unaffordable to produce in E. coli.
Biosynthesis of a clickable pyoverdine via in vivo enzyme engineering of an adenylation domain
Authors: Puja Hélène , Bianchetti Laurent , Revol-Tissot Johan , Simon Nicolas , Shatalova Anastasiia , Nommé Julian , Fritsch Sarah , Stote Roland H. , Mislin Gaëtan L. A. , Potier Noëlle , Dejaegere Annick , Rigouin Coraline
Published: July 2024

The engineering of non ribosomal peptide synthetases (NRPS) for new substrate specificity is a potent strategy to incorporate non-canonical amino acids into peptide sequences, thereby creating peptide diversity and broadening applications. The non-ribosomal peptide pyoverdine is the primary siderophore produced by Pseudomonas aeruginosa and holds biomedical promise in diagnosis, bio-imaging and antibiotic vectorization. We engineered the adenylation domain of PvdD, the terminal NRPS in pyoverdine biosynthesis, to accept a functionalized amino acid. Guided by molecular modeling, we rationally designed mutants of P. aeruginosa with mutations at two positions in the active site. A single amino acid change results in the successful incorporation of an azido-l-homoalanine leading to the synthesis of a new pyoverdine analog, functionalized with an azide function. We further demonstrated that copper free click chemistry is efficient on the functionalized pyoverdine and that the conjugated siderophore retains the iron chelation properties and its capacity to be recognized and transported by P. aeruginosa. The production of clickable pyoverdine holds substantial biotechnological significance, paving the way for numerous downstream applications.
Lifestyles associated with malaria in pregnancy in northwest Colombia: a mixed study from Latin American critical epidemiology
Authors: Cardona-Arias Jaiberth Antonio , Higuita-Gutiérrez Luis Felipe , Carmona-Fonseca Jaime
Published: July 2024

Background

In the scientific literature on Malaria in Pregnancy (MiP), no studies have been conducted on lifestyles based on critical theory. The objective of this study was to analyse the lifestyles or singular processes of social determination of health in MiP in northwestern Colombia.

Methods

Mixed QUAN-QUAL convergent triangulation study. In the quantitative component, a psychometric evaluation and a cross-sectional design were conducted in 400 pregnant women to whom the Pender-Walker lifestyle scale and a survey on MiP prevention were applied. In the qualitative study, a critical ethnography was conducted with 46 pregnant women in whom their narratives and practices regarding lifestyles at home and healthcare were described.

Results

The frequency of MiP was 9%, and a higher occurrence of the disease was identified in those who did not control stagnant water (29%), did not use insecticide-treated net (16%) and went to the hospital (14%) or the microscopist (20%) when they had fever. This coincides with the presence of unhealthy lifestyles, little knowledge about malaria, and a low perception of the risk of getting sick, as well as meanings and experiences about MiP, maternity, and pregnancy that show a high clinical, cultural, and socioeconomic burden for the women studied.

Conclusion

This epidemiological profile and the approach to lifestyles based on the postulates of critical theory in health evidence that pregnant women exposed to malaria suffer serious social, cultural and health injustices that are not possible to impact with the current health model of malaria control in Colombia guided by aetiopathogenic, biomedical, positivist and utilitarian theories.
Malaria and typhoid fever co-infection: a retrospective analysis of University Hospital records in Nigeria
Authors: Olowolafe Tubosun A. , Agosile Oluwaseyi F. , Akinpelu Adekemi O. , Aderinto Nicholas , Wada Ojima Z. , Olawade David B.
Published: July 2024

Background

Studies have long documented the presence of malaria and typhoid fever in sub-Saharan Africa (SSA). However, studies on these diseases have primarily concentrated on rural settings, neglecting the potential impact on urban areas. This knowledge gap hinders effective surveillance and intervention strategies. To bridge this gap, this study investigated the prevalence of malaria and typhoid co-infections in an urban environment.

Methods

This study, conducted at Lead City University Hospital in Ibadan, Nigeria (West Africa’s largest metropolis), analysed medical records of over 3195 patients seen between April and June 2023. Descriptive statistics and chi-square tests were used to understand how these co-infections were distributed across different age and gender groups.

Results

The prevalence of co-infection peaked in May (9.7%), followed by June (8.9%) and April (5.7%). Notably, children aged 6–12 years exhibited the highest co-infection rate (18.5%), while those under five had the lowest (6.3%). Gender analysis indicated a slight difference, with 8.8% of females and 7.1% of males co-infected. Malaria prevalence was highest at the beginning of the rainy season and significantly decreased over time. Conversely, typhoid fever displayed the opposite trend, increasing with the rainy season. Children under five years old were most susceptible to malaria, while typhoid fever predominantly affected adults over 25 years old, with prevalence decreasing significantly with age.

Conclusion

This study sheds light on the previously overlooked risk of malaria and typhoid co-infections in urban settings. These findings highlight the need for enhanced surveillance and targeted public health interventions, particularly for vulnerable groups like young children during peak transmission seasons.
Orlistat for the treatment of antipsychotic-induced weight gain: an eight-week multicenter, randomized, placebo-controlled, double-blind trial
Authors: Xie Peng , Shao Tiannan , Long Yujun , Xie Weiwei , Liu Yangjun , Yang Ye , Huang Yuyan , Wu Renrong , Deng Qijian , Tang Hui
Published: July 2024

Background

Weight gain and metabolic disorders are commonly induced by antipsychotics. Orlistat is a lipase inhibitor used for weight control. The effect of orlistat on weight gain and metabolic disturbances in people (especially women) treated with antipsychotics has not been sufficiently studied. This study aimed to investigate the efficacy of orlistat in mitigating antipsychotic-induced weight gain and abnormal glycolipid metabolism.

Methods

Patients with schizophrenia or bipolar disorder with a weight gain ≥ 7% after taking antipsychotics were recruited. Participants were randomly allocated to two groups: one received eight weeks of orlistat (360 mg/day) and the other received a placebo. Anthropometric and fasting serum biochemical parameters were measured at baseline, week 4 and week 8.

Results

Sixty individuals (orlistat:placebo = 32:28) participated in the study. After controlling for the study center, the eight-week changes in body mass index (BMI), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-CH) and low-density lipoprotein cholesterol (LDL-CH) were significantly different between the groups. According to the mixed linear models, CHOL and LDL-CH were significantly lower in the orlistat group than in the control group at week 8. The week 0-to-8 slopes of BMI, CHOL and LDL-CH were also significantly lower in the orlistat group.

Conclusions

These findings suggested that orlistat is an effective intervention for attenuating weight gain and serum lipid disturbances in antipsychotic-treated patients.

Trial registration

ClinicalTrials.gov NCT03451734.
Spatial dynamics of tertiary lymphoid aggregates in head and neck cancer: insights into immunotherapy response
Authors: Sadeghirad Habib , Monkman James , Tan Chin Wee , Liu Ning , Yunis Joseph , Donovan Meg L. , Moradi Afshin , Jhaveri Niyati , Perry Chris , Adams Mark N. , O’Byrne Ken , Warkiani Majid E. , Ladwa Rahul , Hughes Brett G.M. , Kulasinghe Arutha
Published: July 2024

Background

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response.

Methods

In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform.

Results

Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of ‘hot tumor’ phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes.

Conclusion

The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification.
Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer
Authors: Papulino Chiara , Chianese Ugo , Ali Ahmad , Favale Gregorio , Tuccillo Concetta , Ciardiello Fortunato , Di Mauro Annabella , Mignogna Chiara , Ferrara Gerardo , Budillon Alfredo , Megchelenbrink Wouter Leonard , Del Gaudio Nunzio , Conte Mariarosaria , Merciai Fabrizio , Campiglia Pietro , Altucci Lucia , Carafa Vincenzo , Sommella Eduardo , Benedetti Rosaria
Published: July 2024

Background

Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear.

Methods

In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes.

Results

Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions.

Conclusions

These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.
Survey of knowledge on calcium carbide use in fruit ripening and associated health risks among fruit sellers and consumers in Ado-Ekiti Nigeria
Authors: Orok Edidiong , Okeke Uchenna , Williams Tonfamoworio , Adeniyi Funmilayo , Ikpe Favour , Femi-Oyewo Mbang
Published: July 2024

Background

This study aimed to assess the methods used for ripening fruits by sellers and to examine the knowledge regarding the health risks associated with the use of calcium carbide (CaC2) among both fruit sellers and consumers in Ado-Ekiti.

Methods

The study employed a cross-sectional design, utilizing a semi-structured questionnaire administered in major markets within Ado-Ekiti. Knowledge levels were categorized into good (> 70% score), fair (50–69% score), and poor (< 50% score). One way Analysis of variance (ANOVA) and Independent sample t-test was used to indicate knowledge score difference with respect to socio demographic characteristics.

Results

The study involved 357 consumers and 20 fruit sellers, with a majority being females (54.9% of consumers; 80.0% of sellers) and aged predominantly between 18–27 years and 28–39 years. The findings revealed that the use of CaC2 (50%) and natural ripening methods (100%) were common among fruit sellers. Sellers cited cancer (60%), bacterial infections (35%), and chest tightness (15%) as associated risks with CaC2 usage. Similarly, consumers expressed concerns about consuming CaC2-ripened fruits, attributing risks such as abdominal burns (70%), cancer (70.6%), and diarrhoea (67.3%). A significant proportion of sellers (90%) exhibited poor knowledge regarding the risks associated with CaC2, while 24.6% of consumers demonstrated fair knowledge on the subject.

Conclusion

The study identified common fruit ripening practices among sellers. Fruit sellers showed poor knowledge, while consumers displayed fair to poor understanding of health risks linked to calcium carbide use in artificial fruit ripening.
Elucidating the nature of acinic cell carcinoma of the breast with high-grade morphology: evidence from case report
Authors: Ge Yunjie , Wei Xianping , Liu Jing-Nan , Sun Ping-Li , Gao Hongwen
Published: July 2024

Background

Acinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components.

Case presentation

A 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Next‑generation sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences.

Conclusions

This case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.
Feasibility of dose calculation for treatment plans using electron density maps from a novel dual-layer detector spectral CT simulator
Authors: Zhu Qizhen , Wei Shuoyang , Wang Zhiqun , Xu Haoran , Zhou Bing , Qu Huiying , Nie Mingming , Guo Ning , Wang Wenshuai , Yang Bo , Qiu Jie
Published: July 2024

Background

Conventional single-energy CT can only provide a raw estimation of electron density (ED) for dose calculation by developing a calibration curve that simply maps the HU values to ED values through their correlations. Spectral CT, also known as dual-energy CT (DECT) or multi-energy CT, can generate a series of quantitative maps, such as ED maps. Using spectral CT for radiotherapy simulations can directly acquire ED information without developing specific calibration curves. The purpose of this study is to assess the feasibility of utilizing electron density (ED) maps generated by a novel dual-layer detector spectral CT simulator for dose calculation in radiotherapy treatment plans.

Methods

30 patients from head&neck, chest, and pelvic treatment sites were selected retrospectively, and all of them underwent spectral CT simulation. Treatment plans based on conventional CT images were transplanted to ED maps with the same structure set, including planning target volume (PTV) and organs at risk (OARs), and the dose distributions were then recalculated. The differences in dose and volume histogram (DVH) parameters of the PTV and OARs between the two types of plans were analyzed and compared. Besides, gamma analysis between these plans was performed by using MEPHYSTO Navigator software.

Results

In terms of PTV, the homogeneity index (HI), gradient index (GI), D2%, D98%, and Dmean showed no significant difference between conventional plans and ED plans. For OARs, statistically significant differences were observed in parotids D50%, brainstem in head&neck plans, spinal cord in chest plans and rectum D50% in pelvic plans, whereas the variance remained minor. For the rest, the DVH parameters exhibited no significant difference between conventional plans and ED plans. All of the mean gamma passing rates (GPRs) of gamma analysis were higher than 90%.

Conclusion

Compared to conventional treatment plans relying on CT images, plans utilizing ED maps demonstrated similar dosimetric quality. However, the latter approach enables direct utilization in dose calculation without the requirements of establishing and selecting a specific Hounsfield unit (HU) to ED calibration curve, providing an advantage in clinical applications.
Bridging cultures: Chinese elements in scientific illustrations
Authors: Gu Jianyou , Zhang Wenying , Wang Xianxing , Zhou Qiang , Zhang Junfeng , Xie Fuming , Xia Renpei , Chen Zhe-Sheng , Wang Huaizhi
Published: July 2024

In the context of globalization, the integration of cultural elements into scientific research, particularly through the incorporation of traditional Chinese cultural motifs in scientific illustrations, represents a novel frontier in enhancing the universality and appeal of scientific discoveries. This paper explores the innovative practice of embedding traditional Chinese cultural elements into scientific paper illustrations, highlighting its significant role in augmenting the global appeal of research findings, promoting diversity and innovation in scientific inquiry, and facilitating cross-cultural understanding. Through a series of case studies, including symbolic representations of ancient myths and the use of traditional themes to elucidate complex scientific phenomena, we demonstrate how this cultural integration not only makes scientific content more accessible and engaging but also fosters a deeper appreciation of Chinese heritage among international audiences. This approach not only bridges the gap between science and culture but also contributes to a more inclusive and interconnected global scientific community, underscoring the importance of cultural diversity in enriching scientific exploration and communication.
Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia
Authors: Ji Tongting , Yang Yang , Yu Juanjuan , Yin Hongli , Chu Xinran , Yang Pengju , Xu Ling , Wang Xiaodong , Hu Shaoyan , Li Yizhen , Wu Xiaochen , Liu Wengyuan , Zhou Bi , Wang Wenjuan , Zhang Shuqi , Cheng Wei , Chen Yanling , Shi Lei , Li Zhiheng , Zhuo Ran , Zhang Yongping , Tao Yanfang , Wu Di , Li Xiaolu , Zhang Zimu , Fan Jun-jie , Pan Jian , Lu Jun
Published: July 2024

Background

Despite the use of targeted therapeutic approaches, T-cell acute lymphoblastic leukemia (T-ALL) is still associated with a high incidence of complications and a poor prognosis. Indisulam (also known as E7070), a newly identified molecular glue compound, has demonstrated increased therapeutic efficacy in several types of cancer through the rapid degradation of RBM39. This study aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms and explore the role of the RBM39 gene.

Methods

We verified the anticancer effects of indisulam in both in vivo and in vitro models. Additionally, the construction of RBM39-knockdown cell lines using shRNA confirmed that the malignant phenotype of T-ALL cells was dependent on RBM39. Through RNA sequencing, we identified indisulam-induced splicing anomalies, and proteomic analysis helped pinpoint protein changes caused by the drug. Comprehensive cross-analysis of these findings facilitated the identification of downstream effectors and subsequent validation of their functional roles.

Results

Indisulam has significant antineoplastic effects on T-ALL. It attenuates cell proliferation, promotes apoptosis and interferes with cell cycle progression in vitro while facilitating tumor remission in T-ALL in vivo models. This investigation provides evidence that the downregulation of RBM39 results in the restricted proliferation of T-ALL cells both in vitro and in vivo, suggesting that RBM39 is a potential target for T-ALL treatment. Indisulam’s efficacy is attributed to its ability to induce RBM39 degradation, causing widespread aberrant splicing and abnormal translation of the critical downstream effector protein, THOC1, ultimately leading to protein depletion. Moreover, the presence of DCAF15 is regarded as critical for the effectiveness of indisulam, and its absence negates the ability of indisulam to induce the desired functional alterations.

Conclusion

Our study revealed that indisulam, which targets RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.
Streamlining electronic reporting of serious adverse events (SAEs) using the REDCap data collection system: the eSAE Project
Authors: Black Joanna , Julier Patrick , Eldridge Lucy , Barber Vicki S.
Published: July 2024

Background

It is essential that electronic data collection (EDC) systems are both compliant with regulations and the principles of Good Clinical Practice (GCP) to allow for the timely and accurate reporting of data including safety data. For clinical trials of investigational medicinal products (CTIMPs), investigators must immediately report to the sponsor any serious adverse event (SAE) that occurs in a site for which they are responsible. It is therefore expected that sponsors provide systems for timely review and reporting should a SAE be classified as a suspected unexpected serious adverse reaction (SUSAR). Challenges arise when data related to adverse events (AEs) needs to be re-entered for SAEs; this can be prone to error and may delay reporting. Additionally, recognising what has changed from an initial SAE report when an investigator responds to queries raised can cause errors.

Method

A multi-disciplinary working group came together from a UK academic clinical trials unit (CTU) to establish if an electronic system could be created in the unit’s open-source EDC system—REDCap, to manage SAEs in an efficient way.

Results

A module has been created in REDCap to facilitate electronic SAE reporting: enabling an AE form to automatically trigger an SAE form for any AE which is also a SAE, prepopulating relevant fields of the SAE form, reducing the risk of delay and error when entering data into the SAE form. The system has also been developed with an embedded code to allow for instant visual recognition of any data updated following reporting to allow the sponsor to immediately review and resolve SAEs in a timely manner, complying with UK regulatory reporting. This functionality ‘The eSAE Project’ is now an active project for all of our new trials where data collection is undertaken using the REDCap system.

Conclusion

The eSAE Project coded into REDCap offers a unique way of populating SAE forms with information already entered in the initial AE forms as applicable, coupled with highlighting any updates during the lifetime of the SAE for sponsors to identify any new information that needs to be reassessed to process and report the SAE.
Effect of CdS loading on the properties and photocatalytic activity of MoS2 nanosheets
Authors: Rahman Ashmalina , Khan Fazlurrahman , Jennings James Robert , Tan Ai Ling , Kim Young-Mog , Khan Mohammad Mansoob
Published: July 2024

Molybdenum sulfide (MoS2) and modified MoS2 with different percentages of CdS (10%, 30%, and 50% CdS@MoS2) were successfully synthesized and characterized. The photocatalytic performance of the MoS2 and CdS@MoS2 was evaluated by degrading brilliant green (BG), methylene blue (MB), and rhodamine B (RhB) dyes under visible light irradiation. Amongst the synthesized photocatalysts, 50% CdS@MoS2 exhibited the highest photocatalytic activity, degrading 97.6%, 90.3%, and 75.5% of BG, MB, and RhB dyes, respectively within 5 h. The active species involved in the degradation processes were investigated. All trapping agents inhibited BG and MB degradation to a similar extent, indicating that all of the probed active species play an important role in the degradation of BG and MB. In contrast, h+ and O2•− were found to be the main reactive species in the photocatalytic RhB degradation. A potential mechanism for the photocatalytic degradation of dyes using CdS@MoS2 has been proposed. This work highlights the potential of CdS@MoS2 as a photocatalyst for more efficient water remediation applications.